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Children’s National Hospital at the 2021 Pediatric Academic Societies Meeting

Attending the 2021 Pediatric Academic Societies meeting this week? There will be over 20 Children’s National Hospital-affiliated participants at this year’s meeting. We have compiled their sessions into a mini schedule:

Name Program/Department Session and role Date Time
Taeun Chang, M.D.  Neonatal Neurology and Neurocritical Care Program PAS Postgraduate Course: Neonatal Neurology: HIE-focused Project-Based (Chair) Friday, 30 April

 

9:00 AM –
4:00 PM
CT
Taeun Chang, M.D. Neonatal Neurology and Neurocritical Care Program PAS Postgraduate Course: Neonatal Neurology: HIE-focused Project-Based (Presenter) Friday, 30 April 9:30 AM – 10:00 AM
CT
Yuan-Chiao Lu, Ph.D. Developing Brain Research Laboratory Cardiology Poster: Care of the Fetus and Newborn with CHD (Presenter) Saturday, May 1 4:30 PM – 4:45 PM
CT
Chidiogo Anyigbo, M.D., M.P.H. General and Community Pediatrics Poster: Health Services Research I (Presenter)

 

Saturday, May 1 5:15 PM – 5:30 PM
CT
Panagiotis Kratimenos, M.D. Neonatology Platform (moderator) Saturday, May 1 4:30 PM – 6:00 PM
CT
Sudeepta Basu, MBBS, MS Neonatology Hot Topic Symposia: The Neurological Implications of Abnormal Glycemia in Neonatal Encephalopathy and Prematurity (Chair) Sunday, May 2 9:00 AM – 12:00 PM
CT
Sudeepta Basu, MBBS, MS Neonatology Hot Topic Symposia: The Neurological Implications of Abnormal Glycemia in Neonatal Encephalopathy and Prematurity (Presenter) Sunday, May 2 9:55 AM – 10:15 AM
CT
Ashraf Harahsheh, M.D., F.A.C.C., F.A.A.P.

 

Cardiology Cardiology: Heart Disease in the Older Child Sunday, May 2 10:00 AM – 12:00 PM
CT
Rana F. Hamdy, M.D., MPH, MSCE Infectious Diseases

 

Expanding Outpatient Antibiotic Stewardship: Practical Strategies, Novel Settings, and Sociobehavioral Influences (Presenter) Sunday, May 2 10:15 AM – 10:30 AM
CT
Rana F. Hamdy, M.D., MPH, MSCE Infectious Diseases

 

Hot Topic Debates: Antibiotic Use in Hospitalized Children (Chair) Sunday, May 2 1:00 PM – 3:00 PM
CT
John Idso, M.D. Critical Care Poster: Resuscitation and Potpourri (presenter) Sunday, May 2 2:20 PM – 2:30 PM
CT
Michael Shoykhet, M.D., Ph.D. Critical Care Medicine

 

Critical Care Poster: Resuscitation and Potpourri (presenter) Sunday, May 2 2:20 PM – 2:30 PM
CT
Panagiotis Kratimenos, M.D. Neonatology Neonatal Neurology: Basic & Translational I (moderator) Sunday, May 2

 

4:30 PM – 6:00 PM
CT
Monika Goyal, M.D. Emergency Medicine and Trauma Services Injury Prevention (moderator) Sunday, May 2 10:00 AM – 12:00 PM
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Ioannis Koutroulis, M.D., Ph.D., M.B.A. Genetic Medicine Research

 

Emergency Medicine III (moderator) Tuesday, May 4 2:00 PM – 4:00 PM
CT
Sudeepta Basu, MBBS, MS Neonatology Neonatal Neurology: Clinical: HIE and Other Insults (moderator) Tuesday, May 4 4:30 PM – 6:00 PM
CT
Josepheen De Asis-Cruz, M.D., Ph.D. Center for the Developing Brain Neonatal Neurology: Clinical: HIE and Other Insults (presenter) Tuesday, May 4 4:30 PM – 4:45 PM
CT
Asad Bandealy, M.D., MPH
Priti Bhansali, M.D. Monika Goyal, M.D.
Sabah Iqbal, M.D. Kavita Parikh, M.D. Shilpa Patel, M.D.
Workshop. ThisIsSTILLOurLane: Protect Kids, Not Guns Monday, May 10 9:00 AM – 11:00 AM
CT
Cara Lichtenstein, M.D. General and Community Pediatrics APA Injury Control/Advocacy Training Combined SIG (SIG Chair) Monday, May 10 1:00 PM – 3:00 PM
CT
Terry Kind, M.D., MPH General and Community Pediatrics

 

APA Women in Medicine / Qualitative Research Combined SIG (SIG Chair) Wednesday, May 12 9:00 AM – 11:00 AM
CT

Phase I: April-30-May 4 and Phase II: May 10-June 4

PAS 2021 Virtual Schedule

Purkinje cell

Premature birth disrupts Purkinje cell function, resulting in locomotor learning deficits

Purkinje cell

Children’s National Hospital researchers explored how preterm birth disrupts Purkinje cell function, resulting in locomotor learning deficits.

As the care of preterm babies continues to improve, neonatologists face new challenges to ensure babies are protected from injury during critical development of the cerebellum during birth and immediately after birth. How does this early injury affect locomotor function, and to what extent are clinicians able to protect the brain of preterm babies?

A new peer-reviewed study by Aaron Sathyanesan, Ph.D., Panagiotis Kratimenos, M.D., Ph.D., and Vittorio Gallo, Ph.D., published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS), explores exactly what neural circuitry of the cerebellum is affected due to complications that occur around the time of birth causing these learning deficits, and finds a specific type of neurons — Purkinje cells — to play a central role.

Up until now, there has been a sparsity of techniques available to measure neuronal activity during locomotor learning tasks that engage the cerebellum. To surmount this challenge, Children’s National used a multidisciplinary approach, bringing together a team of neuroscientists with neonatologists who leveraged their joint expertise to devise a novel and unique way to measure real-time Purkinje cell activity in a pre-clinical model with clinical relevance to humans.

Researchers measured neural circuit function by pairing GCaMP6f fiber photometry, used to measure neuronal activity in the brain of a free moving subject, with an ErasmusLadder, in which it needs to travel from point A to point B on a horizontal ladder with touch-sensitive rungs that register the type and length of steps. By introducing a sudden obstacle to movement, researchers observed how the subject coped and learned accordingly to avoid this obstacle. By playing a high-pitch tone just before the obstacle was introduced, researchers were able to measure how quickly the subjects were able to anticipate the obstacle and adjust their steps accordingly. Subjects with neonatal brain injury and normal models were run through a series of learning trials while simultaneously monitoring brain activity. In this way, the team was able to quantify cerebellum-dependent locomotor learning and adaptive behavior, unlocking a functional and mechanistic understanding of behavioral pathology that was previously unseen in this field.

In addition to showing that normal Purkinje cells are highly active during movement on the ErasmusLadder, the team explored the question of whether Purkinje cells of injured pre-clinical models were generally non-responsive to any kind of stimuli. They found that while Purkinje cells in injured subjects responded to puffs of air, which generally cue the subject to start moving on the ErasmusLadder, dysfunction in these cells was specific to the period of adaptive learning. Lastly, through chemogenetic inhibition, which specifically silences neonatal Purkinje cell activity, the team was able to mimic the effects of perinatal cerebellar injury, further solidifying the role of these cells in learning deficits.

The study results have implications for clinical practice. As the care of premature babies continues to improve, neonatologists face new challenges to ensure that babies not only survive but thrive. They need to find ways to prevent against the lifelong impacts that preterm birth would otherwise have on the cerebellum and developing brain.

Read the full press release here.

Read the full journal article here.

structure of EGFR

Study suggests EGFR inhibition reverses alterations induced by hypoxia

structure of EGFR

The study suggests that specific molecular responses modulated by EGFR (seen here) may be targeted as a therapeutic strategy for HX injury in the neonatal brain.

Hypoxic (HX) encephalopathy is a major cause of death and neurodevelopmental disability in newborns. While it is known that decreased oxygen and energy failure in the brain lead to neuronal cell death, the cellular and molecular mechanisms of HX-induced neuronal and glial cell damage are still largely undefined.

Panagiotis Kratimenos, M.D., and colleagues from the Center for Neuroscience Research at the Children’s National Research Institute, discovered increased expression of activated-epidermal growth factor receptor (EGFR) in affected cortical areas of neonates with HX and decided to further investigate the functional role of EGFR-related signaling pathways in the cellular and molecular changes induced by HX in the cerebral cortex.

The researchers found that HX-induced activation of EGFR and Ca2+/calmodulin kinase IV (CaMKIV) caused cell death and pathological alterations in neurons and glia. EGFR blockade inhibited CaMKIV activation, attenuated neuronal loss, increased oligodendrocyte proliferation and reversed HX-induced astrogliosis.

The researchers also performed, for the first time, high-throughput transcriptomic analysis of the cortex to define molecular responses to HX and to uncover genes specifically involved in EGFR signaling in brain injury. Their results indicate that specific molecular responses modulated by EGFR may be targeted as a therapeutic strategy for HX injury in the neonatal brain.

This study defines many new exciting avenues of scientific exploration to further elucidate the beneficial impact of EGFR blockade on perinatal brain injury at the cellular and molecular levels. This analysis could potentially result in the identification of new therapeutic targets associated with EGFR signaling in the developing mammalian brain that are linked with specific long-term abnormalities caused by perinatal brain injury.

Children’s National researchers who contributed to this study include Panagiotis Kratimenos, M.D., Ioannis Koutroulis, M.D., Ph.D., M.B.A., Susan Knoblach, Ph.D., Payal Banerjee, Surajit Bhattacharya, Ph.D., Maria Almira-Suarez, M.D., and Vittorio Gallo, Ph.D.

Read the full article in iScience.

allopregnanolone molecule

Autism spectrum disorder risk linked to insufficient placental steroid

allopregnanolone molecule

A study led by Children’s National Hospital and presented during Neuroscience 2019 finds that loss of allopregnanolone, a key hormone supplied by the placenta, leads to long-term structural alterations of the cerebellum – a brain region essential for smooth motor coordination, balance and social cognition – and increases the risk of developing autism.

An experimental model study suggests that allopregnanolone, one of many hormones produced by the placenta during pregnancy, is so essential to normal fetal brain development that when provision of that hormone decreases – as occurs with premature birth – offspring are more likely to develop autism-like behaviors, a Children’s National Hospital research team reports at the Neuroscience 2019 annual meeting.

“To our knowledge, no other research team has studied how placental allopregnanolone (ALLO) contributes to brain development and long-term behaviors,” says Claire-Marie Vacher, Ph.D., lead author. “Our study finds that targeted loss of ALLO in the womb leads to long-term structural alterations of the cerebellum – a brain region that is essential for motor coordination, balance and social cognition ­– and increases the risk of developing autism,” Vacher says.

According to the Centers for Disease Control and Prevention, about 1 in 10 infants is born preterm, before 37 weeks gestation; and 1 in 59 children has autism spectrum disorder.

In addition to presenting the abstract, on Monday, Oct. 21, Anna Penn, M.D., Ph.D., the abstract’s senior author, will discuss the research with reporters during a Neuroscience 2019 news conference. This Children’s National abstract is among 14,000 abstracts submitted for the meeting, the world’s largest source of emerging news about brain science and health.

ALLO production by the placenta rises in the second trimester of pregnancy, and levels of the neurosteroid peak as fetuses approach full term.

To investigate what happens when ALLO supplies are disrupted, a research team led by Children’s National created a novel transgenic preclinical model in which they deleted a gene essential in ALLO synthesis. When production of ALLO in the placentas of these experimental models declines, offspring had permanent neurodevelopmental changes in a sex- and region-specific manner.

“From a structural perspective, the most pronounced cerebellar abnormalities appeared in the cerebellum’s white matter,” Vacher adds. “We found increased thickness of the myelin, a lipid-rich insulating layer that protects nerve fibers. From a behavioral perspective, male offspring whose ALLO supply was abruptly reduced exhibited increased repetitive behavior and sociability deficits – two hallmarks in humans of autism spectrum disorder.”

On a positive note, providing a single ALLO injection during pregnancy was enough to avert both the cerebellar abnormalities and the aberrant social behaviors.

The research team is now launching a new area of research focus they call “neuroplacentology” to better understand the role of placenta function on fetal and newborn brain development.

“Our team’s data provide exciting new evidence that underscores the importance of placental hormones on shaping and programming the developing fetal brain,” Vacher notes.

  • Neuroscience 2019 presentation
    Sunday, Oct. 20, 9:30 a.m. (CDT)
    “Preterm ASD risk linked to cerebellar white matter changes”
    Claire-Marie Vacher, lead author; Sonia Sebaoui, co-author; Helene Lacaille, co-author; Jackie Salzbank, co-author; Jiaqi O’Reilly, co-author; Diana Bakalar, co-author; Panagiotis Kratimenos, M.D., neonatologist and co-author; and Anna Penn, M.D., clinical neonatologist and developmental neuroscientist and senior author.
newborn in incubator

Working to reduce brain injury in newborns

A new study from Children’s National Health System and Drexel University College of Medicine has identified a promising treatment to reduce or prevent brain injury in newborns who have suffered hypoxia-ischemia.

Research-clinicians at Children’s National Health System and Drexel University College of Medicine led the first study to identify a promising treatment to reduce or prevent brain injury in newborns who have suffered hypoxia-ischemia, a serious complication in which restricted blood flow deprives the brain of oxygen.

Consequences of brain injury resulting from oxygen deprivation affect the entire lifespan and range from mild (learning disabilities) to severe (inability to breathe, walk, talk or see). This complication can occur during or before birth due to maternal/placental problems, such as placental abruption or cord prolapse, or due to fetal/newborn issues, such as asphyxia due to labor difficulties, infection, fetal-maternal bleeding or twin-to-twin transfusion.

Published in Neonatology on Oct. 13, 2017, the study evaluated newborn experimental models exposed to hypoxia-ischemia. The experimental models were given standard cooling therapy (therapeutic hypothermia) alone and in combination with a selective Src kinase inhibitor, PP2, that blocks a regulatory enzyme of apoptosis (cell death), which intensifies as a result of hypoxia-ischemia. The Food and Drug Administration has approved a Src kinase inhibitor as an oncology treatment. This study is the first to test the benefits of blocking this enzyme in reducing the neurological damage caused by brain hypoxia-ischemia.

“In hypoxia-ischemia, CaM kinase is over-activated, but hypothermia has been shown to decrease this enzyme’s activation. We theorized that a Src kinase inhibitor, in addition to hypothermia, would further attenuate the activation of CaM kinase IV and that the result might be less brain damage,” explains Panagiotis Kratimenos, M.D., Ph.D., the study’s lead author, and a specialist in neonatology and neonatal neurocritical care at Children’s National. “From this study, we were pleased that this seems to be the case.”

The research team assessed neuropathology, adenosine triphosphate and phosphocreatine  concentrations as well as CaM kinase IV activity. The CaM kinase IV activity in cerebral tissue was 2,002 (plus or minus 729) with normal oxygen levels and in normal temperatures, 4,104 (plus or minus 542) in hypoxia with hypothermia treatment, and 2,165 (plus or minus 415) in hypoxia with hypothermia treatment combined with PP2 administration.

The authors conclude that hypothermia alone attenuated the over-activation of CaM kinase IV and improved neuropathology after hypoxia. However, the combination of hypothermia with Src kinase inhibition following hypoxia further attenuated the increased activation of CaM kinase IV, compared with hypothermia alone in the newborn experimental model brain.

Currently, the only treatment for hypoxia-ischemia is therapeutic hypothermia. Starting in the first six hours of life, doctors in the neonatal intensive care unit lower a baby’s temperature by about 3 degrees Celsius for three days. This therapy is proven to reduce neural defects by up to 30 percent, yet many infants still have poor outcomes even after the therapeutic cooling treatment.

“In oxygen deprivation of the brain, the pathways leading to cell death are over-activated, including the nuclear enzyme CaM kinase IV. We sought to intervene in this pathway to reduce the heightened cell death, which leads to brain damage,” explains Dr. Kratimenos, an assistant professor of pediatrics at The George Washington University School of Medicine and Health Sciences whose research focus is neonatal encephalopathy and therapeutic hypothermia.

To continue preclinical research into this approach, Dr. Kratimenos envisions studying the effect of other types of small molecule inhibitors to target the apoptotic cascade, perhaps in multiple doses, eliminating the potential side effects, and determining the best dose and duration of treatment.

“If confirmed by further studies, this approach─in combination with cooling─may help to further attenuate neurological damage that babies suffer after experiencing hypoxia-ischemia,” says Dr. Kratimenos.

The study co-authors include Ioannis Koutroulis, M.D., Ph.D., a faculty member in Children’s Division of Emergency Medicine; and Amit Jain, M.D.; Shadi Malaeb, M.D.; and the world-renowned neonatologist and pioneer in bioenergetics of the brain, Maria Delivoria-Papadopoulos, M.D., all of the Drexel University College of Medicine.