Children's National Medical Center Research Articles

Abstract 2480: High-level activation of the Notch pathway in diffuse intrinsic pontine glioma

Abstract Diffuse intrinsic pontine glioma (DIPG) is a universally fatal pediatric brain tumor. Due to its critical location within the brainstem, and its characteristic MRI signature, biopsy is rarely performed. Since many patients die at home in hospice care, autopsy specimens have traditionally been rare. Because of this difficulty in obtaining tissue, three institutions (Johns Hopkins, Children's National Medical Center, and the National Institutes of Health - Pediatric Oncology Branch) have formed the Mid-Atlantic DIPG Consortium (MADC), to collect and disseminate rapid-autopsy material from patients with DIPG. Using a fresh tissue specimen obtained from a rapid autopsy and disseminated through the MADC, we have established a human DIPG xenograft and neurosphere cell line, JHH-DIPG1. In vitro, these cells are GFAP positive and express human neural stem cell markers often observed in glioblastoma, including human specific SOX2 and NESTIN. They also show marked invasive properties in vitro as measured by transwell invasion assay. In vivo, JHH-DIPG1 forms tumor xenografts in approximately six months in immunocompromised mice. Tumor cells diffusely infiltrate distant brain structures, recapitulating the invasive phenotype of DIPG. Due to their high level expression of neural stem cell markers, and the well-known roles of the Notch pathway in stem cell biology and aggressive brain tumors, we examined the expression of members of the Notch pathway in DIPG. Notch downstream effectors, specifically Hes1, Hes5 and Hey1, are highly expressed in JHH-DIPG1, at levels equal to or exceeding those observed in neurosphere cell lines derived from adult supratentorial glioblastoma. The JHH-DIPG1 tumor cell line represents one of only a handful of pediatric DIPG cell lines extant, and the high level of Notch pathway activation in these cells suggests that blockade of the Notch pathway using gamma secretase inhibitors and shRNAs against the canonical Notch effector CBF may be efficacious in DIPG. Our laboratory is actively investigating the role of the Notch pathway in DIPG using this and other DIPG cell lines, with the goal of moving Notch inhibition into clinical trials for these currently highly lethal tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2480. doi:1538-7445.AM2012-2480

Characteristics of Children with Type 1 Diabetes and Persistent Suboptimal Glycemic Control

Objective: This study aims to determine the relationship between the duration of persistent poor glycemic control in type 1 diabetes mellitus (T1DM) children and the likelihood of subsequent improvement.Methods: A retrospective cohort study was conducted on T1DM patients aged 6-18 years, followed for at least six visits at Children’s National Medical Center (Washington, DC) with at least one hemoglobin A1c (HbA1c) ≥10% after the first year since the initial visit (n=151). Medical records of patients with subsequently improved glycemic control were reviewed (n=39).Results: Patients aged 12-18 years, females, and Medicaid patients were twice as likely to be in persistently poor control as patients aged 6-11 years, males, and privately insured patients, respectively. Each additional visit with HbA1c ≥10% and one percentage point increase in the mean HbA1c reduced the likelihood of subsequent improvement by 20% and 50%, respectively. Of the 39 patients with improved control, only 5 (13%) sustained their improvement for ≥2 years. Multiple contributing factors for improved control were identified, but no one factor explained improved control in >25% of patients.Conclusion This study suggests that the longer the duration of poor control, the more difficult it is to reverse the underlying factors of poor diabetes management. Strategies to improve regular clinic attendance along with reinforcement of changes which resulted in improved control are critical. Adolescents, females, and Medicaid patients in particular should be targeted for sustained intervention. Conflict of interest:None declared.

Establishing Pediatric Emergency Medicine in Israel: Reflections and Lessons

This work describes the challenges encountered by the author in establishing and developing emergency medicine and pediatric emergency medicine as medical specialties in Israel. Many of the measures were largely based on his training in the United States, including a clinical fellowship in pediatric emergency medicine at the Children's National Medical Center in Washington, DC, and a research fellowship at the National Institutes of Health in Bethesda, MD. The article covers the clinical precepts on which emergency care is based, their practical applications, administrative obstacles, and new protocols and guidelines. A major milestone was the introduction of guidelines from the Pediatric Advanced Life Support course and other educational activities, followed by the establishment of an infrastructure to encourage local, national, and international educational and collaborative research projects and quality control.

A Pediatric Resident Diabetes Curriculum Targeting Different Learning Styles

Diabetes-related medical errors can lead to excessive morbidity, complications, disability, and even death.1 In the inpatient setting, errors involving insulin therapy have been associated with 33% of deaths that occurred within 48 hours of a medical error.2 There is accumulating evidence that insulin errors can be reduced with increased clinical supervision, along with educational curriculums.3 During the past decade, the endocrinology and diabetes division at Children's National Medical Center (CNMC) in Washington, D.C., implemented a diabetes care pathway to help guide physicians in diabetes management.4 Pathway education was provided to residents via delivery of three 1-hour lectures during the traditional resident core lecture series. Despite transmittal of this information, there continued to be a significant number of diabetes-related errors. Based on analysis, they fell into four categories: insulin dosing and timing, choice of intravenous fluids after pediatric intensive care unit (PICU) transfer, miscommunication between health care professionals, and discharge planning. Pedagogies were altered to embrace a more learner-centered approach that addresses differences in learning styles and requires active engagement on the part of the residents. As a result of this new curriculum, diabetes-related errors decreased significantly.5 This article discusses the curriculum that was developed, focusing on the variety of teaching approaches and their relationship to various styles of learning. ### Curriculum development process The diabetes program director (author FRC) hypothesized that creating a learner-centered curriculum could decrease residents' pathway errors. She received the approval of the director of resident education to go forward with curricular development. Following the general process used in higher education,6 curriculum development by the diabetes program director occurred over a 6-month period with the guidance of authors EG and LG, who serve as education specialists at George Washington University in Washington, D.C. The established goal of the curriculum was to decrease inpatient diabetes-related errors. …

Family History of Autoimmune Disease in Patients with Aicardi-Goutières Syndrome

Purpose. The purpose of this study was to explore anecdotal evidence for an increase in the prevalence of autoimmune diseases in family members of patients with Aicardi-Goutières syndrome (AGS). Methods. Pedigrees of patients and controls were analyzed using chi-square and logistic regression to assess differences in reports of autoimmune disease among family members of cases and controls. Data was collected at Children's National Medical Center in Washington, DC, USA and at the International Aicardi-Goutières Syndrome Association Scientific Headquarters, C. Mondino National Institute of Neurology in Pavia, Italy. Results. The number of individuals with reported autoimmune disease is significantly related to having a family member with AGS (χ 2 = 6.25, P = 0.01); 10% (35/320) of relatives of patients with AGS had a reported autoimmune disease diagnosis compared to 5% (18/344) of relatives of controls. There was a greater percent of maternal relatives of patients with AGS reporting autoimmune disease (14.6%), compared to controls (6.8%), with the association being statistically significant. The association was not significant for paternal relatives. Conclusion. The prevalence of autoimmune disease in relatives of children with AGS is significantly increased compared to controls. More research is needed to better understand this association.

Analysis of pediatric autologous PBSC apheresis and transplant: Age is a major factor affecting post‐transplant toxicity

High-dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT) is used in many therapeutic protocols for pediatric intra- and extra-cranial solid tumors. HCT can be curative, but is associated with significant toxicity. Between January 2001 and June 2009, 92 solid tumor patients (age 6 months to 27 years) underwent 94 autologous apheresis procedures at Children's National Medical Center. Out of that group, 71 patients, who underwent 162 autologous HCT, were analyzed for transplant outcomes. Multiple variable modeling was used to identify independent variables related to transplant toxicity outcome measures, such as bacteremia, intensive care admission, and death. Other outcome measures (time to pre-apheresis peripheral blood CD34+ count, product yield, and time to engraftment) were also analyzed. Independent variables included patient-specific variables (age, weight, tumor type, chemotherapy administered, and primary vs. relapsed disease) and harvest or transplant-related variables (total white blood cell and CD34+ cell counts prior to transplant, and quantity of total nucleated cells and CD34+ cells infused during transplant). Transplant toxicity was significantly greater in younger patients (P = 0.001) and in neuroblastoma patients (P = 0.003). The time to neutrophil engraftment, controlling for weight, age, and chemotherapy, was positively related to absolute CD34+ cells/kg infused (P = 0.01). The time to CD34+ recovery pre-apheresis was affected by patient diagnosis (P = 0.05). Younger patients had increased transplant toxicity, with infants <1 year of age at highest risk for fever, bacteremia, admission to intensive care, and death. Infants would likely benefit from hospitalization after autologous HCT until neutrophil recovery.

The Clinical and Translational Science Institute at Children's National: Improving Health through pediatric Research

The Clinical and Translational Science Institute at Children's National: Improving Health through pediatric Research

Go team go: Recognizing the importance of team training in critical care*

Department of Pediatrics, Children's National Medical Center, The George Washington University, Washington, DC The author has not disclosed any potential conflicts of interest.

The Road to Universal Pulse-Oximetry Screening: Are We There Yet?

Congenital heart disease is the most common birth defect and represents nearly 40% of all deaths caused by congenital anomalies.1 Critical congenital heart disease (CCHD), which encompasses the more severe forms, is present in 2.5 to 3 in 1000 live births.2 In general, prenatal ultrasound or physical examination alone can easily miss newborns with CCHD.3,4 Failure to diagnose CCHD early in life can result in high morbidity and mortality rates, because symptoms frequently present after closing of the pulmonary ductus arteriosus, after nursery discharge. Pulse-oximetry screening is a low-cost, painless, noninvasive test that increases the ability to identify newborns with CCHD before they clinically decompensate.5,–,8 In 2009 the American Heart Association and American Academy of Pediatrics published a scientific statement regarding the role of pulse oximetry in examining newborns for CCHD.9 Despite presenting strong support for this method, they stopped shy of recommending universal screening and called for further studies on implementation. In September 2010, the US Department of Health and Human Services (HHS) Secretary's Advisory Committee on Heritable Disorders in Newborns and Children recommended that CCHD be added to the uniform screening panel. However, … Address correspondence to Sandra Cuzzi, MD, Division of Hospitalist Medicine, Children's National Medical Center, 111 Michigan Ave NW, Washington, DC 20010. E-mail: scuzzi{at}childrensnational.org

Ineffective Therapy, Underpowered Studies, or Merely Too Little, Too Late?

It is estimated that 2% to 3% of pregnant women carry the anti-SSA/Ro antibody, which can be found in various autoimmune disorders, including Sjogren syndrome (SS), systemic lupus erythematosus, rheumatoid arthritis, and mixed connective tissue disorder.1,2 In addition, many women are asymptomatic carriers, with less than one third of anti-SSA/Ro–positive women diagnosed with a rheumatological disorder preceding the discovery of advanced heart block in the fetus.3,4 Prospective studies have demonstrated that, in the absence of a previously affected pregnancy, the fetuses of these women bear up to a 3% risk of developing cardiac manifestations of neonatal lupus (NL), including cardiac conduction abnormalities, structural cardiac defects, and isolated cardiomyopathies.5–7 In women with a previously affected pregnancy, the recurrence rate of congenital heart block can reach as high as 17%.8,9 Articles see p 1919 and p 1927 The cardiac conduction manifestations of NL are thought to result from a pathological response to the transplacental acquisition of anti-SSA/Ro whereby an immune-mediated inflammatory pathway triggers injury and eventually fibrosis of the atrioventricular (AV) node.10 In addition, anti-SSA/Ro antibodies appear to inhibit activation of the cardiac L-type calcium channels, which are essential to normal AV node conduction.11 The role of anti-SSB/La antibodies is less clearly defined. Although anti-SSB/La alone has not been associated with conduction abnormalities, some evidence suggests that it may potentiate the effects of anti-SSA/Ro–mediated injury.12 Antibody-exposed infants without cardiac involvement at birth have little risk of later developing AV block; however, complete AV block can evolve in fetuses with second-degree AV block in utero or neonates born with first- or second-degree AV block.9 Jaeggi and colleagues3 reported that the timing of initial presentation of complete AV block correlated with mortality. Among the 29 cases diagnosed …

A Therapeutic Group for Parents of Transgender Adolescents

Therapy for transgender, transsexual, and gender variant persons has traditionally assisted individuals in the process of adjusting to their newly adopted gender role. Increasingly, younger gender variant patients,teens and preteens, present to the clinical consultation raising the need to develop therapeutic interventions that better address the psychosocial needs of minors. The Gender and Sexuality Development Program at Children's National Medical Center (CNMC) in Washington,DC (http://www.childrensnational.org/gendervariance), provides outpatient psychosocial evaluations and therapeutic services for children,adolescents, and their families.

Propionic acidemia consensus conference summary

In January 2011, Children's National Medical Center in Washington, D.C. hosted a consensus conference to discuss and develop recommendations for the diagnosis and management of propionic acidemia. Several resulting manuscripts from this conference are included in this issue. Topics covered include recommendations for acute management of metabolic decompensations, recommendations for chronic management and health monitoring, natural history of disease in patients with propionic acidemia, and neurologic complications in propionic acidemia.

African American parents’ partnership with their children’s healthcare providers

African American children experience poorer health outcomes and their parents are often less satisfied with pediatric primary care, even after adjusting for difficulties in access because of insurance coverage. Horn et al from Children's National Medical Center performed a telephone survey of 425 African American parents whose children had a recent health visit in Washington, DC. They evaluated the factors that appeared to influence the parents' perceptions of the partnership. For example, parents seen in community health centers were more likely to report high partnership building compared with those seen at primary or hospital-based practices. There were other factors, such as parental education and the ethnicity of the provider, that had significant effects. The authors conclude that future studies should continue to evaluate these factors, with the goal of increasing partnership and improving healthcare outcomes.Article page 262▶ African American children experience poorer health outcomes and their parents are often less satisfied with pediatric primary care, even after adjusting for difficulties in access because of insurance coverage. Horn et al from Children's National Medical Center performed a telephone survey of 425 African American parents whose children had a recent health visit in Washington, DC. They evaluated the factors that appeared to influence the parents' perceptions of the partnership. For example, parents seen in community health centers were more likely to report high partnership building compared with those seen at primary or hospital-based practices. There were other factors, such as parental education and the ethnicity of the provider, that had significant effects. The authors conclude that future studies should continue to evaluate these factors, with the goal of increasing partnership and improving healthcare outcomes. Article page 262▶ African-American Parents’ Perceptions of Partnership with their Child’s Primary Care ProviderThe Journal of PediatricsVol. 159Issue 2PreviewTo identify family, provider, and healthcare setting characteristics associated with African-American parents’ perceptions of partnership with their child’s primary care provider. Full-Text PDF

Steroids for respiratory syncytial virus: Is it finally time to just say “no”?*

Children's National Medical Center; Critical Care Medicine; Washington DC The author has not disclosed any potential conflicts of interest.

EPIDEMIOLOGY OF CHILDHOOD TUBERCULOSIS

We used the Pediatric Health Information System (PHIS) administrative database to compare the incidence of childhood tuberculosis at Children's National Medical Center (CNMC) in Washington, DC, with national rates and evaluated PHIS as an epidemiologic tool. The incidence rate of tuberculosis at CNMC was approximately twice that of the national PHIS rate (incidence rate ratio, 1.9; 95% confidence interval 1.4-2.5). Of the 51 cases listed by PHIS as tuberculosis at CNMC between 2003 and 2007, 41 represented active tuberculosis validated by internal chart review, with a positive predictive value of 80%.

A Local, Regional, and National Assessment of Pediatric Malaria in the United States

Imported malaria remains a public health concern in the United States, but the health impact on children and the financial costs to society have not been well defined. Inpatient and outpatient malaria cases diagnosed at Children's National Medical Center (CNMC) in Washington, DC over an 8-year period are retrospectively reviewed. Cases are mapped against Census Bureau population data. These observations are compared with the national burden of pediatric malaria, including both disease severity and cost, by reviewing inpatient malaria cases in the Pediatric Health Information System (PHIS), January 2003 to June 2008. At CNMC, malaria most commonly affects children who traveled to West Africa to visit friends and relatives. Poor adherence to prophylaxis and self-treatment with antimalarial medications were commonly identified. Mapping demonstrates case clustering in communities with large sub-Saharan African populations. The cumulative incidence (CI) of malaria at CNMC of 9.0 per 10,000 admissions is 7.6 times the national average. The CI of malaria at PHIS hospitals is 1.2 per 10,000 admissions with an average cost of $17,519. Malaria is a preventable disease for which the risk to life and costs of treatment are significant. Patterns of risk can be used by health planners to target prevention strategies at the community level. In regions with a high density of immigrants, particularly from sub-Saharan Africa, physicians must be aware of the risk, understand recommended prophylaxis and treatment regimens, and advocate for their appropriate use in the community.

Connections in chronic kidney disease: connexin 43 and connexin 37 interaction

the prevalence of chronic kidney disease is rising sharply worldwide and affects 13.1% of the population in the US ([3][1]). Patients with chronic kidney disease represent a population not only at risk of progression to end-organ failure but also at higher risk for cardiovascular diseases ([22][2

Life at the Frontier

Life at the Frontier

Mental, motor, and language difficulties in neurofibromatosis type 1

The mental, motor, and language development of toddlers with neurofibromatosis type 1 (NF1) was studied in 39 infants by Lorenzo et al from The Children's Hospital at Westmead, New South Wales, Australia, and Children's National Medical Center, Washington, DC. The children were compared with 42 age-matched controls on several instruments for developmental assessment. The results showed that the toddlers with NF1 had significantly poorer mental and motor development compared with controls, and the parents indicated that most of them had delayed language skills. There were no differences in terms of behavior and executive functioning. Given that these abnormalities were present at 30 months, the authors suggest that 24 months might be the best time to perform an initial developmental assessment to identify children with NF1 with impaired development. Article page 660▶ Mental, Motor, and Language Development of Toddlers with Neurofibromatosis Type 1The Journal of PediatricsVol. 158Issue 4PreviewTo examine the mental, motor, and language development of toddlers with neurofibromatosis type 1 (NF1). Full-Text PDF

A Roundtable Discussion Alarm Safety: A Collaborative Effort

<i>A Roundtable Discussion</i> Alarm Safety: A Collaborative Effort