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Effects of age rearing and separation stress on immunoglobulin levels in rhesus monkeys.

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American Journal of Primatology 13:ll-22 (1987)
Effects of Age, Rearing, and Separation Stress on
Immunoglobulin Levels in Rhesus Monkeys
JAMES M. SCANLAN'.~, CHRISTOPHER L. COE', ADAM LAWS,
AND STEPHEN J. SUOMI1,'
'University of Wisconsin Primate Laboratory, Madison, and 'Laboratory of
Comparative Ethology, National Institute of Child Health and Development
The study reported here examined the effect of different rearing conditions
and psychological stress on immunoglobulin levels in rhesus monkey infants. In the first experiment, 24 rhesus neonates were placed in one of the
three following rearing conditions: Separated from their mothers and reared
in the laboratory nursery; kept with their biological mothers; or removed at
birth from their biological mothers and cross-fostered to adoptive rhesus
mothers. Plasma samples were obtained from the nursery-reared infants
immediately after birth and at weekly intervals for the next 30 days.
Samples were also obtained from mother-reared and foster-reared infants
on days 15 and 29. All samples were tested for IgG and IgM levels. The
results indicated that neither rearing nor diet affected Ig levels. IgG levels
were highest at birth and decreased progressively for the first 30 days,
suggesting that placental transfer of maternal IgG is the critical determinant of IgG levels in primate infants as in humans. IgM changes were
also similar to those in human infants: Low levels at birth, a significant
increase from birth to day 15, and a moderate decline from day 15 to day 30.
When IgG levels and IgM levels were correlated across the first month,
many significant correlations were found which were consistent with human data relating both infant IgG and IgM levels to infant maturation. In
the second experiment, 11 of the previously tested nursery infants were
subjected to four consecutive social separationsfrom peer groups at 6 months
of age. Plasma samples were obtained before and after the first and fourth
weeks of separation and tested for IgG and IgM levels. Small but significant
decreases in both immunoglobulinswere detected after 4 days of separation,
particularly on the fourth week.
Key words: rhesus macaque, immunoglobulin, age, separation stress, rearing
INTRODUCTION
Macaque monkey infants, like human infants, are typically born with relatively
high levels of immunoglobulins in circulation [Eitzman, 1970; Fujimoto et al, 19821.
Received September 29, 1986; revision accepted January 9,1987.
Address reprint requests to J.M. Scanlan, MA, Harlow Primate Laboratory, University of Wisconsin, 22
N. Charter St., Madison, WI 53715.
0 1987 Alan R. Liss, Inc.
12 / Scanlan et a1
The immunoglobulins are predominantly of the IgG class and are derived largely
from the placental transfer of maternal antibody. In humans, it appears that the
IgG is actively transferred to the fetus, because immunoglobulin levels are usually
higher in cord blood than in maternal sera after weeks 37-40 of gestation [Allansmith et al, 1968; Cederqvist et al, 19781. This prenatal contribution to infant
immunity is of considerable significance because it is the only opportunity for the
mother to pass on IgG to the infant. Antibodies in colostrum and milk are mostly of
a different class (secretory IgA) and serve primarily a bactericidal function in the
gut [Lasonsky & Ogra, 19811. The levels of maternal IgG in human infants begin to
decline soon after birth, and circulating levels of IgG reach a nadir between 3 to 6
months of age, before the onset of substantial IgG synthesis by the infant’s immune
system [Allansmith et al, 1986; Fulginiti et al, 19661.
Although the developmental course of IgG has been extensively studied in
human infants it has not been evaluated in detail in infant nonhuman primates.
The existing studies have assessed monkeys of different ages using cross-sectional
designs and have documented high levels of IgG at birth and lower levels at 6
months of age [Eitzman, 1970; Fujimoto et al, 1982; Voormolen-Kalova et al, 19741.
For that reason, we conducted a more specific study of the developmental pattern of
IgG utilizing a longjtudinal approach across the first month of life. In addition, we
were interested in whether certain rearing events would alter either the rate of
decay in IgG or the overall level of immunoglobulins in the infant. Our study
compared the following three rearing conditions in rhesus monkey infants: Rearing
by the biological mother (mother-rearing);rearing by adoptive mothers (cross-fostering); and nursery-rearing by human caretakers. Several investigators have suggested that immune components in mother’s milk other than secretory IgA may
have a facilitatory influence in infant immunity [Hanson et al, 1982;Leissring et al,
1962; Ogra et al, 19831. We hypothesized, therefore, that we might see differences
between the infants reared on rhesus milk and those reared on cow’s milk. First, we
anticipated that the nursery-reared infants might have low immunoglobulin levels
if there were immune-enhancing substances in rhesus milk. Alternatively, it was
possible that the nursery-reared infants might show evidence of an adverse reaction
to the cow’s milk in Similac similar to that observed in lactose-intolerant human
infants [Burgin-Wolff et al, 19801. It was also thought possible that cross-fostered
infants might show a reaction to foreign proteins in the milk of their nonbiological
mothers.
The possibility that psychological disturbance could also influence circulating
levels of IgG was evaluated in a subgroup of the nursery-reared infants when they
reached 6 months of age. Previous studies have demonstrated that infant squirrel
monkeys show reduced levels of immunoglobulins and complement proteins after a
7-day separation from the mother, as well as a hampered capacity t o mount an
antibody response to viral challenge [Coe et al, 19851. Similarly, mouse pups subjected to daily separations from the mother develop lower levels of IgG and show a
reduced antibody response to sheep erythrocytes when tested later in life [Michaut,
19811. In contrast, one study on mother-reared rhesus infants indicated that they
did not show significant changes in either immunoglobulin levels or antibody response following a 7-day separation from the mother [Coe et al, 19851. To reconcile
this discrepancy between species, we extended our evaluation to include the response
of nursery-reared rhesus infants to separation from peers. Previous research has
indicated that nursery-reared infants show a greater emotional reaction to social
separations than do mother-reared subjects, and that repeated social separations
appear to increase infant distress [Kraemer & McKinney, 1979; Mineka & Suomi,
19781. We hypothesized that nursery-reared infants might be predisposed to show
Immunoglobulin Response in Rhesus Infants I 13
changes in IgG not observed in mother-reared subjects, particularly if the separations were repeated over several weeks. Measurements of IgM were also included
because IgM is the first class of immunoglobulins to respond during primary antibody response, and because IgM, in contrast to IgG, is not transferred across the
placenta. As a consequence, low levels of IgM are found at birth and increase over
the course of development. Thus IgM levels provide both an index of the infant’s
general state of health and a measure of the infant’s endogenous synthesis of
immunoglobulins.
MATERIALS AND METHODS
Subjects
Subjects were 24 infant rhesus monkeys (Macaca mulatta)bred at the Wisconsin
Primate Laboratory. The infants were either reared by adult rhesus females (n= 10)
or nursery-reared by human caretakers (n=14) for the first 30 days of life. Three of
the 10 mother-reared infants were raised by lactating females to which they had
been transferred within 2-3 days after birth. These infants were included in order
to evaluate whether any antigenic aspects of the nonbiological “foster” mother
would influence the level of immunoglobulins in the infant. The nursery-reared
infants were removed from their mothers at birth and raised in the laboratory
nursery. At 1month of age, 12 of the nursery-reared infants were placed into three
peer groups, each consisting of four subjects, from which they were separated at 6
months of age (one subject, AM10, died of natural causes before the 6-month separation, reducing the number of subjects to 11in that condition).
Housing
Mother-reared infants were housed in mother-infant dyads in standard adultsize laboratory cages. All cages were located in large colony rooms permitting visual,
auditory, and olfactory contact with other monkeys. Nursery-reared infants were
raised for the first month in individual cages with a waterbed floor to sit on and a
terry cloth surrogate. They were hand-fed Similac at 2-hr intervals until they were
able to feed independently from a formula bottle mounted on the wall of their cage,
which generally occurred by 3-4 days of age (average daily Similac consumption
was approximately 300 ml). These infants were handled only for feeding and testing
[additional details of the general procedure can be obtained from Blomquist &
Harlow, 19611. After they were rehoused with peer groups at 1month of age, they
were maintained on a standard laboratory regimen: 12-hr-lightll2-hr-darkschedule,
with Purina Chow provided once in the morning. They continued to receive 300 ml
of Similac daily until age 6 months.
-
Assessment of Immunoglobulin Levels
IgG and IgM levels were determined by single radial immunodiffusion tests
using Kallestad endoplates (Austin, TX). Prior experience with these plates had
shown that the human antisera in the agarose gel cross-reacts extensively and in a
linear manner with the homologous proteins in the sera of nonhuman primates [Coe
et al, 19851. Studies using immunoeledrodiffusion tests have also supported this
observation [Fujimoto et al, 19821. Nevertheless, because of known differences in
IgG across primate species [Monte-Wicheret al, 19701, the values will be reported in
relative terms based on the square of the ring diameters, rather than as specific Ig
concentration. For IgG determinations, 5 p1 of plasma were pipetted into each well
of IgG endoplates; for IgM, 10 pl of plasma were pipetted into each well of low-level
IgM endoplates. The plates were then incubated at room temperature until the
14 / Scanlan et a1
precipitin ring reached maximum size (48 hr for IgG, 72 hr for IgM). The diameter
of each ring was quantified to the nearest 0.1 mm by two independent raters who
had an interrater agreement of r = .99 using a Transidyne calibrating viewer.
Procedure
In order to evaluate the effect of rearing conditions, immunoglobulin levels were
assessed in all infants at 2 and 4 weeks after birth. Blood samples were collected
from the femoral vein in Vacutainers containing EDTA. Plasma was separated by
centrifugation for 15 min at 2,000 rpm and 4°C and then frozen at -20°C until
analysis.
A more detailed examination of the 14 nursery-reared infants was conducted by
determining immunoglobulin levels in samples obtained on days 1, 8, 15, 22, and
29. The immune data were correlated with other biological variables, including
gestation length, birth weight, and sex. Gestation length was determined by calculating the interval between the first day of the 4-day timed mating of the mother
and the birth of the infant. Females were paired with breeding males for 4-day
periods thought to correspond to ovulation on the basis of menstrual cycle (day 1of
menstruation + 10 days) and sex-skin coloration.
After the nursery-reared infants reached 1 month of age, they were combined
into peer groups and left undisturbed until 6 months of age. At this point, each of
the three peer groups was subjected to a series of social separations. Each group was
separated for 4 days and then reunited for 3 days across 4 consecutive weeks.
Immunoglobulin levels were determined from blood samples obtained immediately
prior to the first and fourth separations and at the end of these 4-day separations
(designated Basal 1, Sep 1, Basal 2, and Sep 2, respectively). During the separation,
infants were housed individually in novel cages in a n unfamiliar room in which
they could hear, but not see or touch, the other infants. During the reunion phase,
they were returned to their original home cage.
Data Analyses
The effect of rearing condition on immunoglobulin levels was evaluated by
analysis of variance (ANOVA). Weekly immunoglobulin levels during the first month
and during the later 6-month separation were also compared by ANOVA. Several
correlation matrices were obtained by correlating IgG and IgM at all timepoints, as
well a s by correlating immunoglobulin levels with birth weight, gestational age,
and sex.
RESULTS
Evaluation of the infants’ immunoglobulin levels at 2 and 4 weeks of age
indicated that IgG and IgM were not significantly affected by the different rearing
conditions. The three foster-reared infants did not differ from the seven motherreared infants, and their data were combined for statistical comparison with the
nursery-reared infants (Fig. la, F [1,22]= 5 9 , p > . l ; F [1,22]= 1.82, p > .1, respectively). All infants showed a significant decrease in IgG from week 2 to week 4 fF
[1,22]=23.4, p < .0001), but neither the magnitude of the decrease nor the overall
levels differed across rearing conditions. Similarly, there was a significant developmental decline in IgM levels between weeks 2 and 4 (F [1,22]=12.07, p<.OO5), but
the levels did not differ significantly across rearing conditions (Fig. lb). Consistent
with these nonsignificant results, no significant differences were found between
mother-reared (MR) and peer-reared (PR) infants in either gestational age (MR mean
+ SD = 167 t- 6.7 days, PR = 166.6 3.6 days) or birth weight (MR mean f. SD =
485 & 49.9 g, PR = 465 k 47.6 g).
Immunoglobulin Response in Rhesus Infants / 15
6o
1
DAY 16
DAY 29
O(
a
YR (N-7)
XF (N=3)
NR (N=l4)
REARING CONDITIONS
DAY 16
DAY
29
-I-
b
=
W (N-7)
NR (N-14)
REARING CONDITIONS
Fig. 1. a: Comparison of IgG levels across rearing groups (NR = nursery-reared,MR
X F = cross-fostered).b: Comparison of IgM levels across rearing groups.
=
mother-reared,
More detailed data on the 14 nursery-reared subjects revealed the underlying
pattern accounting for the differences between weeks 2 and 4. As can be seen in
Figure 2a, IgG levels on day 1 were relatively high (ie, within the normal range for
female adult rhesus monkeys using these methods: 6.73-7.09, n=4, Coe, unpublished data). Thereafter, there was a progressive and significant decrease in IgG
value across the first month of life (F [4,52]=38.76, p<.OOOOOl). In contrast, IgM
(Fig. 2b) values followed a biphasic pattern, with higher levels occurring on day 15
than on either day 1 or 29 (F [4,48]= 16.59, p < .OOOOOl). Correlation of IgG and IgM
'i
16 I Scanlan et a1
60
P
0
zCG
10
a o
DAY 1
DAY 8
DAY 16
DAY 22
DAY 28
DAY 22
DAY 28
DAYS OF LIFE
80
-
60 -
c1
9 40 g
rn
m
2 30-
1
fa 200
Bm
10
b
-
OL
DAY 1
DAY 8
DAY 15
DAYS OF LIFE
Fig. 2. a: IgG levels over the first month of life (nursery infants only, n
month of life (nursery infants only, n = 13).
=
14).b: IgM levels over the first
values across the first month indicated that individual differences in immunoglobulin levels were extremely stable (Table I). High levels at birth were strongly predictive of high levels throughout the first month of life. In addition, the levels of IgG
and IgM tended to be highly correlated within individuals when they were between
8 and 22 days of age.
The immunoglobulin levels of these infants did not correlate significantly with
either gestation length (mean f S.D. = 166.6 f 3.61 days, range = 159-171 days)
or birth weight (465 & 47.6 g, range = 395-550 g), although heavier infants did
tend to have higher IgM levels on Day 1 (r = 5 4 , p < .06).
Immunoglobulin Response in Rhesus Infants / 17
TABLE 1. Correlations of IgG and IgM Over the First Month of Life (N = 13)
IgG on days15
22
1
8
XXX
.78*
.73*
.62*
XXX
.86*
XXX
29
IgM on days15
22
1
8
29
.49
.34
.38
.26
.41
.30
.84*
.67*
.ll
.36
.59*
.71*
.06
.89*
.78
.48
.58*
.77*
.85*
.05
XXX
.91*
.29
.49
.82*
.go*
.10
XXX
.35
.39
.83*
.82*
.22
XXX
.62*
.41
.28
.17
XXX
.56*
.49
-.14
xxx
,93*
.06
xxx
- .06
xxx
*p<.05.
For the nursery-reared subjects that were used in the separation study, we
extended the evaluation of IgG to include a 3-month and a 6-month basal sample.
Individual profiles for seven individual monkeys are shown in Figure 3 and illustrate the continuing decline in IgG levels across this period of infancy. However, the
extent of individual differences is noteworthy, since some monkeys showed continuous decreases to extremely low levels, whereas others showed a more abbreviated
decline followed by a rapid return to higher levels. High or low IgG levels tended to
be a stable individual characteristic, as evidenced by the strength of the correlations
over time. IgG levels at 1 month tended to be correlated with values at 3 months
(r= .73, p < .OW, and 3-month IgG values were significantly correlated with 6-month
values (r = .89, p < .01). IgM values were not as consistent over time, although 3- and
6-month values were significantly correlated 0= .89, p < .01).
At 6 months of age, the peer groups were subjected to 4 weeks of repeated social
separation. Evaluation of IgG levels indicated that there was a small but significant
decrease in IgG levels following separation (F [1,10]= 15.06, p < .005).The magnitude
of the decrease was substantially greater during the fourth separation than during
the first separation, although this may have been due in part to the elevation in
basal values from week 1to week 4 (Fig. 4a). IgM levels after the 4-day separations
were also significantly decreased (Fig. 4b, F[1,10] = 18.28, p < .002). Individual differences in IgG levels remained stable within and across separation weeks with almost
all correlations reaching statistical significance (Table 11). IgM levels were significantly correlated within but not across weeks (Table II).No significant correlations
were found between IgG and IgM levels during the 6-month separation.
18 / Scanlan et a1
6o
+ AM04
1
* AM05
* AM15
--P-
AM4 1
AM44
AM52
AM55
+O
DAY 1
I
I
1
DAY 30
DAY 90
DAY 180
DAYS OF LIFE
Fig. 3. Comparison of individual differences in IgG response from birth to 6 months (nursery-reared
infants, n = 7).
TABLE 11. Correlations of IgG and IgM During 6 Month Separation (N = 11)
IgM
IgG
Wkl
base
Week1
Baseline
Week 1
Thursday
Week 4
Baseline
Week 4
Thursday
Week 1
Baseline
Week 1
Thursday
Week 4
Baseline
Week 4
Thursday
*p < .05.
XXX
Wkl
Thurs.
Wk4
base
Wk4
Thurs.
Wkl
base
Wkl
Thurs.
Wk4
base
Wk4
Thurs.
.93*
.53
.71*
21
.39
-21
-.12
xxx
.yo*
.82*
.39
.52
-.16
-.02
XXX
.87*
.23
.22
.25
.48
xxx
.22
.31
.13
.38
xxx
.88*
.28
.25
xxx
.29
21
xxx
.93*
xxx
Immunoglobulin Response in Rhesus Infants / 19
DAY 1
DAY4
401
I
E
1 324
21
0-
R'EEK 1
a
WEEK 4
WEEKS OF SEPARATION
Wl
Lu
DAY1
DAY4
80
0-
i
=EX 1
b
wEmc4
WEEKS OF SEPARATION
Fig. 4. a: IgG response to repeated separation at 6 months of age (nursery-rearedinfants).b IgM response
to repeated separation at 6 months of age (nurseryreared infants).
DISCUSSION
The results confirm previous studies on nonhuman primate species, indicating
that the contribution of maternal IgG to the neonate is similar to that observed in
humans [Eitzman, 1970; Fujimoto et al, 1982; Voormolen-Kalova,et al, 19741. IgG
levels on the day of birth were within the normal range for adult rhesus monkey
females, which is consistent with human data demonstrating that neonatal IgG
titers are equal to or greater than maternal serum values [Allansmith et al, 19681.
It is also of interest that the decline in IgG during the first several months of life
20 I Scanlan et a1
follows a course similar to that of humans, given the considerable species differences
in the speed of many other aspects of infant development.The similarity in this
aspect of immune development may have different consequences across species. For
example, the occurrence of low IgG levels between 3 and 6 months of age is a
relatively benign event in human development, but in monkey infants it coincides
with weaning from the mother. In some monkey infants with particularly low levels
of maternal antibody, this may result in a heightened susceptibility to bacterial
infection during the weaning process.
The data also support the belief that the prenatal contribution of maternal IgG
is the primary factor determining levels of IgG in the young infant. Early rearing
conditions did not affect either overall levels of immunoglobulin or the rate of decline
in IgG. These results reiterate the importance of the placental transmission of
maternal antibody during the final weeks of gestation as a means of providing a
passive immunity to certain bacteria and viruses. In our data we could not detect
any influence of gestation length on IgG levels, but this may have been due to the
restricted variation in the normal infant population utilized (all infants being born
+6 days of the species-typical 165-day gestation period). Birth weight also failed to
show a significant influence on IgG, although there was a borderline (p < .06)positive
correlation with IgG levels on day 1.This again may be due to the extremely normal
character of the nursery infants used in this study, as all of their birth weights fell
within approximately +1 SD of the population norm (calculated by Scanlan et a1
[1985]to be 480 k 77 g on a sample of 453 rhesus neonates). In studies on premature
human infants or on infants of low birth weight (less than 2,000 g), it is possible to
distinguish a clear influence of these factors on IgG levels at birth [Berg, 19681.
When IgG levels are low in the neonate, the trajectory of the decrease in the
maternal IgG can lead to abnormally low levels of IgG at 3-6 months and result in
a condition known as transient hypogammaglobulinemia. Some investigators have
suggested that abnormally low levels of immunoglobulins may result in a heightened susceptibility to bacterial infection, and thus it may be one important longterm consequence of prenataI events [Lentz & Gershwin, 19841. We also noted that
in the monkeys monitored for 6 months, there were some individuals in which IgG
decreased to particularly low levels. A follow-up study will evaluate whether these
subjects are at greater risk for disease.
Another finding of interest was the rapid increase in IgM observed at 2 weeks
of age in the nursery-reared animals. Similar increases have also been detected in
data from cross-sectional studies of monkey and human infants [Allansmith et al,
1968; Fujimoto et al, 19821, which strongly suggests that the increase in this study
was not a specific response to a particular antigenic feature of our laboratory
environment. Instead, it probably reflects a primary antibody response to the initial
bacterial colonization of the gut which occurs in both bottle-fed and suckled animals.
Previous research with low-birth-weight human infants also indicates that the
magnitude of the 2-week IgM response is related to the maturational age of the
infant [Berg, 19681. Premature infants showed weaker responses than did full-term
infants. This might. explain the significant correlation in our infants between mean
IgM and mean IgG levels in the first month of life, as both IgG levels and IgM
responses could have been influenced by infant maturity. It should be noted that
these IgM determinations were made on low-level IgM endoplates, and thus, the
level of antibody was not indicative of a prior disease condition in utero or perinatal
infection [eg, Puri et al, 19811.
Although the early rearing conditions did not influence the developmental
pattern of IgG or IgM, we did find an effect of social separation on Ig levels at 6
Immunoglobulin Response in Rhesus Infants / 21
months of age. The transient decrease in IgG levels following social separation of
the nursery-reared subjects concurs with observations of alterations in other immune responses in separated squirrel monkeys [Coe et al, 19851 and pigtailed
macaques [Reite et al, 19811. However, it does differ from prior results with motherreared rhesus monkeys in which no significant immune change was found following
a 7-day separation [Coe et al, 19851. The contrasting results in the present experiment may be due to a greater psychophysiological reactivity on the part of nurseryreared infants, as previously reported by Kraemer and McKinney [1979]. These
findings may also be influenced by the increased stress of the separation paradigm
used in the present experiment. Coe et a1 [1985] separated the mother from her 6month-old infant, with the infant remaining in its home cage, while in the present
experiment the infants were separated into novel cages. The higher levels of stress
evoked by repeated separation may also be seen in the greater IgG decline after the
fourth week of separation than after the first, consistent with reports that infants
do not habituate to repeated separations and may actually sensitize [Coe et al, 1985;
Mineka & Suomi, 19781. However, it should be recognized that the immunoglobulin
changes were relatively small. Social separation appears to have considerably less
effect on immune functions in rhesus infants than on those in squirrel monkey
infants, which also show greater endocrine responses to separation.
The numerous correlations of IgG levels over time indicate that IgG levels are
a relatively stable characteristic of individual infants over the first 6 months of life.
IgM levels are less consistent, in keeping with the fact that they were not derived
from the mother and would be the first immunoglobulin class to respond to environmental antigens. Further studies are needed to examine the significance of these
consistent individual differences. Is the infant with chronically low IgG actually
more prone to bacterial infection and illness? These differences could be compounded
by exposure to psychosocial stressors, since we have shown that separation results
in transient decreases in immunoglobulins. Several studies on rodents and farm
animals have shown that early separation experiences and weaning from the mother
can affect a wide range of immune responses [Michaut, 1981; Kelley, 19801. The
question remains whether early immunoglobulin profiles are predictive of a subsequent vulnerabilty.
CONCLUSIONS
1. Rearing conditions had no apparent effects on either IgG or IgM levels during
the first month of life.
2. IgG levels in nursery-reared subjects declined across the first month, consistent with the belief that neonatal IgG levels are primarily the result of placental
transfer of maternal antibody.
3. IgM levels in nursery-reared infants were low at birth, increased during the
first 2 weeks of life, and then declined by 4 weeks of age. These changes may reflect
bacterial colonization of the gut.
4.IgG and IgM levels were both highly correlated across the first month of life,
although IgG correlations were more consistent than those of IgM.
5. IgG and IgM levels showed small but significant declines after exposure to
repeated social separation stressors. The greatest change occurred after the fourth
separation week.
6. During the repeated separation paradigm, IgM measurements were again
found to be highly correlated, while IgM measures showed fewer significant correlations.
22 I Scanlan et a1
ACKNOWLEDGMENTS
This research was partially supported by MH-41659 from NIMH to C.L. Coe,
and by funding from NICHD to S.J. Suomi. C.L. Coe is also partially supported by
RR00157 from NIH.
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