ORCP-522; No.

of Pages 9 ARTICLE IN PRESS

Obesity Research & Clinical Practice (2015) xxx, xxx—xxx

ORIGINAL ARTICLE

Metabolic pathways link childhood

adversity to elevated blood pressure
in midlife adults
Judith A. Crowell a,b,∗, Cynthia R. Davis b,c,
Kyoung Eun Joung d,e, Nicole Usher b,
Sean-Patrick McCormick b,f, Eric Dearing g,
Christos S. Mantzoros c,d

a Department of Psychiatry, Stony Brook University School of Medicine, Stony Brook,

NY, United States
b Judge Baker Children’s Center, Harvard Medical School, Boston, MA, United States
c Boston VA Healthcare System, Boston, MA, United States
d Division of Endocrinology, Diabetes & Metabolism, Beth Israel Deaconess Medical

Center, Harvard Medical School, Boston, MA, United States

e Division of Newborn Medicine, Boston Children’s Hospital, Boston, MA, United States
f Suffolk University, Boston, MA, United States
g Boston College, Boston, MA, United States

Received 27 May 2015 ; received in revised form 13 September 2015; accepted 22 October 2015

KEYWORDS Summary Childhood adversity is a risk factor for adult health outcomes, including
Childhood adversity; obesity and hypertension. This study examines whether childhood adversity pre-
Leptin; dicted mean arterial pressure through mechanisms of central obesity and leptin,
Blood pressure; adiponectin, and/or insulin resistance, and including dietary quality.
Hypertension; 210 Black/African Americans and White/European Americans, mean age = 45.8;
Obesity ±3.3 years, were studied cross-sectionally. Path analyses were used to specify a
chain of predictive variables in which childhood adversity predicted waist—hip ratio
and dietary quality, circulating levels of hormones, and in turn, mean arterial pres-
sure, adjusting for race, gender, and antihypertensive medications.
Direct paths were found between childhood adversity, waist—hip ratio, and leptin
levels and between leptin and dietary quality to mean arterial pressure. Systolic and
diastolic blood pressures were similarly predicted.

∗
Corresponding author at: Putnam Hall, Division of Child and Adolescent Psychiatry, Putnam Hall-South Campus, Child and Adoles-
cent Psychiatry, Stony Brook University, Stony Brook, NY 11794, United States. Tel.: +1 631 632 8848; fax: +1 631 632 8953.
E-mail address: Judith.crowell@stonybrookmedicine.edu (J.A. Crowell).

http://dx.doi.org/10.1016/j.orcp.2015.10.009
1871-403X/© 2015 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Crowell JA, et al. Metabolic pathways link childhood adversity to elevated blood
pressure in midlife adults. Obes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.orcp.2015.10.009
ORCP-522; No. of Pages 9 ARTICLE IN PRESS
2 J.A. Crowell et al.

Early adversity appears to developmentally overload and dysregulate endocrine

systems through increased risk for obesity, and through a direct impact on leptin that
in turn, impacts blood pressure.
© 2015 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd.
All rights reserved.

Introduction (BMI) [15]. This suggests that leptin dysregulation

Childhood adversity has been identified as a key
risk factor in the development of adult obesity
and a number of disease states, such as Type
2 diabetes, ischaemic heart disease, cancer, and
emphysema [1—3]. Childhood adversity has also
been identified as a risk factor in the development
of hypertension [4—8]. However, despite the well-
described association between childhood adversity
and obesity and between obesity and hypertension,
there little evidence regarding mechanisms linking
childhood adversity to hypertension in adulthood
[8].
A large body of research has examined the
stress—hypertension link, yielding mixed results.
Although acute stress leads to increased heart rate
and raised blood pressure, it is not yet understood
how this translates into sustained hypertension
[9,10]. There is speculation that repeated activa-
tion of the hypothalamic-pituitary-adrenal (HPA)
axis with failure to recover or habituate is a factor
in the development of hypertension [10]. Similarly,
it is hypothesised that repeated adverse expe-
riences with little recovery time and/or chronic
exposure to stress, e.g., allostatic overload, is a
mechanism by which adverse events early in life
lead to physical and mental health disorders in
adult life [11,12].
There is mounting evidence that childhood
stress and adversities directly alter metabolic
functioning [12—16]. Furthermore, a chain of dys-
regulation from obesity to adipocytokine activity
to sympathetic nervous system (SNS) function and
hypertension has been hypothesised. However, we
found no studies that examine how early adversi-
ties are linked to a metabolic path to hypertension
[14,16—18].
Adipocytokines, especially leptin, appear to reg-
ulate metabolic links between stress, the HPA axis,
neuropeptide Y and appetite, energy expenditure,
and weight [13,16,19]. Perceived stress has been
linked to higher leptin levels [20], and the spe-
cific stress of sleep deprivation has been shown
to impact leptin, hunger, diet, and hypertension.
Childhood adversity is associated with elevated cir-
culating leptin, but not adiponectin, controlling for
demographic variables, physical activity, smoking,
diet, current mental health, and body mass index
has a role in the pathogenesis of adult obesity in
the context of childhood adversity [13].
Obesity-related hypertension is hypothesised to
be due not only to mechanical load, but the effect
of energy homeostatic mediator molecules, e.g.,
leptin, on increased sympathetic nervous system
activity, arteriole constriction, and renal sodium
reabsorption [14,18,21—27]. A number of cross-
sectional and prospective studies have identified
links between obesity, leptin and adiponectin,
insulin resistance, dietary quality, and hypertension
[17,18,22—24,27—31].
Current study
In this study, we examine childhood adver-
sity as a predictor of mean arterial pressure
(MAP), that is, the steady flow of blood through
arteries combining childhood cardiac output and
vascular resistance [32,33], as well as systolic
and diastolic blood pressures. In a sample of
mixed-risk midlife Black/African Americans and
White/European American men and women, we use
path analyses to specify a chain of predictive vari-
ables in which childhood adversity predicts central
obesity (waist—hip ratio, WHR) that in turn impact
leptin levels. We hypothesise that childhood adver-
sities will be directly associated with leptin and
through WHR, and that circulating leptin, dietary
quality, and WHR are associated with MAP. We also
examine path models for the potential roles of
insulin resistance using homeostatic model assess-
ment (HOMA) and adiponectin (see Fig. 1).
This diverse sample allows us to control for race
and gender-related differences in obesity, leptin,
and hypertension [10,31,34—36]. We also con-
trol for anti-hypertensive medications. We include
dietary quality both because of its association with
blood pressure, but because childhood adversity
may impact dietary quality for psychosocial rea-
sons, e.g., poverty [2,37,38].
Methods
Sample
Participants were 210 White/European Ameri-
can and Black/African American adults (mean

Please cite this article in press as: Crowell JA, et al. Metabolic pathways link childhood adversity to elevated blood
pressure in midlife adults. Obes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.orcp.2015.10.009
ORCP-522; No. of Pages 9 ARTICLE IN PRESS
Leptin links childhood adversity and blood pressure in midlife
Figure 1 Hypothesised model linking childhood adversity to mean arterial pressure through obesity and adipokines.
age = 45.8; ±3.3; range 35—55 years) of diverse
socioeconomic backgrounds who were part of a
study examining psychosocial influences on phys-
ical and mental health in midlife. The sample
was generally representative of the population
of Boston, MA with regard to the proportion of
men and women, White/European Americans, and
those with a Bachelor’s degree or higher, although
it included a greater proportion of Black/African
Americans [39]. The sample was 57% Black/African
American and 53% were women. Recruitment aimed
at balancing first employment status and then
educational level within groups divided by race
and gender. Institutional Review Boards of all of
the authors’ participating institutions approved the
study and procedures were in accordance with
institutional guidelines. Participants gave written
informed consent.
Forty-seven participants of predominantly Euro-
pean American-descent (96.5%) were recruited
from a 30+ year longitudinal study that originally
assessed a range of psychosocial functioning in
adolescents of middle-to-high socioeconomic sta-
tus. This cohort is described elsewhere [40,41].
An additional 163 participants of similar age
and socioeconomic status were recruited over 20
months through advertising (radio, newspapers, fly-
ers, health fairs, academic conferences) in the
Boston area. Eligibility criteria included being
between 40 and 50 years old and identification
of a stable residence. Among the eligible popu-
lation, those with serious medical illness, e.g.,
heart disease, cancer, diabetes were excluded from
the study. Of 963 individuals who inquired about
participation, 247 did not return calls or did not
come for their visit, 44 were not interested after
learning more, 501 were ineligible or their inclu-
sion would skew the balance among groups with
respect to employment and education, and 171
Please cite this article in press as: Crowell JA, et al. Metabolic pathways link childhood adversity to elevated blood
pressure in midlife adults. Obes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.orcp.2015.10.009
3
came for assessment. Eight potential participants
were excluded from overall study participation
during the physical health evaluation, because of
electrocardiogram (ECG) findings indicative of past
myocardial infarction or a fasting finger-stick blood
glucose level indicative of diabetes.
To ensure that the two recruitment samples were
comparable, a dummy variable indicating the sam-
ple group and interactions between sample group
and each of the predictors of interest were included
as covariates in statistical models, first with the
dummy only and second with the dummy and inter-
actions. There were no significant differences in
the outcomes associated with the sample group,
and patterns of association between predictors and
outcomes did not statistically vary across groups.
Moreover, the pattern of results remained evi-
dent with or without the sample group covariates.
Given this, the two samples were combined to
enhance statistical power. This mixed-risk sample
was 23% (n = 49) White/European American men;
19% (n = 39) White/European American women; 24%
(n = 51) Black/African American men; 34% (n = 71)
Black/African American women. Thirty-four per-
cent of participants had a Bachelor’s degree or
higher, and 31% was unemployed.
Procedure
Participants arrived at 8:00 AM at the Clinical
Research Center of Beth Israel Deaconess Medical
Center (BIDMC, Boston, MA, USA) after an overnight
fast. Registered nurses conducted screening ECGs
and measured seated blood pressure twice with a
5-min interval, and once standing using either a
Dinamap GE Pro 300V2 or a Phillips SureSigns VS3
monitor. A physician conducted a physical examina-
tion and standardised medical history that included
current medications. A dietician measured height,
ORCP-522; No. of Pages 9 ARTICLE IN PRESS
4 J.A. Crowell et al.
Table 1 Descriptive statistics for study variables.
Mean/frequency
Age (years) 45.8
Race (Black/African American) 57%
Gender (Female) 53%
Overall childhood adversity 22.4
Waist—hip ratio (ratio by gender) 1.1
Body mass index (BMI) (kg/m2 ) 30.4
Leptin (ng/mL) 26.8
Adiponectin (ug/mL) 8.6
Insulin resistance (HOMA)
Antihypertensive medications 12%
Mean arterial pressure (MAP) 92.6
Overall childhood adversity = cumulative adversity × adversity severity × adversity chronicity. Antihypertensive medica-
tions = currently taking physician-prescribed medications for hypertension.
weight, smallest waist and iliac hip circumferences.
Participants then went to Judge Baker Children’s
Center (Boston, MA, USA) for psychosocial assess-
ments.
Measures
Overall childhood adversity
Cumulative adversity [11] occurring before age 18
was assessed using (a) the Evaluation of Lifetime
Stressors interview assessing trauma exposure [42],
(b) the Structured Clinical Interview for Diagnoses
Diagnostic and Statistical Manual (DSM) IV-R Non-
Patient Version Axis 1 including the Post-Traumatic
Stress Disorder module [43], and (c) the Adult
Attachment Interview yielding narrative descrip-
tions of childhood adversities [44].
Two coders reviewed each interview. An adver-
sity was tallied if the participant presented an
unambiguous description, regardless of meaning
attributed to the experience. The most prevalent
adversities were parental divorce (42%), physical
abuse (41%), prolonged separation from parent
(34%), sexual abuse (30%), domestic violence (29%),
emotional abuse (23%), parental substance abuse
(21%), and death of a first-degree family mem-
ber (20%). A cumulative adversity sum score was
obtained (range 0—13).
Severity and chronicity of adversity was assessed
as described in Davis et al. [13]. Scores for overall
adversity ranged from 0 to 156. Because this vari-
able was positively skewed, a log transformation
was performed that improved the normality of the
distribution.
Dietary quality
The Block Food Frequency Questionnaire (FFQ) is
a detailed, well-validated assessment of dietary
intake over the past year [45]. A nutrient intake
Please cite this article in press as: Crowell JA, et al. Metabolic pathways link childhood adversity to elevated blood
pressure in midlife adults. Obes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.orcp.2015.10.009
Standard deviation Range
3.3 35—55
30.0 0—156
0.1 0.9—1.3
7.2 18.2—51.5
23.0 1.2—112.2
5.5 0.3—28.8
11.8 64.3—125.0
score was calculated by multiplying the consump-
tion frequency for each food item by its serving
size, and then summing according to the Alternative
Healthy Eating Index 2010 food groups (AHEI-2010)
[46]. The AHEI 2010 score is based on vegetables,
fruit, cereal fibre, nuts and soy, ratio of white to
red meat, trans fat, ratio of polyunsaturated to sat-
urated fatty acids, multivitamin use, and alcohol
consumption. The possible range of scores is 2.5
(worst) to 87.5 (best).
Central obesity
A ratio score for the waist—hip ratio (WHR) mea-
surement was created to compensate for differing
cut-off scores for men versus women. Scores
above 1.00 indicated a non-optimal waist—hip ratio
indicative of central obesity.
Adipocytokines and insulin resistance
Fasting venous blood samples were collected
and processed at the BIDMC. Serum and plasma
were isolated within 90 min of collection and
stored at −80 ◦ C. Adiponectin and leptin was
measured by radioimmunoassay (RIA) (Millipore.
Billerica, MA, USA). Inter- and intra-assay CVs
were 3.6—6.2% and 3.4—8.3% for leptin, 6.9—9.3%
and 1.8—6.2% for adiponectin. Homeostasis model
assessment for insulin resistance (HOMA-IR) was
calculated as [(fasting insulin (U/mL) × fasting glu-
cose (mg/dL)/18)/22.5] [47].
Mean arterial pressure
Average mean arterial pressure (MAP) [(2 × average
diastolic) + average systolic]/3] was calculated
from three blood pressure readings (seated, 5-min
seated, standing).
ORCP-522; No. of Pages 9 ARTICLE IN PRESS
Leptin links childhood adversity and blood pressure in midlife 5

Statistical analysis

Race: 1 = Black/African American; 0 = White/European American. Gender: 1 = Woman; 0 = Man. Adversity = cumulative adversity × adversity severity × adversity chronicity, log trans-
.955**
11
Study data were collected and managed using RED-
Cap electronic data capture tools hosted at BIDMC
[48]. Descriptive analyses were performed. Pearson

formed. AHEI diet = American Healthy Eating Index 2010. WHR = waist—hip ratio. Antihypertensive medications = taking physician-prescribed medications for hypertension.
.743**
.908**
correlations examined bivariate relations among

10
study variables to check for multicollinearity; they
were not hypothesis-generating. Analyses were per-

−.207**
−.185**
formed using a series of path analysis models using

−.126ˆ
SPSS v21 and Lisrel v8.80. Path analysis is simi-

—
lar to multiple regression, providing estimates of
the magnitude and significance of hypothesised

.239**
.199**
.231**
causal connections between variables (see Fig. 1)

−.099
[49]. Although they are correlational, path analyses

—
can determine the more important and significant
associations between variables and thus they have
implications for how plausible the causal hypothe-

.346**
−.481**
.273**
.210**
.252**
ses are. The statistics examined for path model fit

—
were chi-square test (2 ) and root mean square
error of approximation (RMSEA).
Across all participants and variables, 83% of the

.481**
.356**
−.463**
.213**
.223**
.234**
data was complete. Reasons for missingness varied
6

—
(e.g., unable to draw blood, recording equipment
failure) and were unrelated to key variables.

.335**

.192**

.185**
.160*
.114

.099
−.109
Results
5

—
Descriptive statistics for the variables of interest
−.250**
−.250**

−.302**
−.298**
−.320**
.176ˆ
−.194*

0.084
are presented in Table 1. Anthropometric assess-
ments are consistent with those described in the
4

Third National Health and Nutrition Examination

Survey [35]. Zero-order Pearson correlations are
.249**
−.300**
−.136ˆ

.212*
.101

.153

.072
.118
.105
presented in Table 2. The metabolic variables of
leptin and adiponectin, but not HOMA, were sig-
3

—
Pearson correlation coefficients for study variables.

nificantly correlated with childhood adversity and

with WHR. All three metabolic variables, WHR, and
.314**
.233**

−.134ˆ
−.141*
.075
.111
.054
−.075
−.003

−.102

dietary quality were significantly associated with

MAP.
2

—
.443**

.207**
−.237**
.132ˆ

−.150ˆ
.136ˆ

.142ˆ
.152*
.158*

Predicting mean arterial pressure with

.053
.077

childhood adversity
1
—

A series of path analyses were conducted to exam-

11. Mean diastolic blood pressure

ine the nature of the associations between overall

10. Mean systolic blood pressure
5. Antihypertensive medication

childhood adversity and MAP observed in the zero-

order correlations, adjusting for race, gender, and
12. Mean arterial pressure

antihypertensive medications usage. We first tested

the hypothesised model shown in Fig. 1. However,
7. Insulin resistance

this was not a good fit for the data [2 (13) = 50.62,
p < .001; RMSEA = .118] given its statistically signif-
1. Race (Black)

9. Adiponectin

icant 2 and a RMSEA value greater than .8. We

3. Adversity
4. AHEI diet

** p ≤ .01.
* p ≤ .05.
ˆ p ≤ .10.
2. Gender

then used a data driven approach by removing

8. Leptin
Table 2

6. WHR

non-significant paths and adding paths that were

suggested by the modification indices. The final
path model, presented in Fig. 2, was a good fit for

Please cite this article in press as: Crowell JA, et al. Metabolic pathways link childhood adversity to elevated blood
pressure in midlife adults. Obes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.orcp.2015.10.009
ORCP-522; No. of Pages 9 ARTICLE IN PRESS
6 J.A. Crowell et al.

Figure 2 Path model with unstandardised (standardised) beta coefficients linking childhood adversity to mean arterial
pressure through leptin; the solid arrows represent significant paths at the *p < .05 and the dashed arrows represent
non-significant paths. Note: The model was adjusted for race, gender, and antihypertensive medication.

the data [2 (6) = 7.03, p > .05; RMSEA = .029] given
its non-significant 2 and a RMSEA value with a
≤.05 close approximate fit [50]. Our final model,
presented in Fig. 2, presents two pathways link-
ing childhood adversity to MAP. First, childhood
adversity was linked to increased circulating lep-
tin through increased WHR. Second, and accounting
for the first path, childhood adversity was linked to
increased circulating leptin directly. Leptin, in turn,
was associated with increased MAP. Third, dietary
quality was linked with both WHR and MAP. This
model predicted 17% of the variance in MAP.
Similar results were obtained using the more
traditional assessment of childhood adversity,
that is, a cumulative adversity score, as well as
with systolic [2 (5) = 6.66, p > .05, RMSEA = .04]
and diastolic [2 (5) = 7.25, p > .05, RMSEA = .047]
pressures, each entered into the model separately.
A model that included HOMA instead of leptin
[2 (6) = 8.29, p > .05, RMSEA = .042] did not show
a link between childhood adversity and HOMA or
between HOMA and MAP. A model that included
adiponectin instead of leptin [2 (6) = 9.21, p > .05,
RMSEA = .051] did not show a link from adiponectin
to MAP.
Discussion
Consistent with our hypotheses that trauma and
toxic stress in childhood are associated with adult
blood pressure levels, the path analysis s a set of
predicted relations among key variables such that
childhood adversity is associated with a chain of
mediators linking dietary quality, central obesity,
and leptin to MAP in a midlife sample of mixed-risk
adults. The path model reveals direct links between
childhood adversity and increased leptin levels, and
between leptin and dietary quality to MAP. Similar
models were observed for both systolic and dia-
stolic blood pressure.
Leptin and dietary quality were the most prox-
imal predictors of blood pressure, indicating that
at least two routes to MAP were evident in our
model. First, with respect to dietary quality, the
model suggests that diet plays a direct role in ele-
vated blood pressure, independent of childhood
psychosocial factors that may be associated with
dietary quality. Second, there was a direct path
from childhood adversity to circulating leptin lev-
els independent of central obesity. Independent of
race, gender, WHR, and dietary quality, individuals
who experienced childhood adversity had higher
circulating leptin levels. The result supports the
concept that leptin intolerance develops in the con-
text of repeated and/or sustained stress occurring
early in life through the action of glucocorti-
coids that both stimulate the release of leptin and
reduce end-organ sensitivity to this adipocytokine
[15,51,52]. The direct connection between adver-
sity and between circulating leptin and leptin and
MAP level is consistent with other work indicating

Please cite this article in press as: Crowell JA, et al. Metabolic pathways link childhood adversity to elevated blood
pressure in midlife adults. Obes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.orcp.2015.10.009
ORCP-522; No. of Pages 9 ARTICLE IN PRESS
Leptin links childhood adversity and blood pressure in midlife
that high levels of leptin negatively impact haemo-
dynamics beyond other obesity-related mechanisms
[27].
Although there are significant positive correla-
tions between WHR and blood pressure, we did
not find a direct association between WHR and
MAP in our path model. Increased inflammation and
oxidative stress, decreased endothelial nitric oxide
synthase enzyme reactions, up-regulated renin-
angiotensin-aldosterone system (RAAS) have bee
hypothesised as possible mechanisms for a link
between visceral obesity and MAP [26,53]. How-
ever, in our model, leptin levels mediated the
association between WHR and MAP.
Examining the relations among childhood adver-
sity, WHR, and adiponectin, we find adiponectin
was significantly correlated with childhood adver-
sity, WHR, and MAP. However, consistent with other
findings regarding adiponectin and hypertension
[19], the path between adiponectin and MAP did
not hold when dietary quality was included in the
model. Insulin resistance (HOMA) was also signifi-
cantly related to other metabolic variables (leptin,
adiponectin), dietary quality, WHR, and MAP. How-
ever it was not significantly to childhood adversity,
and thus in this model did not provide an explana-
tory mechanism linking early life stress to blood
pressure.
Limitations
Path analyses allow us to order variables based upon
hypothesised mechanisms and to demonstrate that
the data indeed fits well with such a hypothesised
model. Nevertheless, it is important to remem-
ber that the study is cross-sectional and thus we
cannot truly examine causal pathways nor can we
fully confirm the model without using indepen-
dent data given the process of modification used.
The relatively small sample size is a limitation to
including other potentially explanatory variables
such as health behaviours or combined hormonal
pathways that would predict greater variance in
hypertension, but the findings are robust within this
context.
Bias in retrospective reporting of childhood
adversities may represent another limitation. How-
ever, several important studies support the validity
of such retrospective reports, finding negligible
differences between prospective and retrospec-
tive reports [54,55]. Furthermore our retrospective
evaluations of adversity are based on interview data
rather than self-report questionnaires and employ
a comprehensive method of assessing childhood
adversity [13].
Please cite this article in press as: Crowell JA, et al. Metabolic pathways link childhood adversity to elevated blood
pressure in midlife adults. Obes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.orcp.2015.10.009
7
Perspectives
This is the first study to demonstrate the asso-
ciation of childhood adversity on midlife mean
arterial pressure through a path involving obe-
sity and the leptin that includes dietary quality
and is applicable across race and gender. It adds
to the literature as an interdisciplinary endeav-
our demonstrating that childhood adversity is a
potent risk factor for a number of adult health out-
comes [11], in this case, elevated blood pressure,
and the findings are consistent with hypothe-
sised mechanisms by which its impact is exerted
[14,16,22]. In addition to examining childhood
adversity, the study is novel in its examination
of how significant external stresses in childhood
and adolescence may impact hypertension. Early
adversity appears to developmentally overload and
dysregulate endocrine systems directly and through
increased risk for obesity and thus to elevated blood
pressure.
Source of funding
This study was supported by the National Institute
of Aging, R01 AG032030 (for Judith A. Crowell),
and National Institute of Diabetes and Digestive
and Kidney Diseases grant 81913 (for Christos S.
Mantzoros), Grant Number UL1 RR025758 — Har-
vard Clinical and Translational Science Center, from
the National Center for Research Resources (for
Christos S. Mantzoros). The content is solely the
responsibility of the authors and does not neces-
sarily represent the official views of the National
Center for Research Resources or the National Insti-
tutes of Health.
Conflict of interest
The authors have nothing to disclose.
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