VACCINE PACKING A
Varela, Johns Hopkins University, Baltimore, Md.
Ebola Glycoprotein Antibody Response in Immunized Nonhuman Primates
Using Enzyme-Linked Immunosorbent Assay (ELISA)"
Bailey and preceptor Nancy
Sullivan, Biodefense Research Section, NIAID-VRC
after Ebola virus outbreaks are as high as 90 percent. Two Ebola
virus subtypes, the Zaire strain (Z) and the Sudan strain (S), account
for 99 percent of all human Ebola-related deaths. There is currently
no licensed vaccine for Ebola, but an effort is underway at NIH
to develop a multivalent vaccine that protects against both virus
who is starting her sophomore year at Hopkins, tested the immunogenicity
of a combination genetic Z/S Ebola vaccine in cynomolgus macaques.
Essentially two vaccines delivered simultaneously, each consisted
of an adenoviral vector encoding slightly different Ebola virus
surface glycoproteinsGP(Z) and GP(S).
In a previous
study, the GP(Z) vaccine generated a robust immune response, as
measured by antibody production, and protected macaques against
challenge with live Zaire virus.
after immunization with the combination vaccine, sera from eight
macaques were assayed via enzyme-linked immunosor-bent assay (ELISA)
to determine specific GP(Z) and GP(S) antibody responses.
In all cases,
Zaire strainspecific antibody production was similar to that
in the previous study in which all macaques survived subsequent
challenge with live Zaire virus. In all but one subject, GP(S) generated
antigen-specific antibody titers that rivaled those for GP(Z), suggesting
that multiple antigens can be included in the vaccine and simultaneously
elicit robust immune responses.
Why one macaque
did not demonstrate a GP(S) response is not known, Varela said,
but she noted that the ELISA data indicate that all the other macaques
developed protective immunity against the Sudan as well as the Zaire
DISEASE AND THE ENVIRONMENT
OF DISCORDANT SIBS
Conlon, Georgetown University, Washington, D.C.
Environmental Factors Implicated in the Pathogenesis of Systemic
Autoimmune Diseases in Twins or Siblings Discordant for Disease"
Lisa Rider, and preceptors Mark Gourley and Frederick Miller,
Office of Clinical
Autoimmunity Group, NIEHS
known about the causes of autoimmune disorders, but as Mary Conlon
pointed out in her poster presentation, a less than 50 percent autoimmune
disease concordance in monozygotic twins presents "strong evidence
for an environmental influence."
is entering her senior year at Georgetown, examined data gathered
through the NIEHS Twin-Sibs study, conducted at the NIH Clinical
Center, to identify environmental risk factors associated with four
specific autoimmune disordersrheumatoid arthritis, scleroderma,
systemic lupus erythematosus, and myositis.
one of these four conditions and an unaffected twin or same-sex
sibling separated in age by no more than 47 months made up the study
group; healthy volunteers who did not have an affected sibling made
up the control group.
a physical examination and completed an extensive questionnaire
about their health history and exposure to suspected environmental
risk factors. Conlon analyzed data related to vaccination history,
past infections, ultraviolet light sensitivity, and past surgical
of this ongoing study (more families are being recruited) show a
significant association between prior Herpes zoster infection
and the subsequent development of autoimmune disease. Other environmental
exposures continue to be evaluated as possible risk factors.
AND NEURONAL SYNAPSES
S. Park, University of Maryland, College Park
Effects on Corticostriatal Synaptic Plasticity"
Lovinger and preceptor Henry
for Integrative Neuroscience, NIAAA
defined as the long-lasting strengthening of a neuronal synapse,
long-term potentiation (LTP) in the central nervous system is believed
to play an important role in learning and memory.
a college sophomore, examined ethanols (EtOH) effects on LTP
using an in vitro rat model consisting of a fresh coronal brain
slice comprising the dorsomedial striatuma region known to
contribute to memory. Brain slices were bathed in an artificial
cerebral spinal fluid to which ethanol was added to concentrations
2 mM, 10 mM, and 50 mM.
model, Park took field potential readings to measure LTP. The readings
were made by stimulating the striatum via small electric pulses
emitted through a tiny electrode inserted into the brain slice.
were then received through a second recording electrode inserted
nearbyalong a neuronal pathway leading through the striatum.
Once a baseline
measurement was established, a series of high-frequency stimulations
(HFS) was delivered to the striatum, and then recording was resumed
using the baseline stimulation parameters. The administration of
HFS was used to induce LTP through the activation of calcium-dependent
second-messenger systems in the postsynaptic cell.
the signal received becomes greater, indicating that LTP has occurred
and that synapses along the stimulated neuronal pathway have become
controls, LTP of ethanol-exposed samples decreased in a dose-dependent
manner and were significantly lower at the 50-mM EtOH concentration.
took LTP field potential readings of samples exposed to the NMDA
receptor antagonist APV because ethanol is known to inhibit NMDA
receptors, a type of glutamate receptor believed to induce LTP through
LTP was significantly
reduced in the presence of APV, but was reduced even further in
the presence of APV plus 50 mM EtOH. This phenomenon, Park said,
suggests that LTP may involve multiple pathways.
PAIN RELIEF AND SEX
AND STRESS HORMONES
Meunier, Louisiana State University School of Medicine, New
of Opioid versus Placebo Administration on Sex and Stress Hormones
in Men with Chronic Musculoskeletal Pain"
Max, and preceptor Marc
of Clinical Investigation, NCCAM
pain in the general population is underreported and undertreated.
Opioid medications can help manage pain but may also affect sex
and stress hormones in menan associated drop in testosterone
levels has been documented among male chronic heroin users, for
consequences of a decrease in testosterone, such as that naturally
associated with aging or that induced by chronic opioid use, include
loss of skeletal muscle mass and bone mass and an increased risk
of heart disease.
The sex hormones
under investigation in the current study are leutinizing hormone
(LH) and testosterone, and the stress hormones are adrenocorticotropic
hormone (ACTH) and cortisol.
now a second-year medical student, presented data from an ongoing
two-part investigation of the effects of low-dose opioid administration
on sex and stress hormones in men with chronic musculoskeletal pain
due to osteoarthritis (OA).
Part 1 of
the study asked the question: "Does chronic pain alone have
effects on male sex and stress hormones?"an important
question, Meunier observed, because it has been demonstrated that
acute pain causes increased catecholaminergic axis activity and
decreased gonadal steroid function.
Based on findings
in the 16 men with chronic OA pain and 12 healthy volunteers involved
in the study, however, the answer, Meunier reported, is "No."
was designed with stringent recruitment criteria, excluding individuals
with confounding illnesses that might have affected findings, such
as endocrine dysfunction, inflammatory arthritis, too high or too
low body mass index, and depression. Men with a history of prior
opioid use were also excluded.
function appears not to be significantly altered in healthy men
with chronic musculoskeletal pain, suggesting that prior reports
to the contrary resulted from the confounding effects of coexistent
illness or medication use.
Part 2 of
the study, expected to be completed by the spring of 2007, asks
the question: "Does low-dose administration of opioid medication
or placebo have effects on male sex and stress hormones?" There
are three study cohorts: an experimental treatment group given increasing
doses of a brand of prescription, time-released morphine sulfate,
an opioid; a placebo group; and a standardized treatment (nonopioid
analgesic) group, which serves as a control for the placebo group
so that placebo effects on the hormones in question may also be
involves two visits to the NIH Clinical Center for overnight blood
samplingone at the outset and one after the drug-escalation
period. Blood is collected every 20 minutes for a 12-hour period
and then analyzed for levels of ACTH, cortisol, LH, and testosterone.
Also during both visits a 24-hour urine sample is collected to measure
epinephrine, norepinephrine, dopamine, and cortisol.
OF WISDOM TEETH:
A SOURCE OF STEM CELLS?
Sakai, Harvard School of Dental Medicine, Boston
of Neuronal Differentiation Potential of Dental Pulp Stem Cells"
Mineshiba and preceptor Pamela
and Skeletal Diseases Branch, NIDCR
a lot being done to determine the potential of bone-marrow stem
cells as a source of neural cells, but no one knows the potential
of dental-pulp stem cells. This has been a really exciting project,"
said Maiko Sakai, describing her quest to establish neuronal cell
differentiation in mouse and rat brain slices from stem cells originating
in human dental pulp.
that dental pulp stem cells could be a source of neural cells emerged
in a previous study demonstrating expression of neural markers in
cell culture; the challenge now is to achieve similar results in
organ culture and in vivo, Sakai said.
course of her summer project, Sakai obtained pulp cells from adult
third molars that had been extracted in the context of needed dental
care; identified the mesenchymal stem cell marker CD146 by immunocytochemistry;
carried out magnetic- and fluorescent-activated cell-sorting techniques,
and fluorescently labeled the cells for tracing their activity in
rat and mouse brain tissue.
But she was
doubtful that she would still be at NIH to observe firsthand the
outcome of her work here. Her first attempt at preparing the tissue
samples for her experiment fell short of perfect and, consequently,
"my initial results are not that reliable," she said.
Her technique improved the second time aroundshe collected
more slices and from more propitious brain areas in the hippocampus
that are known to house neural cellsbut, she noted, there
would probably be more time required for the differentiation process
than she would have before returning to Boston for her second year
at the Harvard School of Dental Medicine.
of her first round of experiments suggest that dental-pulp cells
survive in brain tissue, with some developing axon-like structures.
Thus far, Sakai said, dental-pulp stem cells seem to have the potential
for differentiating into neurons, "but we still dont
FACTORS IN THE BIRTH
Gold, Maret School, Washington, D.C.
Complications as a Risk Factor for Schizophrenia: Data from the
Sibling Data Base
Weinberger and preceptor Stefano
Brain Disorders Branch, NIMH
really knows that much about the causes of schizophrenia, and the
results so far from our study are "iffy," Allie Gold observed,
but the study is providing a foundation for the development of a
new, more detailed questionnaire to probe the potential relationship
of specific obstetric complications (OCs) and the development of
schizophrenia in the affected offspring.
compared information gathered from the NIMH Sibling Study with reports
in the literature linking various OCs to later schizophrenia. These
previous reports are not entirely consistent with one another regarding
specific OC occurrence, severity, or patterns, and the current exploration
yielded findings consistent with some reported associations and
Rh incompatibility, and the use of drugslegal or illegalduring
pregnancy emerged as significant factors in the later development
of schizophrenia in offspringthe first two consistent with
some previously reported findings and the third heretofore absent
from discussion in the literature.
the number and severity of OCs reflecting prematurity, fetal malnutrition,
and fetal distressincluding preeclampsia, a strongly associated
finding in some previous studieswere similar in patients and
control subjects in the current study.
of OCs on intelligence, as measured by the Wide Range Achievement
Test (WRAT), was also examined. Patients had significantly lower
WRAT scores than healthy volunteers, and patients with an OC history
had lower WRAT scores than patients without an OC history. But there
were also some unexpected WRAT findings, such as higher scores among
healthy volunteers with an OC history and higher scores among both
patients and healthy volunteers with a history of Rh incompatibility.
The NIMH team
gathered its information from responses to a questionnaire given
to the mothers of 373 patients with schizophrenia and 380 control
subjects whose offspring did not have schizophrenia. The response
rate in the former group was 50 percent and that in the latter,
in response rate was considered a potential source of bias, as was
the mothers perhaps faulty memory regarding long-past obstetric
events, Gold noted. The new questionnaire should help clarify some
of these issues, she said.
NIH summer experience came between her junior and senior years in
high school and a year after an accident in which she sustained
a severe brain injury. She attributes her survival and complete
recovery to an "incredible shock-trauma team and medical staff."
Her intention, she said, is to become a doctor, "like everyone
in my family," and focus on the brain and cognition.
RESPONSE, AND CHRONIC
Zou, Georgia Institute of Technology, Atlanta
Length and Telomerase Activation in Peripheral Blood Lymphocytes
of Chronically Stressed Individuals"
Weng and Amanda
of Immunology, NIA
the critical role of telomeres in the aging process and immune response,
and prompted by the observation that chronically stressed individuals
tend to have weakened immune responses, Yixiao Zou and his mentors
investigated the effect of chronic stressin the form of long-term
caregiving to Alzheimers disease patientson telomere
length and telomerase activity in such primary caregivers.
29 healthy caregivers (mostly spouses) 57 to 75 years old and their
age- and sex-matched control subjects have been analyzed so far.
"Telomere length, activation-induced T cell telomerase activity,
as well as T cell proliferation rate, were comparable between two
groups," Yixiao Zou acknowledged, "but further analysis
is needed to characterize the duration and intensity of stress experienced
by the caregivers."
The one significant
difference that emerged between the cohorts was a decreased percentage
of natural killer cells in the caregivers, "which concurs with
the weaker immune system hypothesis," Zou observed.
cohorts were recruited by investigators at Ohio State University
in Columbus, who collected and sent samples of peripheral blood
mononuclear cells to the NIH researchers.
The NIA researchers
anticipate continuing this workincreasing the number of subjects
and conducting a longitudinal study to determine the rate of telomere
shortening and loss of telomerase activity, Zou said.
engineering student at Georgia Tech, Zou characterized the summer
program as a "great hands-on experience" that will serve
him well in his chosen field.
AND POLYPS RECURRENCE
Lee, Richard Montgomery High School, Rockville, Maryland
Promoter Gene Polymorphisms and Their Influence on Interleukin-10
Protein Levels among Participants in the Polyp Prevention Trial"
Sansbury and preceptor Elaine
of Cancer Prevention, NCI-CCR
In the summer
after her graduation from Richard Montgomery High School in Rockville,
Md., and preceding her freshman year at the Massachusetts Institute
of Technology in Cambridge, Grace Lee explored the relationship
of interleukin-10 (IL-10, an anti-inflammatory cytokine) promoter
polymorphisms, IL-10 serum levels, and the risk of recurrence of
adenomatous polyps in the colona precursor to colorectal cancer.
She and her
co-workers analyzed data collected from 558 people enrolled in the
Polyp Prevention Trial. They focused on three polymorphisms of interest,
with special attention to the G/G genotype of the -1082 polymorphism,
an allele variously reported to be associated with increased and
decreased levels of IL-10 in other studies, Lee said.
In the current
study, the other two polymorphisms (-819 and -592) had no apparent
influence on IL-10 serum levels, but serum levels were significantly
lower in individuals with the -1082
G/G genotype (P = 0.01).
that genotype nor the lower serum levels of this anti-inflammatory
cytokine appeared to correlate with an increased risk of adenoma
recurrence over the four years covered by the data, a finding at
theoretical odds with a previously reported association of the genotype
with increased cancer risk.
period covered by the study, 212 individuals experienced adenoma
recurrence and 346 did not. The study cohort had a personal history
of adenoma but not of colorectal cancer, their average age was 62,
and the majority was white and male.
statistical models that would adjust for individual and adenoma
characteristics are on the teams agenda, Lee said, as are
studies on the influence of serum levels of other inflammation-related
cytokines on adenoma recurrence. Her own plans, Lee added, include
becoming a premed and majoring in biology.
DACLUZIMAB IN MS TREATMENT
Griffith, Grove City College, Grove City, Pennsylvania
of Anti-CD25 Monoclonal Antibody Therapy on Regulatory T Cells in
Patients with Multiple Sclerosis"
McFarland, and preceptor Steve
Jacobson, Neural Immunology Branch, NINDS
of anti-CD25 monoclonal antibody (dacluzimab)an agent developed
at NIH and already FDA-approved to treat uveitis and to prevent
post-transplantation organ rejectionpoint to its potential
therapeutic usefulness in ameliorating autoimmune disorders such
as multiple sclerosis (MS).
study sought to measure the ability of dacluzimab to block activation
of regulatory T cells (T reg)and also of activated effector
CD4+ T cellsin patients with relapsing-remitting MS.
A group of
10 patients with MS received dacluzimab infusions monthly for one
year. Peripheral blood analysis showed a significant decline in
T reg, as reflected in levels of T regspecific markers such
as Foxp3, and a somewhat smaller decline in effector T cells as
activity, however, as revealed by MRI, did not correlate with T
a biochemistry major beginning her second college year, called the
lack of correlation a "phenomenon." She noted that the
MRI picture also "does not reflect the clinical findings"
that have been reported to accompany dacluzimab administration.
Continuing dacluzimab studies, she said, will include functional
HEALTH: THE INFLUENCE
Little, Winston-Salem State University, N.C.,
Link Between Self-reported Health and Demographics in the HANDLS
Kitner-Triolo, and preceptor Alan
Resources Branch, Clinical
Research Branch, and Laboratory
of Personality and Cognition, NIA
If you know
someones age, race, socioeconomic status, and perceived degree
of friendliness in the neighborhood, youll have a pretty good
idea of how that person views his or her health.
responses to an in-home questionnaire taken by 657 Baltimore residents
enrolled in the HANDLS
study (Healthy Aging in Neighborhoods of Diversity across the Life
Span) supported most of the hypotheses informing the design of the
older respondents, African-Americans, and people of lower socioeconomic
status (SES) reported being in poorer health than participants who
were younger, white, and of higher SES.
Only one of
several neighborhood characteristics expected to influence self-rated
health status was borne outagreeing that people not getting
along well with one another was linked to poorer self-rated health.
Contrary to expectations, women were no more likely than men to
rate themselves healthy.
low SES (below 125 percent of the poverty level) erased the differences
in self-reported health status between whites and African-Americans.
Although higher-SES whites reported better health than higher-SES
African-Americans, lower-SES whites were as likely to report poorer
health status as lower-SES African- Americans.
Little, a gerontology majorbiology minor at Winston-Salem
State University, establishing reliable predictors of self-reported
health status is just the beginning of her explorations in the field.
She will be returning to NIH next spring to spend her last semester
continuing this research.
On her research
agenda are adding certain items to the questionnaire, correlating
self-reported with actual health status of the participants, targeting
particular areas in Baltimore to discern changes from one block
to another, and parsing out "cultural" factorssuch
as diet, exercise, fear of the medical establishmentin self-reported
and actual health status.
SYNDROME: THE INFLUENCE
OF AGE AND RACE
Easter, Princeton University, Princeton, N.J.
Syndrome and Insulin Sensitivity in African-American and Caucasian
Children and Adolescents"
Gustafson, Margaret Rutledge, Joan Han, Sheila Brady, and preceptor
Yanovski, Unit on Growth and Obesity, Developmental
Endocrinology Branch, NICHD
of the current studyinvolving 104 African-American and 161
Caucasian children ages 6 through 13was to explore the relationship
between metabolic syndrome and insulin sensitivity in the pediatric
population and to examine the prevalence by race of the various
components of metabolic syndrome.
particular criteria used to diagnose metabolic syndrome in the pediatric
population are debated, and its prognosis is unclear," Benjamin
Easter said. "We are trying to untangle all the components
and see how race figures into establishing criteria for metabolic
syndrome." The study, he added, is part of two larger long-term
studies on growth and obesity.
a senior at Princeton who will be applying to medical school, noted
that his being an economics major had given him an edge in using
a novel statistical model called "ordered probit analysis"
to determine the effect of insulin sensitivity on the likelihood
of an individuals meeting from zero to five of the criteria
for metabolic syndrome. The five components were age- and sex-specific
cutoffs for waist circumference, blood pressure, HDL cholesterol,
fasting glucose, and triglyceride level, with three or more of these
deemed to constitute metabolic syndrome.
of metabolic syndrome did not differ by race, but the prevalence
of triglyceride levels high enough to meet metabolic syndrome criteria
was significantly lower in African-Americans, supporting findings
in previous studies and suggesting that race-specific criteria might
be appropriate, Easter said. Other race-specific differences fell
short of statistical significance.
was ascertained both by the elaborate hyperglycemic clamp procedure
and by fasting insulin and glucose levels (the QUICKI index). The
two correlated well with one another, supporting the use of the
more easily tolerated QUICKI method in clinical situations involving
children, Easter noted.
for age, race, sex, and body- mass index, insulin sensitivity as
measured by the QUICKI index, but not hyperglycemic clamp, was significantly
associated with meeting more criteria for metabolic syndrome.
interest was the finding that three factorsbody-mass index,
waist circumference, and HDL cholesterolwere predictive of
insulin sensitivity, but metabolic syndrome itself was not predictive
when its individual components were included in the analysis.
be that the diagnosis of metabolic syndrome isnt all that
useful in children. Maybe just those three factors tell us what
we need to know," Easter said.