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Early Life Stress and Inherited Variation in Monkey Hippocampal Volumes
David M. Lyons, PhD;
Chou Yang, MA;
Anne M. Sawyer-Glover, RT(R)(MR);
Michael E. Moseley, PhD;
Alan F. Schatzberg, MD
Arch Gen Psychiatry. 2001;58:1145-1151.
ABSTRACT
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Background Opportunities for research on the causes and consequences of stress-related
hippocampal atrophy are limited in human psychiatric disorders. Therefore,
this longitudinal study investigated early life stress and inherited variation
in monkey hippocampal volumes.
Methods Paternal half-siblings raised apart from one another by different mothers
in the absence of fathers were randomized to 1 of 3 postnatal conditions that
disrupted diverse aspects of early maternal care (n = 13 monkeys per condition).
These conditions were previously shown to produce differences in social behavior,
emotional reactivity, and neuroendocrine stress physiology. Hippocampal volumes
were subsequently determined in adulthood by high-resolution magnetic resonance
imaging.
Results Adult hippocampal volumes did not differ with respect to the stressful
postnatal conditions. Based on paternal half-sibling effects, the estimated
proportion of genetic variance, ie, heritability, was 54% for hippocampal
size. Paternal half-siblings with small adult hippocampal volumes responded
to the removal of all mothers after weaning with initially larger relative
increases in cortisol levels. Plasma cortisol levels 3 and 7 days later, and
measures of cortisol-negative feedback in adulthood were not, however, correlated
with hippocampal size.
Conclusions In humans with mood and anxiety disorders, small hippocampal volumes
have been taken as evidence that excessive stress levels of cortisol induce
hippocampal volume loss. Results from this study of monkeys suggest that small
hippocampi also reflect an inherited characteristic of the brain. Genetically
informed clinical studies should assess whether inherited variation in hippocampal
morphology contributes to excessive stress levels of cortisol through diminished
neuroendocrine regulation.
INTRODUCTION
SMALL HIPPOCAMPAL volumes are found in adult humans with recurrent major
depression1, 2 and posttraumatic
stress disorder.3, 4 Childhood
stress increases the risk of developing these mood and anxiety disorders,5 and small hippocampal volumes are evident in adult
survivors of childhood maltreatment.6, 7
Hippocampal morphology is altered by stress in carefully controlled studies
of rodents,8, 9, 10, 11
and small hippocampal volumes in humans have been taken as evidence that stress-related
disorders induce hippocampal volume loss.2, 11, 12
An alternative possibility that cannot be dismissed in the absence of prospective
longitudinal research is that small hippocampal volumes are inherited and
predispose toward the development of psychiatric disorders that are triggered
or aggravated by stress.3, 11
Aside from a limited number of reports on inherited variation in autonomic
activity13 and cerebrospinal fluid monoamine
levels,14, 15 primate research
on stress neurobiology has focused on maternal deprivation.16
Rhesus macaque monkeys raised without mothers exhibit increased brain dopamine
and norepinephrine sensitivity,17, 18
exaggerated hypothalamic-pituitary-adrenal (HPA) responses to stress,19, 20 altered regulation of autonomic activity,21 fragmented sleep patterns,22
depressionlike behavior,18 and excessive consumption
of alcohol.23 Ecologically informed research
on maternal availability has likewise identified untoward effects on primate
postnatal development. Bonnet macaque monkeys raised by their mothers in variable
foraging-demand conditions are impaired in social and emotional development.24, 25 In early adulthood, these same monkeys
exhibit elevated cerebrospinal fluid levels of monoamines, somatostatin, and
corticotropin-releasing factor (CRF).26, 27
Studies of stress and hippocampal plasticity in primates have produced
conflicting results. Maternal deprivation in rhesus macaque monkeys increases
dentate gyrus non–phosphorylated neurofilament protein levels, a neuronal
marker of vulnerability in Alzheimer disease, Huntington disease, Parkinson
disease, and amyotrophic lateral sclerosis.28
Hippocampal cell damage in adult vervet monkeys is induced by sustained and
fatal stress29 or long-term treatment with
cortisol implanted in adult hippocampus.30
Yet elderly adult pigtailed macaque monkeys treated long-term with oral cortisol
do not respond with diminished volumes or neuron numbers in any hippocampal
cell field.31 Rhesus macaque monkeys raised
in social isolation also fail to show altered hippocampal volumes as determined
in vivo at 18 months of age by magnetic resonance imaging (MRI).32
Here we test for early stress effects and inherited variation in hippocampal
volumes in 39 squirrel monkeys. Paternal half-siblings raised apart from one
another by different mothers in the absence of fathers were randomized to
conditions that disrupted diverse aspects of early maternal care. In one condition
on 5 occasions offspring were briefly separated from groups composed of 3
or 4 mother-infant pairs. Intermittent separations consistently elicit short-term
elevations in cortisol levels with baseline cortisol levels restored soon
after the subsequent social reunions.33, 34, 35
In 2 other postnatal rearing conditions, differences in maternal availability
were produced by manipulating the effort required to find food. Body weights
and amounts of food consumed in each foraging condition were not significantly
different, but high-foraging demand mothers stopped carrying their infant
earlier, and these infants displayed modest prolonged increases in cortisol
levels throughout the high-demand condition.36, 37
Following completion of each 12-week condition at 21 weeks of age, all
mothers were removed from natal groups after weaning at 36 weeks. At this
stage of development squirrel monkeys are no longer reliant on maternal care.
Sexual maturity is achieved at 3 years, and the squirrel monkey life span
is approximately 21 years.38 As previously
described elsewhere in greater detail,39 social
behavior, emotional responses, and increases in cortisol levels elicited by
removing all mothers after weaning were examined at 36 weeks of age for the
study cohort. In early adulthood at 5 years we tested for differences in cortisol-negative
feedback regulation of the HPA-axis response to exogenous stimulation by CRF.40 Then 5 weeks later hippocampal volumes were determined
by high-resolution MRI.
MATERIALS AND METHODS
MATERIALS
Forty infants sired by fathers that had no contact with their offspring
were distributed randomly in groups each composed of 3 or 4 mother-infant
pairs. All monkeys were of Guyanese origin (Saimiri sciureus) and were born and maintained at the Stanford University Primate Facility,
Stanford, Calif. One monkey from the low-foraging demand condition (see "Experimental
Design and Procedures" section) was excluded for reasons unrelated to the
study. Twelve fathers and 30 mothers produced the 39 monkeys that constituted
the study cohort. Twenty-one mothers each contributed 1 offspring, and 9 mothers
produced with different fathers on separate occasions 2 offspring. Two fathers
each sired a single offspring, 3 fathers each sired 2 offspring, 2 fathers
each sired 3 offspring, 3 fathers each sired 4 offspring, 1 father sired 5
offspring, and 1 father sired 8 offspring. All procedures were conducted in
accord with and as required by the Animal Welfare Act, and approved by Stanford
University's Administrative Panel on Laboratory Animal Care.
EXPERIMENTAL DESIGN AND PROCEDURES
Four natal groups were randomly assigned to each of the following 3
rearing conditions when infants were 10 weeks old (age range, 8-13 weeks).
- Low-foraging demands.
Thirteen infants (7 males and 6 females) and their 13 mothers were maintained
from 10 to 21 weeks post partum in low-foraging demand conditions. Each group
received 600% by weight of their normal daily food intake buried in foraging
boards.37 All 80 holes in the foraging boards
contained abundant amounts of food.
- High-foraging demands.
Thirteen infants (7 males and 6 females) and 13 mothers were maintained from
10 to 21 weeks post partum in high-foraging demand conditions where each group
was provisioned with 120% of their daily food intake buried in the foraging
boards. Many holes in the foraging boards contained little or no food, so
more time and effort were required to find food.
- Intermittent social separations. Thirteen infants (6 males and 7 females) and 13 mothers fed from standard
food-hoppers were separated intermittently for 5 sessions each lasting 5 hours
in duration. Every other week from 13 to 21 weeks post partum, each infant
was removed one at a time, placed in a cage adjacent to unfamiliar monkeys,
and temporarily deprived of all contact with members of the natal group.
After completion of these postnatal protocols at 21 weeks of age, all
monkeys were housed in standard conditions. Social behavior, emotional reactivity,
and increases in plasma cortisol levels elicited by removing all mothers after
weaning were examined at 36 weeks.39 Shortly
thereafter monkeys were housed with 2 or 3 animals of the same sex from different
rearing conditions. Approximately 4 years later in early adulthood (age range,
3.6-5.9 years) a neuroendocrine challenge was administered to test cortisol-negative
feedback regulation of the HPA-axis response to exogenous stimulation by CRF.40 Then 5 weeks later hippocampal volumes were determined
by MRI.
BRAIN IMAGE ACQUISTION AND ANALYSIS
Magnetic resonance imaging was performed using a 1.5-T (General Electric
Medical Systems, Milwaukee, Wis) system. Monkeys were scanned under anesthesia
induced by a subcutaneous injection of a combination of 20 mg/kg of ketamine
hydrochloride, 4 mg/kg of xylazine hydrochloride, and 0.04 mg/kg of atropine
sulfate. Body temperatures were maintained within the normal range using a
cushioned heating pad. Earplugs provided protection from noises generated
by the scanner.
The first scan for each monkey was acquired in the sagittal plane with
a 2-dimensional sequential spoiled gradient acquistion pulse sequence: repetition
time, 18 milliseconds; echo time, 4 milliseconds; flip angle, 30°; 1 signal
averaged; acquisition matrix, 256 x 128 pixels; voxel size, 0.5 x
1.0 x 4.0 mm; and slice thickness, 4 mm. This initial localizer scan
was used to standardize head tilt and rotation by assuring that 2 external
markers (vitamin E capsules in the meatus of each ear) were aligned in both
the coronal and axial planes. The head was repositioned as required, and another
sagittal localizer scan was performed. Head pitch was then standardized against
the midsagittal image, with the final scan acquired in the coronal plane.
The final scan used for hippocampal measurements (Figure 1) was a 3-dimensional inversion recovery prepared fast spoiled
gradient acquistion pulse sequence: repetition time, 12 milliseconds; echo
time, 3 milliseconds, inversion time, 300 milliseconds; flip angle, 15°;
4 signals averaged; acquistion matrix, 256 x 224 pixels; voxel size,
0.31 x 0.36 x 1.00 mm; and slice thickness,1 mm.
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Figure 1. Representative images of adult
squirrel monkey hippocampus (arrows) at 2-mm intervals in the coronal plane.
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Image processing was performed offline with ANALYZE software (Biomedical
Imaging Resource; Mayo Foundation, Rochester, Minn) as previously described
for human studies of hippocampal volumes.2
To minimize interscan variation a Histogram Match function in ANALYZE was
used to normalize gray-scale pixel values for each brain against a single
standard. A trained human rater blind to each monkey's identity then measured
hippocampal volumes on each brain side.
Stereological methods were used with ANALYZE software to generate unbiased
estimates of hippocampal volumes. Sampling parameters were set to yield at
least 150 "hits" per measurement, a number previously shown to generate reliable
determinations.41 For sampling purposes, a
rigid grid was superimposed on each brain image with grid placement randomly
determined by ANALYZE. All grid points falling directly on hippocampal gray
matter were identified by the trained human rater. From these determinations
ANALYZE generated an unbiased estimate of hippocampal volumes based on the
Cavelieri Principle.
Rules for identifying hippocampal volumes were adapted from human protocols.2, 42 The most posterior coronal slice for
volumetry was identified when gray matter hippocampus first appeared adjacent
to the trigone of the lateral ventricle. Hippocampal gray matter in all coronal
slices anterior to this location was bordered superiorly by the fornix-fibria
white matter junction, inferiorly by parahippocampal gyrus white matter, medially
by subarchnoid spaces of the ambient cistern, and laterally by the cerebrospinal
fluid–filled lateral ventricle or temporal horn white matter. The most
anterior coronal slice used for volumetry fell at the head of the hippocampus
medial to the amygdala in the coronal plane. One or two 1-mm slices anterior
to this location were excluded from determinations of hippocampal volumes
due to the lack of reliable boundaries for distinguishing amygdala from hippocampus.
To adjust for variation in overall brain size, brain volumes were defined
and subsequently measured as all gray and white matter in both hemispheres,
including the midbrain superior to the pons. The superior border of the pons
was choosen for demarcation because it is easily recognized on MRIs of brain.2 Based on the measurements of 2 trained raters independently
scoring the same 13 monkey brains, interrater reliabilities expressed as intraclass
correlations ranged from 0.90 to 0.97 (left hippocampus, 0.94; right hippocampus,
0.90; and overall brain size, 0.97).
DATA ANALYSIS
Sex, paternity (offspring grouped by father), and rearing condition
main effects for adult hippocampal volumes were examined with repeated-measures
analysis of variance (ANOVA) using least squares estimates from general linear
models (Systat, Evanston, Ill). Sex, paternity, and rearing condition were
between-subjects factors, and hippocampal volume on each brain side was considered
the within-subjects factor. Paternity was not analyzed as a random factor
because the error terms for sex and rearing condition could not be generated
from appropriate interactions in the unbalanced factorial design.39 This did not influence the analysis of paternity
since the same error term is used regardless of whether paternity is random
or fixed.43
Quantitative estimates of heritability (h2)were generated
from 1-way ANOVAs used to evaluate paternal half-sibling effects.44 From separate ANOVAs for each measure of interest,
the between-father mean square minus the within-father mean square was divided
by 3.25 (average number of offspring per father), multiplied by 4 (paternal
half-siblings share, on average, 25% of their genome by common descent), and
divided by the total variance. Heritabilities resemble intraclass correlations
adjusted for genetic relatedness. Under the null hypothesis of no hereditary
effect, within- and between-father components of variance are equivalent,
and the resulting F ratios approximate 1. As the between-father component
of variance increases relative to within-father variance, F ratios grow larger
in the half-sibling analysis and the null hypothesis is rejected. All test
statistics were evaluated with 2-tailed probabilities ( <.05), and
descriptive statistics are presented as mean ± SD.
RESULTS
Analysis of adult hippocampal volumes revealed a brain side main effect
(F1,24 = 6.78, P = .02). Right hippocampal
volumes were 4% larger than hippocampal volumes on the left side of the brain.
Neither sex nor rearing condition differences were discerned, and none of
the brain side interactions was significant, but the repeated measures ANOVA
uncovered a paternity main effect (F11,24 = 2.47, P = .03).
Certain fathers produced monkeys with large hippocampi, other fathers
produced monkeys with smaller hippocampi, and similar hippocampal volumes
were found among monkeys that shared a common father (Figure 2). Right and left hippocampal volumes were correlated with
one another (Figure 3), and these
measures were added together to create a total hippocampal volume score. The
estimated proportion of genetic variance, ie, heritability, was 54% for total
hippocampal volume size (F11,27 = 2.58, P
= .02). Heritabilities for the right (h2 = 49%, F11,27
= 2.34, P = .04) and left hippocampal volumes (h2 = 52%, F11,27 = 2.45, P = .03)
were not significantly different. The distribution of total hippocampal volumes
was Gaussian in the sample of 39 monkeys (Figure 4), suggesting contributions from multiple additive genetic
effects on hippocampal size.
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Figure 2. Adult hippocampal volumes grouped
according to each monkey's father (average n = 3.25 offspring per father).
Error bars signify mean ± SD.
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Figure 3. Correlation between mean right
and mean left hippocampal volumes grouped according to each monkey's father
(average n = 3.25 offspring per father). Dashed lines signify 95% confidence
intervals.
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Figure 4. Distribution of total hippocampal
volumes in 39 monkeys.
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Following completion of the rearing conditions at 21 weeks of age, all
mothers were removed well after weaning at 36 weeks post partum. Plasma cortisol
levels in their offspring 1 day later were 146% higher than the preseparation
levels assessed with identical procedures (197 ± 9 µg/dL vs 485
± 27 µg/dL). Significant differences in these relative elevations
in cortisol levels were produced by the prior rearing conditions (F2,24 = 18.11, P .001), but these rearing-related
differences were not associated with significant differences in hippocampal
size (Figure 5).
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Figure 5. Postnatal rearing effects on the
relative increase in cortisol levels elicited by removing all mothers and
subsequent adult hippocampal volumes (n = 13 monkeys per condition). Error
bars signify mean ± SD.
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Paternal half-siblings that responded with larger relative 1-day increases
in cortisol levels had smaller adult hippocampal volumes after correcting
for sex, rearing condition, and overall brain size (r
= -0.58, df = 10, P
= .048; Figure 6). Half-sibling
group differences in hippocampal volumes were not correlated with differences
in overall brain size, and the relation between cortisol and hippocampal volume
was absent when the 1-day cortisol measures were analyzed as absolute cortisol
concentrations. Average cortisol levels remained higher than baseline 3 and
7 days after the removal of all mothers, but these cortisol levels were not
correlated with differences in adult hippocampal size. Half-sibling group
differences in hippocampal volumes were also not correlated with subsequent
measures of cortisol negative feedback in early adulthood.
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Figure 6. Correlation between mean increases
in cortisol levels elicited by removing all mothers after weaning and mean
total adult hippocampal volumes grouped according to each monkey's father
(average n = 3.25 offspring per father). Dashed lines signify 95% confidence
intervals.
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COMMENT
In previous studies the subset of monkeys that we separated intermittently
prior to weaning differed in assessments of social behavior, emotional reactivity,
and cortisol-induced suppression of CRF-stimulated secretion of adrenocorticotropic
hormone.39, 40 Rearing-related
differences in these monkeys were not found in adult hippocampal volumes.
Rhesus monkeys raised in social isolation also fail to show altered hippocampal
volumes as determined in vivo by MRI,32 despite
striking changes in other brain systems and numerous aspects of behavior.17, 18, 19, 20, 21, 22, 23
Maltreated children with posttraumatic stress disorder do not differ from
healthy children in hippocampal volumes,45
but show elevated baseline urinary free cortisol and catecholamine concentrations.46 Chronic alcohol abuse is known to produce hippocampal
atrophy in humans47 and rats,48
but alcohol abuse was not common in the studies of children with posttraumatic
stress disorder, and was absent altogether in monkeys. Early life stress without
alcohol abuse may have minimal effects on hippocampal volumes determined in
human and nonhuman primates by high-resolution MRI.
Paternal half-sibling group differences were apparent in monkey hippocampal
volumes. Certain fathers produced offspring with large hippocampi, other fathers
produced offspring with smaller hippocampi, and similar adult hippocampal
volumes were found in monkeys that shared a common father. Since paternal
half-siblings were raised apart from one another by different mothers in the
absence of fathers, phenotypic similarities within half-sibling groups cannot
be attributed to shared family environments. Based on a standard half-sibling
analysis the estimated heritability was 54% for total hippocampal size. This
estimate is not inflated by including in the sample 9 maternal half-sibling
pairs.39
High heritabilities for overall brain size have been reported in humans49, 50, 51 and rhesus macaque
monkeys,52 but little is known about the genetics
of variation in regional brain morphologies. Neuroimaging research has identified
in human twins a genetic basis for differences in surface features of cerebral
cortex,49, 53 corpus callosum size,51, 54 and volumetric measures of other
subcortical structures.50 Our findings support
preliminary evidence in humans55 indicating
that individual differences in hippocampal volumes are in part determined
by genes. The Gaussian distribution of hippocampal volumes in monkeys suggests
a polygenic trait, and not the effects of genetic epistasis nor a single major
gene. Inherited variation in volumes may reflect heritable differences in
hippocampal cell numbers,56, 57
or differences in physiological factors related to in vivo tissue perfusion.
Paternal half-siblings with small adult hippocampal volumes responded
to the removal of all mothers after weaning with larger relative 1-day elevations
in cortisol levels. In humans with mood and anxiety disorders small hippocampal
volumes have been taken as evidence that excessive stress levels of cortisol
induce hippocampal volume loss.2, 11, 12
But in monkeys large rearing-related differences in cortisol levels elicited
by removing all mothers after weaning did not produce differences in hippocampal
size. An alternative explanation for the observed correlation is that small
hippocampal volumes are inherited and predispose toward excessive stress levels
of cortisol through diminished neuroendocrine regulation. The hypothesis that
genes affect cortisol levels by acting on aspects of hippocampal morphology
is consistent with evidence that the hippocampus plays a role in suppressing
the HPA-axis stress response.58, 59
Various measures of cortisol negative feedback in monkeys were not, however,
correlated with hippocampal size.
A limitation of our finding heritable differences in monkey hippocampal
volumes is that heritabilities are specific to the population and circumstance
in which they are assessed. Genetically diverse populations in homogeneous
environments demonstrate larger heritabilities than do inbred populations
in diverse environments.44 Very few parents
that produced the study cohort shared a common mother or father, but extended
family pedigrees could not be determined from monkey breeding colony records.
The generality of our findings should therefore be tested in studies of other
populations.
The absence of postnatal rearing effects must likewise be considered
with caution. Rodent research has convincingly demonstrated that stress or
glucocorticoids alone induce altered regulation of hippocampal serotonin receptor
expression,60 apical dendritic atrophy of CA3
pyramidal cells,8 suppression of neurogenesis,
and decreased survival of newborn granule cells.10
Our failure to uncover neuroimaging-based differences does not rule out the
possibility that microstructural plasticity occurs in the primate hippocampus.28, 29, 30 There are, in fact,
excellent reasons to expect subcellular plasticity in monkeys.
Following completion of the rearing conditions and well after weaning
at 36 weeks of age, the monkeys we separated intermittently responded to the
removal of all mothers with smaller increases in cortisol levels, fewer distress
peep-calls, and more time spent near peers.39
Monkeys from the low-foraging and high-foraging demand conditions did not
differ on any of these measures. In early adulthood at 5 years of age, only
the intermittently separated monkeys showed signs of enhanced negative feedback
regulation of the HPA-axis response to stimulation by exogenous CRF.40 These findings parallel studies indicating that in
rats brief postnatal intermittent social stress diminishes emotionality and
HPA-axis reactivity throughout adolescence and adulthood.61, 62
In rats blunted HPA-axis stress responses are mediated by enhanced negative
feedback regulation resulting from increased glucocorticoid receptor expression
in adult hippocampus.62 Experience-dependent
augmentation of glucocorticoid receptor densities might likewise account for
enhanced negative feedback described elsewhere for the intermittently separated
monkeys.40
A final aspect of this study that warrants comment concerns the lack
of long-lasting foraging demand effects on squirrel monkey brain and behavior.
Squirrel monkey mothers in the high-foraging demand condition consistently
exhibit increased cortisol levels relative to mothers in the low-foraging
demand condition where food is easy to find.37
High-foraging demand condition mothers stop carrying infants earlier, but
continue to demonstrate otherwise normal nursing patterns.37
By selectively accelerating certain aspects of development, squirrel monkey
mothers apparently spare their offspring from abnormal outcomes previously
reported for bonnet macaque monkeys raised by mothers under variable-foraging
demands.25, 26, 27
The high-foraging demand condition does not subsequently alter social or emotional
aspects of behavior, HPA-axis stress physiology, or adult hippocampal volumes.
AUTHOR INFORMATION
Accepted for publication June 26, 2001.
This work was supported in part by the Nancy Pritzker Network, New York,
NY, and Public Health Service grant MH47573 from the National Institute of
Mental Health, Bethesda, Md.
We thank Blake Mobley and Nadia Sachs for assistance with MRI processing,
and Robert Sapolsky, PhD, and Bruce McEwen, PhD, for thoughtful comments on
this research.
From the Departments of Psychiatry and Behavioral Science (Drs Lyons
and Schatzberg and Mr Yang) and Radiology (Ms Sawyer-Glover and Dr Moseley),
Stanford University Medical School, Stanford, Calif.
Corresponding author: David M. Lyons, PhD, Department of Psychiatry
and Behavioral Science, 1201 Welch Rd, Medical School Laboratory Surge Bldg,
Room P104–Mail Code 5485, Stanford University School of Medicine, Stanford,
CA 94305-5485 (e-mail: dmlyons{at}stanford.edu).
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