NSIDRC Journal Article Alert — July 11, 2008
Prepared by the National Sudden Infant Death Resource Center
at Georgetown University.
This journal article alert provides selected items added to
the National Library of Medicine’s PubMed database in
the last week.
Past issues of NSIDRC journal alerts are available at http://www.sidscenter.org.
Availability of full-text journal articles is often limited to
subscribers or through inter-library loan. Please see
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Sudden Infant Death
1. Doi A, Ramirez JM
Neuromodulation and the orchestration of the respiratory rhythm
Respir Physiol Neurobiol. 2008 Jun 12. [Epub ahead of print]
Department of Organismal Biology and Anatomy, The University
of Chicago, 1027 East 57th Street Chicago, IL 60637, USA.
The respiratory system is continuously modulated by numerous
aminergic and peptidergic substances that act at all levels
of integration: from the sensory level to the level of central
networks and motor nuclei. The same neuronal networks receive
inputs from multiple modulators released locally as well as
from distal nuclei. All parameters of respiratory control are
controlled by multiple neuromodulators. By partly converging
onto similar G-proteins and second messenger systems, acetylcholine,
norepinephrine, histamine, serotonin (5-HT), dopamine, ATP,
substance P, cholecystokinin (CCK) can increase frequency,
regularity and amplitude of respiratory activity. Yet, the
same modulator can also exert differential effects on respiratory
activity by acting on different receptors partly in the same
neurons. In the pre-Bötzinger complex (pre-BötC)
modulators can differentially modulate frequency and amplitude
in different types of pacemaker neurons. Similarly motoneurons
located in different motor nuclei receive differential amplitude
modulation from different modulators. Thus, modulators are
capable of orchestrating and modulating different parameters
of respiratory activity by differentially targeting different
cellular targets. A disturbance in modulatory control may lead
to Sudden Infant Death Syndrome (SIDS) and erratic breathing.
2. Audero E, Coppi E, Mlinar B, Rossetti T, Caprioli A, Banchaabouchi
MA, Corradetti R, Gross C
Sporadic autonomic dysregulation and death associated with
excessive serotonin autoinhibition
Science. 2008 Jul 4;321(5885):130-3
Mouse Biology Unit, European Molecular Biology Laboratory
(EMBL), Via Ramarini 32, 00015 Monterotondo, Italy.
Sudden infant death syndrome is the leading cause of death
in the postneonatal period in developed countries. Postmortem
studies show alterations in serotonin neurons in the brainstem
of such infants. However, the mechanism by which altered serotonin
homeostasis might cause sudden death is unknown. We investigated
the consequences of altering the autoinhibitory capacity of
serotonin neurons with the reversible overexpression of serotonin
1A autoreceptors in transgenic mice. Overexpressing mice exhibited
sporadic bradycardia and hypothermia that occurred during a
limited developmental period and frequently progressed to death.
Moreover, overexpressing mice failed to activate autonomic
target organs in response to environmental challenges. These
findings show that excessive serotonin autoinhibition is a
risk factor for catastrophic autonomic dysregulation and provide
a mechanism for a role of altered serotonin homeostasis in
sudden infant death syndrome.
3. Behan M, Wenninger JM
Sex steroidal hormones and respiratory control
Respir Physiol Neurobiol. 2008 Jun 12. [Epub ahead of print]
Department of Comparative Biosciences, University of Wisconsin,
Madison, WI 53706-1102, USA.
There is a growing public awareness that sex hormones can
have an impact on a variety of physiological processes. Yet,
despite almost a century of research, we still do not have
a clear picture as to the effects of sex hormones on the regulation
of breathing. Considerable data has accumulated showing that
estrogen, progesterone and testosterone can influence respiratory
function in animals and humans. Several disorders of breathing
such as obstructive sleep apnea (OSA) and sudden infant death
syndrome (SIDS) show clear sex differences in their prevalence,
lending weight to the importance of sex hormones in respiratory
control. This review focuses on questions such as: how early
do sex hormones influence breathing? Which is the most effective?
Where do sex hormones exert their effects? What mechanisms
are involved? Are there age-associated changes? A clearer understanding
of how sex hormones influence the control of breathing could
enable sex- and age-specific therapeutic interventions for
diseases of the respiratory control system.
4. Otagiri T, Kijima K, Osawa M, Ishii K, Makita N, Matoba
R, Umetsu K, Hayasaka K
Cardiac Ion Channel Gene Mutations in Sudden Infant Death Syndrome
Pediatr Res. 2008 Jun 25. [Epub ahead of print]
Department of Pediatrics [T.O., K.K., K.H.], Department of
Pharmacology [K.I.], and Department of Forensic Medicine [K.U.],
Yamagata University School of Medicine, Yamagata 990-9585,
Japan; Department of Forensic Medicine [M.O.], Tokai University
School of Medicine, Sagamihara 259-1193, Japan; Department
of Cardiovascular Medicine [N.M.], Hokkaido University Graduate
School of Medicine, Sapporo 060-8638, Japan; Department of
Legal Medicine [R.M.], Osaka University Graduate School of
Medicine, Osaka 565-0871, Japan.
Sudden infant death syndrome (SIDS) is multifactorial and
may result from the interaction of a number of environmental,
genetic, and developmental factors. We studied three major
genes causing long QT syndrome (LQTS) in 42 Japanese SIDS victims
and found five mutations, KCNQ1-K598R, KCNH2-T895M, SCN5A-F532C,
SCN5A-G1084S, and SCN5A-F1705S, in four cases; one case had
both KCNH2-T895M and SCN5A-G1084S. All mutations were novel
except for SCN5A-F532C, which was previously detected in an
arrhythmic patient. Heterologous expression study revealed
significant changes in channel properties of KCNH2-T895M, SCN5A-G1084S
and SCN5A-F1705S, but did not in KCNQ1-K598R and SCN5A-F532C.
Our data suggests that nearly 10% of SIDS victims in Japan
have mutations of the cardiac ion channel genes similar to
in other countries.
Other Infant Death
1. Klemm RD, Labrique AB, Christian P, Rashid M, Shamim AA,
Katz J, Sommer A, West KP Jr
Newborn vitamin a supplementation reduced infant mortality
in rural Bangladesh
Pediatrics. 2008 Jul;122(1):e242-50
DrPH, Johns Hopkins University, Center for Human Nutrition,
Department of International Health, Bloomberg School of Public
Health, 615 North Wolfe St, Baltimore, MD 21205. rklemm@jhsph.edu.
OBJECTIVES: We assessed the effect of supplementing newborns
with 50000 IU of vitamin A on all-cause infant mortality through
24 weeks of age. PATIENTS AND METHODS: This was a community-based,
double-masked, cluster-randomized, placebo-controlled trial
conducted in 19 unions in rural northwest Bangladesh. The study
was nested into and balanced across treatment arms of an ongoing
placebo-controlled, weekly maternal vitamin A or beta-carotene
supplementation trial. Study-defined sectors (N = 596) were
evenly randomized for newborns of participating mothers to
receive a single, oral supplement of vitamin A (50000 IU) or
placebo as droplets of oil squeezed from a gelatinous capsule.
Mothers provided informed consent for newborn participation
at approximately 28 weeks' gestation. After birth, typically
at home (where >90% of births occurred), infants were supplemented
and their vital status was followed through 24 weeks of age.
The main outcome measure was mortality through 24 weeks of
age. RESULTS: We obtained maternal consent to dose 17116 live-born
infants (99.8% of all eligible) among whom 15937 (93.1%) were
visited to be supplemented <30 days after birth and for
whom vital status at 24 weeks of age was known. Dosed infants
(n = 15902 [99.8%]) received their study supplement at a median
age of 7 hours. Relative to control subjects, the risk of death
in vitamin A-supplemented infants was 0.85, reflecting a 15%
reduction in all-cause mortality. Protective relative risks
were indistinguishable by infant gender, gestational age, birth
weight, age at dosing, maternal age, parity, or across the
3 treatment arms of the maternal supplementation trial. CONCLUSIONS:
Newborn vitamin A dosing improved infant survival through the
first 6 months of life in Bangladesh. These results corroborate
previous findings from studies in Indonesia and India and provide
additional evidence that vitamin A supplementation shortly
after birth can reduce infant mortality in South Asia.
Bereavement
1. Mann JR, McKeown RE, Bacon J, Vesselinov R, Bush F
Predicting depressive symptoms and grief after pregnancy loss
J Psychosom Obstet Gynaecol. 2008 Mar 29:1-6. [Epub ahead of
print]
University of South Carolina School of Medicine, SC, USA.
Women who experience pregnancy loss are at high risk for depression
and grief. We conducted a prospective cohort study to identify
antenatal predictors of depressive symptoms and grief following
pregnancy loss. Particular emphasis was given to the potential
role of religiosity and spirituality. In multivariable linear
regression models, depressive symptoms were significantly positively
associated with baseline depression score and a history of
mental illness. Depression scores were significantly inversely
associated with age. Increasing age was also protective against
post-pregnancy loss grief, as was participation in organized
religious activities. Clinicians should be particularly alert
to signs of depression following pregnancy loss in younger
women and in women with a history of mental illness during
or before pregnancy. The inverse association between religious
attendance and grief following pregnancy loss merits further
study.
2. Hensley PL, Slonimski CK, Uhlenhuth EH, Clayton PJ
Escitalopram: An open-label study of bereavement-related depression
and grief
J Affect Disord. 2008 Jul 1. [Epub ahead of print]
Department of Psychiatry, School of Medicine, University of
New Mexico Health Sciences Center, Albuquerque, New Mexico,
United States.
BACKGROUND: Approximately 8 million Americans suffer the loss
of an immediate family member each year. Chronic depression
may develop following bereavement-about 15% of the bereaved
are depressed at 1 year. Several studies of psychotropic medications
have demonstrated improvement in depression ratings, but little
data exists for selective serotonin reuptake inhibitor treatment
in bereavement-related depression. METHODS: Thirty adults were
treated with escitalopram for 12 weeks in open fashion for
a major depressive episode following loss of a close family
member (parent, sibling, child, or spouse/significant other).
Main outcome measures were the Hamilton Depression Rating Scale,
the Montgomery-Asberg Rating Scale, the Texas Revised Inventory
of Grief, and the Inventory of Complicated Grief. RESULTS:
Twenty-nine of thirty participants returned for at least one
set of efficacy measures after starting medication. Nineteen
subjects (66%) experienced a 50% or greater improvement on
the Hamilton Depression Scale. Fifteen subjects (52%) achieved
remission, defined as a final score of 7 or less on the Hamilton
Depression Scale. Escitalopram significantly reduced depressive
symptoms (P<0.001) over time. Subjects with uncomplicated
grief and those with complicated grief improved similarly over
time. Subjects with and without PTSD improved to a similar
degree. Escitalopram was well tolerated. LIMITATIONS: Open-label
design, psychotherapy was not controlled, relatively short
treatment period, variation in grief scales make comparisons
to other studies difficult, all subjects with complicated grief
also were clinically depressed, and gender discrepancy of sample.
CONCLUSIONS: Escitalopram improved depressive, anxiety, and
grief symptoms in individuals experiencing a major depressive
episode related to the loss of a loved one.
Miscarriage/Stillbirth/Prenatal Issues
1. Rosenberg H, Allard D
Women and statin use: A women's health advocacy perspective
Scand Cardiovasc J. 2008 Apr 1:1-6. [Epub ahead of print]
Health and Society Program, Division of Social Science, York
University, Toronto, Ontario, Canada.
This paper is based on a longer report on the benefits, safety
and modalities of information representation with regard to
women and statin use, situated within the historical context
of Women's Health Movement which has advocated for unbiased,
appropriate medical research and prescribing for women based
on the goals of full-disclosure, informed consent, evidence-based
medicine and gender-based analysis. The evidence base for prescribing
statins for women, especially for primary prevention is weak,
yet Canadian data suggest that half of all prescriptions are
for women. Safety meta-analyses do not disaggregate for women;
do not consider female vulnerability to statin induced muscle
problems, and women-centred concerns such as breast-cancer,
miscarriage or birth defects are under-researched. Many trials
have not published their non-cardiac serious adverse event
data. These factors suggest that the standards of full-disclosure,
informed consent, evidence-based prescribing and gender-based
analysis are not being met and women should proceed with caution.
2. Yurdakan G, Ekem TE, Bahadir B, Gun BD, Kuzey GM, Ozdamar
SO
Expression of adhesion molecules in first trimester spontaneous
abortions and their role in abortion pathogenesis
Acta Obstet Gynecol Scand. 2008 Jun 18:1-8. [Epub ahead of
print]
Department of Pathology, Faculty of Medicine, Zonguldak Karaelmas
University, Zonguldak, Turkey.
Background. Early placental development is associated with
complex regulatory mechanisms, and molecular communication
problems that arise during the developmental process are dangerous
for continuation of the pregnancy. As studies on the process
of invasion and migration of trophoblast cells have shown the
importance of cell-cell and cell-matrix interactions, we examined
the effects of adhesion molecules on the mechanism(s) of spontaneous
abortions and compared them to elective abortion materials
using histopathological and immunohistochemical methods. To
the best of our knowledge, this is the first study to investigate
adhesion molecules in spontaneous abortions. Methods. Curettage
materials from abortions were examined retrospectively in the
Department of Pathology, Zonguldak Karaelmas University School
of Medicine, Zonguldak, Turkey. CD31/PECAM-1 (endothelial cell
marker), CD44v (variant 3), E-cadherin, CD54/ICAM-1, and CD106/VCAM-1
expression profiles were evaluated by immunohistochemistry,
and cellular localization was determined under light microscopy.
The results of spontaneous abortions were compared to those
of elective abortions. Results. The staining percentages of
CD31, CD44, CD106, and E-cadherin decreased in cases of spontaneous
abortion, but CD54 (ICAM-1) expression increased. Statistically
significant differences were detected between spontaneous and
elective abortion materials with regard to cytotrophoblasts
(CTs), syncytiotrophoblasts (STs), and extravillous trophoblasts
(EVTs) with the anti-CD31 antibody (p=0.0001). In addition,
CD54 (p=0.007 and p=0.002) and E-cadherin (p=0.002 and p=0.02)
expression in CTs and STs, respectively, were significantly
different. Furthermore, CD44 expression (p=0.003) in decidual
(D) cells and CD106 (p=0.0001) expression in vessels of endometrial
(E) and villous tissues were also significantly different.
Conclusions. Decreased CD31 expression in CTs that invade the
spiral arterioles and mimic E cells in spontaneous abortion
cases suggests that CD31/PECAM-1 is an important molecule in
uteroplacental adequacy. Moreover, diminished expression of
CD44 in D cells caused impaired stroma-villous connections.
Enhancement of ICAM-1 in placental and invading STs may be
useful as a diagnostic marker for patients who may have a tendency
to have spontaneous abortions. A down-regulation of E-cadherin
was observed, which may be responsible for impaired CT differentiation
and loss of the pregnancy. Furthermore, decreased VCAM-1 expression
in spontaneous abortions may be consistent with the importance
of VCAM-1 in trophoblast-endothelial cell interactions. Many
adhesion molecules are known to be effective in the normal
development of a pregnancy, and the analysis of adhesion molecules
in spontaneous abortions will provide useful information for
clarifying the physiopathology of spontaneous abortions.
3. El Bishry G, Ganta S
The role of single serum progesterone measurement in conjunction
with beta hCG in the management of suspected ectopic pregnancy
J Obstet Gynaecol. 2008 May;28(4):413-7
University Hospital of North Durham, UK. bishry20@hotmail.com.
Our aim was to test the use of single serum progesterone measurement
together with beta hCG in the management of women with pregnancy
of unknown location. This was a retrospective study of 126
patients presenting with a clinical picture suggestive of ectopic
pregnancy, when ultrasound examination was inconclusive. All
the patients had serum progesterone level measured by radioimmunoassay
in conjunction with beta hCG. The study showed that a protocol
combining single serum progesterone measurement and beta hCG
is helpful in managing women with suspected ectopic pregnancies,
when the ultrasound examination is inconclusive. High levels
of progesterone are reassuring as regards ongoing viable pregnancies
and low levels allow a definitive differentiation between viable
and non-viable pregnancies. However, low progesterone could
not efficiently differentiate between miscarriage and ectopic
pregnancy. The use of beta hCG levels in conjunction with serum
progesterone is helpful, particularly with serum progesterone
levels between 16-80 nmol/l.
4. Dargaud Y, de Mazancourt P, Rugeri L, Hanss M, Borg JY,
Gaucherand P, Negrier C, Trzeciak C
An unusual clinical presentation of factor XIII deficiency
and issues relating to the monitoring of factor XIII replacement
therapy
Blood Coagul Fibrinolysis. 2008 Jul;19(5):447-452
Clinical Haemostasis Unit, Edouard Herriot Hospital, France
bEA 4174 University of Lyon, France cLaboratory of Molecular
Biology, Poincare Hospital, Garches, France dHaemostasis Laboratory,
Louis Pradel Hospital, Lyon, France eHaemostasis Unit-Haematology,
Charles Nicolle Hospital, Rouen, France fDepartment of Gynecology & Obstetrics,
Edourad Herriot Hospital, Lyon, France.
Congenital factor XIII deficiency is a very rare bleeding
disorder. Patients with severe FXIII deficiency usually exhibit
severe bleeding diatheses. Factor XIII is also involved in
maintaining pregnancy, and women with factor XIII deficiency
have a high risk of spontaneous abortions. We report here the
case of a patient with a mild bleeding history before her pregnancy
but who had three spontaneous haemorrhagic miscarriages. The
patient was homozygous for G 501 R mutation of the factor XIII
A subunit gene. We also detected a coinherited heterozygous
factor V Leiden mutation, probably leading to a milder bleeding
tendency. The patient had successful factor XIII replacement
therapy throughout her fourth pregnancy. The efficacy of the
factor XIII infusions was monitored using thromboelastometry
and routine factor XIII measurements. This case report shows
that factor XIII deficiency should be ruled out in patients
with recurrent fetal loss but with a normal miscarriage workup,
even in the absence of a history of severe bleeding since childhood.
We also showed that thromboelastometry could be a valuable
tool for the monitoring of factor XIII replacement therapy.
5. Habayeb OM, Taylor AH, Bell SC, Taylor DJ, Konje JC
Expression of the Endocannabinoid System in Human First Trimester
Placenta and its Role in Trophoblast Proliferation
Endocrinology. 2008 Jul 3. [Epub ahead of print]
Endocannabinoid Research Group, Reproductive Sciences Section,
Department of Cancer Studies and Molecular Medicine, University
of Leicester, United Kingdom.
Context: The endocannabinoid, anandamide, which binds to two
major receptor proteins, the cannabinoid receptors 1 and 2
(CB1 and CB2), has been shown to play a role in first trimester
miscarriage possibly through impairment of the developing trophoblast.
Although the precise molecular mechanisms underlying this are
unknown, plasma anandamide levels are known to be regulated
by the progesterone-induced enzyme, fatty acid amide hydrolase
(FAAH). Objective: Here, we tested the hypothesis that temporal-spatial
expression of FAAH, CB1 and CB2 are regulated during early
pregnancy and that anandamide detrimentally alters trophoblast
proliferation. Results: Transcripts for CB1, CB2 and FAAH were
demonstrated in first trimester trophoblast extracts with only
the CB1 transcript being significantly regulated. The significant
4.7-fold increase in expression at week 10 of gestation was
reduced to 8.9% of the peak value by week 12. Transcripts for
CB2 showed a similar pattern of expression but were not significantly
induced. By contrast, FAAH transcript levels appeared to increase
towards the end of the first trimester, but again did not reach
significance. These observations were supported by immunohistochemical
studies that demonstrated a similar pattern of expression at
the protein level, with cellular localisation for all three
proteins concentrated within the syncytiotrophoblast layer.
Anandamide also prevented BeWo trophoblast cell proliferation
in a dose-dependent manner with a 50-60% significant inhibition
of cell proliferation with concentrations in excess of 3 microM.
This effect was mediated through the CB2 receptor. Conclusion:
Taken together, these data provide insights into how elevated
plasma anandamide levels increase the risk of first trimester
miscarriage.
6. Bustamante-Aragones A, Pérez-Cerdá C, Pérez
B, Rodriguez de Alba M, Ugarte M, Ramos C
Prenatal diagnosis in maternal plasma of a fetal mutation causing
propionic academia
Mol Genet Metab. 2008 Jul 1. [Epub ahead of print]
Department of Genetics, Fundacion Jimenez Diaz-Capio, CIBERER,
Avda. Reyes Catolicos, 2, 28040, Madrid, Spain.
Prenatal diagnosis (PD) is available to families affected
with propionic acidemia (PA), however, it entails a risk of
miscarriage. Fetal DNA circulating in maternal blood could
allow performing a safe prenatal diagnosis of fetal mutations.
Exclusion of the paternal mutation in maternal plasma may avoid
conventional PD in cases of recessive disorders such us PA.
In this work, we have correctly diagnosed in maternal plasma
the status of a fetus at risk of PA for the paternal mutation.
7. Slattery MM, Geary M, Morrison JJ
Obstetric antecedents for preterm delivery
J Perinat Med. 2008;36(4):306-9
Rotunda Hospital, Parnell Square, Dublin 1, Ireland and Department
of Obstetrics and Gynecology, National University of Ireland
Galway, Clinical Science Institute, University College Hospital
Galway, Newcastle Road, Galway, Ireland.
Abstract Objectives: To investigate the obstetric antecedents
for preterm delivery (PTD) in an Irish urban obstetric population,
and to evaluate the incidence and outcome of such deliveries.
Study design: A retrospective observational study of all preterm
deliveries at the Rotunda Hospital, Dublin during the six-year
period 1997-2002. The findings for early preterm deliveries
(EPTD) (24+0-31+6 weeks' gestation), and late preterm deliveries
(LPTD) (32+0-36+6 weeks' gestation) were analyzed separately.
Results: There were 38,795 deliveries after 24 weeks' gestation
or >500 g birth weight, of which 2839 (7.3%) were preterm.
Of all preterm deliveries, 626 (22.1%) were EPTD and 2213 (77.9%)
were LPTD, resulting in an EPTD rate of 1.6% and an LPTD rate
of 5.7%. Spontaneous unexplained preterm delivery accounted
for 1221 (43.0%) of preterm deliveries (PTD), and of these
213 (34%) cases were EPTD and 1008 (45.5%) LPTD. The other
most frequently observed obstetric causative factors, in order
of importance, were multiple gestation (676; 23.8% of PTD),
hypertensive disorders of pregnancy (243; 8.6%), antepartum
hemorrhage (194; 6.8%), stillbirth (105; 3.7%), intrauterine
growth restriction (53; 1.9%) and preterm prelabor rupture
of membranes+/-chorioamnionitis (32; 1.1%). There were 75 early
neonatal deaths among infants born prematurely, plus 105 stillbirths,
resulting in a perinatal mortality rate of 63 per 1000 for
PTD (n=180), which on subsequent analysis was 158 per 1000
for EPTD (n=99) and 37 per 1000 for LPTD (n=81). Conclusions:
These data outline the obstetric factors linked to preterm
delivery within a recent Irish urban obstetric population.
Spontaneous idiopathic preterm labor was the principle causative
factor in 43% of all preterm deliveries, and represents the
proportion of women for whom future therapeutic intervention
may be of benefit.
8. Guerriero C, Lanza Silveri S, Sisto T, Rosati D, De Simone
C, Fossati B, Pomini F, Rotoli M, Amerio P, Capizzi R
Impetigo herpetiformis occurring during N-Butyl-Scopolammonium
bromide therapy in pregnancy: case report
J Biol Regul Homeost Agents. 2008 Apr-Jun;22(2):141-4
Department of Dermatology, Catholic University of the Sacred
Heart, Rome, Italy.
Impetigo herpetiformis (IH) is a rare dermatosis arising during
the third trimester of pregnancy which is generally considered
as a form of pustular psoriasis of unknown aetiology. Clinically
it is characterized by erythematous plaques surrounded by sterile
pustules associated with fever, diarrhea, sweating and increasing
risk of stillbirth for placental insufficiency. We describe
a case of developed erythematous plaques surrounded by pustules
localised initially to the trunk of a 35-year-old woman at
the 34th week of gestation after 5 days of treatment with N-Butyl-Scopolammonium,
and which later involved the upper and lower limbs. Skin histology
confirmed the diagnosis of generalised pregnancy pustular psoriasis
(impetigo herpetiformis). IH is reported to be associated with
hypocalcemia, hypoparathyroidism, use of oral contraceptives
and bacterial infections. This is the first report suggesting
the potential role of drugs other than oral contraceptives
in the pathogenetic mechanism of this disease. In this case
an adverse cutaneous reaction to BB could be the cause of the
development of Koebner isomorphism.
Prepared by the
National Sudden Infant Death Resource Center
Georgetown University
2115 Wisconsin Avenue, N.W., Suite 601
Washington, DC 20007
(866) 866-7437 toll free
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(202) 784-9777 fax
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