Public Health

muscle cells

Experimental model mimics early-stage myogenic deficit in boys with DMD

muscle cells

Muscle regeneration marked by incorporation of muscle stem cell nuclei (green) in the myofibers (red) in dystrophic muscles with low TGFβ level (upper image), but not with high TGFβ level (lower image). Inflammatory and other nuclei are labeled blue.

Boys with Duchenne muscular dystrophy (DMD) experience poor muscle regeneration, but the precise reasons for this remain under investigation. An experimental model of severe DMD that experiences a large spike in transforming growth factor-beta (TGFβ) activity after muscle injury shows that high TGFβ activity suppresses muscle regeneration and promotes fibroadipogenic progenitors (FAPs). This leads to replacement of the damaged muscle fibers by calcified and connective tissue, compromising muscle structure and function. While blocking FAP buildup provides a partial solution, a Children’s National Hospital study team identifies correcting the muscle micro-environment caused by high TGFβ as a ripe therapeutic target.

The team’s study was published online March 26, 2020, in JCI Insight.

DMD is a chronic muscle disease that affects 1 in 6,200 young men in the prime of their lives. The disorder, caused by genetic mutations leading to the inability to produce dystrophin protein, leads to ongoing muscle damage, chronic inflammation and poor regeneration of lost muscle tissue. The patients experience progressive muscle wasting, lose the ability to walk by the time they’re teenagers and die prematurely due to cardiorespiratory failure.

The Children’s National team finds for the first time that as early as preadolescence (3 to 4 weeks of age), their experimental model of severe DMD disease showed clear signs of the type of spontaneous muscle damage, regenerative failure and muscle fiber loss seen in preadolescent boys who have DMD.

“In boys, the challenge due to muscle loss exists from early in their lives, but had not been mimicked previously in experimental models,” says Jyoti K. Jaiswal, MSc, Ph.D., principal investigator in the Center for Genetic Medicine Research at Children’s National, and the study’s co-senior author. “TGFβ is widely associated with muscle fibrosis in DMD, when, in fact, our work shows its role in this disease process is far more significant.”

Research teams have searched for experimental models that replicate the sudden onset of symptoms in boys who have DMD as well as its complex progression.

“Our work not only offers insight into the delicate balance needed for regeneration of skeletal muscle, but it also provides quantitative information about muscle stem cell activity when this balanced is disturbed,” says Terence A. Partridge, Ph.D., principal investigator in the Center for Genetic Medicine Research at Children’s National, and the study’s co-senior author.

This schematic depicts the fate of injured myofibers in healthy or dystrophic muscle

This schematic depicts the fate of injured myofibers in healthy or dystrophic muscle (WT or mdx experimental models) that maintain low TGFβ level, compared with D2-mdx experimental models that experience a large increase in TGFβ level. As the legend shows, various cells are involved in this regenerative response.

“The D2-mdx experimental model is a relevant one to use to investigate the interplay between inflammation and muscle degeneration that is seen in humans with DMD,” adds Davi A.G. Mázala, co-lead study author.  “This model faithfully recapitulates many features of the complex disease process seen in humans.”

Between 3 to 4 weeks of age in the experimental models of severe DMD disease, the level of active TGFβ spiked up to 10-fold compared with models with milder disease. Intramuscular injections of an off-the-shelf drug that inhibits TGFβ signaling tamped down the number of FAPs, improving the muscle environment by lowering TGFβ activity.

“This work lays the foundation for studies that could lead to future therapeutic strategies to improve patients’ outcomes and lessen disease severity,” says James S. Novak, Ph.D., principal investigator in Children’s Center for Genetic Medicine Research, and co-lead study author. “Ultimately, our goal is to improve the ability of patients to continue to maintain muscle mass and regenerate muscle.”

In addition to Mázala, Novak, Jaiswal and Partridge, Children’s National study co-authors include Marshall W. Hogarth; Marie Nearing; Prabhat Adusumalli; Christopher B. Tully; Nayab F. Habib; Heather Gordish-Dressman, M.D.; and Yi-Wen Chen, Ph.D.

Financial support for the research described in this post was provided by the National Institutes of Health under award Nos. T32AR056993, R01AR055686 and U54HD090257; Foundation to Eradicate Duchenne; Muscular Dystrophy Association under award Nos. MDA295203, MDA480160 and MDA 477331; Parent Project Muscular Dystrophy; and Duchenne Parent Project – Netherlands.

Vittorio Gallo

Special issue of “Neurochemical Research” honors Vittorio Gallo, Ph.D.

Vittorio Gallo

Investigators from around the world penned manuscripts that were assembled in a special issue of “Neurochemical Research” that honors Vittorio Gallo, Ph.D., for his leadership in the field of neural development and regeneration.

At a pivotal moment early in his career, Vittorio Gallo, Ph.D., was accepted to work with Professor Giulio Levi at the Institute for Cell Biology in Rome, a position that leveraged courses Gallo had taken in neurobiology and neurochemistry, and allowed him to work in the top research institute in Italy directed by the Nobel laureate, Professor Rita Levi-Montalcini.

For four years as a student and later as Levi’s collaborator, Gallo focused on amino acid neurotransmitters in the brain and mechanisms of glutamate and GABA release from nerve terminals. Those early years cemented a research focus on glutamate neurotransmission that would lead to a number of pivotal publications and research collaborations that have spanned decades.

Now, investigators from around the world who have worked most closely with Gallo penned tributes in the form of manuscripts that were assembled in a special issue of “Neurochemical Research” that honors Gallo “for his contributions to our understanding of glutamatergic and GABAergic transmission during brain development and to his leadership in the field of neural development and regeneration,” writes guest editor Arne Schousboe, of the University of Copenhagen in Denmark.

Dr. Gallo as a grad student

Vittorio Gallo, Ph.D. as a 21-year-old mustachioed graduate student.

“In spite of news headlines about competition in research and many of the negative things we hear about the research world, this shows that research is also able to create a community around us,” says Gallo, chief research officer at Children’s National Hospital and scientific director for the Children’s National Research Institute.

As just one example, he first met Schousboe 44 years ago when Gallo was a 21-year-old mustachioed graduate student.

“Research can really create a sense of community that we carry on from the time we are in training, nurture as we meet our colleagues at periodic conferences, and continue up to the present. Creating community is bi-directional: influencing people and being influenced by people. People were willing to contribute these 17 articles because they value me,” Gallo says. “This is a lot of work for the editor and the people who prepared papers for this special issue.”

In addition to Gallo publishing more than 140 peer-reviewed papers, 30 review articles and book chapters, Schousboe notes a number of Gallo’s accomplishments, including:

  • He helped to develop the cerebellar granule cell cultures as a model system to study how electrical activity and voltage-dependent calcium channels modulate granule neuron development and glutamate release.
  • He developed a biochemical/neuropharmacological assay to monitor the effects of GABA receptor modulators on the activity of GABA chloride channels in living neurons.
  • He and Maria Usowicz used patch-clamp recording and single channel analysis to demonstrate for the first time that astrocytes express glutamate-activated channels that display functional properties similar to neuronal counterparts.
  • He characterized one of the spliced isoforms of the AMPA receptor subunit gene Gria4 and demonstrated that this isoform was highly expressed in the cerebellum.
  • He and his Children’s National colleagues demonstrated that glutamate and GABA regulate oligodendrocyte progenitor cell proliferation and differentiation.
Purkinje cells

Purkinje cells are large neurons located in the cerebellum that are elaborately branched like interlocking tree limbs and represent the only source of output for the entire cerebellar cortex.

Even the image selected to grace the special issue’s cover continues the theme of continuity and leaving behind a legacy. That image of Purkinje cells was created by a young scientist who works in Gallo’s lab, Aaron Sathyanesan, Ph.D. Gallo began his career working on the cerebellum – a region of the brain important for motor control – and now studies with a team of scientists and clinician-scientists Purkinje cells’ role in locomotor adaptive behavior and how that is disrupted after neonatal brain injury.

“These cells are the main players in cerebellar circuitry,” Gallo says. “It’s a meaningful image because goes back to my roots as a graduate student and is also an image that someone produced in my lab early in his career. It’s very meaningful to me that Aaron agreed to provide this image for the cover of the special issue.”

bacterial extracellular vesicle

Once overlooked cellular messengers could combat antibiotic resistance

bacterial extracellular vesicle

Children’s National Hospital researchers for the first time have isolated bacterial extracellular vesicles from the blood of healthy donors. The team theorizes that the solar eclipse lookalikes contain important signaling proteins and chromatin, DNA from the human host.

Children’s National Hospital researchers for the first time have isolated bacterial extracellular vesicles from the blood of healthy donors, a critical step to better understanding the way gut bacteria communicate with the rest of the body via the bloodstream.

For decades, researchers considered circulating bacterial extracellular vesicles as bothersome flotsam to be jettisoned as they sought to tease out how bacteria that reside in the gut whisper messages to the brain.

There is a growing appreciation that extracellular vesicles – particles that cells naturally release – actually facilitate intracellular communication.

“In the past, we thought they were garbage or noise,” says Robert J. Freishtat, M.D., MPH, associate director, Center for Genetic Medicine Research at Children’s National Research Institute. “It turns out what we throw away is not trash.”

Kylie Krohmaly, a graduate student in Dr. Freishtat’s laboratory, has isolated from blood, extracellular vesicles from Escherichia coli and Haemophilus influenzae, common bacteria that colonize the gut, and validated the results via electron microscopy.

“The images are interesting because they look like they have a bit of a halo around them or penumbra,” Krohmaly says.

The team theorizes that the solar eclipse lookalikes contain important signaling proteins and chromatin, DNA from the human host.

“It’s the first time anyone has pulled them out of blood. Detecting them is one thing. Pulling them out is a critical step to understanding the language the microbiome uses as it speaks with its human host,” Dr. Freishtat adds.

Krohmaly’s technique is so promising that the Children’s National team filed a provisional patent.

The Children’s research team has devised a way to gum up the cellular works so that bacteria no longer become antibiotic resistant. Targeted bacteria retain the ability to make antibiotic-resistance RNA, but like a relay runner dropping rather than passing a baton, the bacteria are thwarted from advancing beyond that step. And, because that gene is turned off, the bacteria are newly sensitive to antibiotics – instead of resistant bacteria multiplying like clockwork these bacteria get killed.

“Our plan is to hijack this process in order to turn off antibiotic-resistance genes in bacteria,” Dr. Freishtat says. “Ultimately, if a child who has an ear infection can no longer take amoxicillin, the antibiotic would be given in tandem with the bacteria-derived booster to turn off bacteria’s ability to become antibiotic resistant. This one-two punch could become a novel way of addressing the antibiotic resistance process.”

ISEV2020 Annual Meeting presentation
(Timing may be subject to change due to COVID-19 safety precautions)
Oral with poster session 3: Neurological & ID
Saturday May 23, 2020, 5 p.m. to 5:05 p.m. (ET)
“Detection of bacterial extracellular vesicles in blood from healthy volunteers”
Kylie Krohmaly, lead author; Claire Hoptay, co-author; Andrea Hahn, M.D., MS, infectious disease specialist and co-author; Robert J. Freishtat, M.D., MPH, associate director, Center for Genetic Medicine Research at Children’s National Research Institute and senior author.

buttons that say census

Pediatrician uses her ‘trusted voice’ to help kids

buttons that say census

Chidiogo Anyigbo, M.D., MPH, hopes to disrupt the cycle of poverty for the families she serves by informing them about the importance of the Census well beyond the April 1, 2020, official Census Day, the Children’s National Hospital general pediatrician and health services researcher writes in an essay published by Academic Pediatrics.

For months in 2019, Chidiogo Anyigbo, M.D., MPH, had been consumed by the need to learn more and read more about the upcoming 2020 Census. Dr. Anyigbo realized that in asking peers to underscore the importance of the Census with patients and families, the pediatrician hadn’t yet put herself in their shoes.

In late-December 2019, she decided it was time act. She fastened a big yellow pin provided by the DC Mayor’s Census Complete Count Committee that stated “Ask me about the 2020 Census” and that day strove to weave her brief spiel into patients’ clinical visits.

“To my surprise, I was able to have a meaningful exchange in two minutes. I discovered ways to work the topic into conversation while gathering the social history, finishing the physical exam or when providing anticipatory guidance. While some parents met my question with a quizzical look, others were excited to share their positive and negative thoughts about the Census,” Dr. Anyigbo writes in “In the Moment,” the latest installment in a narrative series published by Academic Pediatrics.

Dr. Anyigbo’s research focuses on the relationship between stress, health and social determinants of health. She aims to develop family-centered interventions that can support parents in minimizing the toxic effects of adversity on children. For her, an accurate Census count can play a critical role since the data drives funding for key resources such as health care, schools, grocery stores and nutrition programs that are critical to disrupting the negative effects of poverty and other adverse experiences.

One of her encounters that clinic day was with a mother and her 11-year-old son who had not participated in the 2010 Census. Dr. Anyigbo’s narrative describes how she was able to learn why and discuss with the family the importance of completing this year’s Census.

“The exchange with this mother and son put a face to the statistic of the 1 million children not counted in the 2010 Census,” Dr. Anyigbo writes in the narrative.  “Thinking about my patient, I realize that for a majority of his childhood, he was invisible and not counted in the planning and allocation of resources for programs such as Medicaid, Women, Infants and Children (WIC) and funding for Title I schools for his community. His complex housing situation put him, along with children who live with grandparents or households with low English proficiency, at the greatest risk of being missed in the Census.”

Because of her passion for her patients and the community she serves, Dr. Anyigbo plans to bring up the importance of the Census again and again, well beyond the April 1, 2020, official Census Day.

“Few other two-minute investments of my time can have such a profound and lasting impact,” Dr. Anyigbo writes. “My message to families is simple: Please complete the Census, include all children who live in your home, and know that your responses are safe and secure.”

preterm baby

Validating a better way to stratify BPD risk in vulnerable newborns

preterm baby

Factoring in the total number of days that extremely preterm infants require supplemental oxygen and tracking this metric for weeks longer than usual improves clinicians’ ability to predict respiratory outcomes according to bronchopulmonary dysplasia severity.

Factoring in the total number of days that extremely preterm infants require supplemental oxygen and tracking this metric for weeks longer than usual improves clinicians’ ability to predict respiratory outcomes according to bronchopulmonary dysplasia (BPD) severity, a research team led by Children’s National Hospital writes in Scientific Reports. What’s more, the researchers defined a brand-new category (level IV) for newborns who receive supplemental oxygen more than 120 days as a reliable way to predict which infants are at the highest risk of returning to the hospital due to respiratory distress after discharge.

About 1 in 10 U.S. infants is born preterm, before 37 weeks gestation, according to the Centers for Disease Control and Prevention. That includes extremely preterm infants who weigh about 1 lb. at birth. These very low birthweight newborns have paper thin skin, frail hearts and lungs that are not yet mature enough to deliver oxygen throughout the body as needed. Thanks to advances in neocritical care, an increasing number of them survive prematurity, and many develop BPD, a chronic lung disease characterized by abnormal development of the lungs and pulmonary vasculature.

“About half of the babies born prematurely will come back to the hospital within the first year of life with a respiratory infection. The key is identifying them and, potentially, preventing complications in this high-risk population,” says Gustavo Nino, M.D., a Children’s National pulmonologist and the study’s lead author.

For decades, the most common way to stratify BPD risk in these vulnerable newborns has been to see if they require supplemental oxygen at 36 weeks corrected gestational age.

“The problem with this classification is it doesn’t take into account the very premature babies who are on oxygen for much longer than other babies. So, we asked the question: Can we continue risk stratification beyond 36 weeks in order to identify a subset of babies who are at much higher risk of complications,” Dr. Nino says.

The longitudinal cohort study enrolled 188 infants born extremely preterm who were admitted to the neonatal intensive care unit (NICU) at Children’s National and tracked their data for at least 12 months after discharge. The team used a multidimensional approach that tracked duration of supplemental oxygen during the newborns’ NICU stay as well as scoring lung imaging as an independent marker of BPD severity. To validate the findings, these U.S.-born newborns were matched with 130 infants who were born preterm and hospitalized at two NICUs located in Bogotá, Colombia.

“Babies who are born very preterm and require oxygen beyond 120 days should have expanded ventilation of the lungs and cardiovascular pulmonary system before going home,” he notes. “We need to identify these newborns and optimize their management before they are discharged.”

And, the babies with level IV BPD risk need a different type of evaluation because the complications they experience – including pulmonary hypertension – place them at the highest risk of developing sleep apnea and severe respiratory infection, especially during the first year of life.

“The earlier we identify them, the better their outcome is likely to be,” Dr. Nino says. “We really need to change the risk stratification so we don’t call them all ‘severe’ and treat them the same when there is a subset of newborns who clearly are at a much higher risk for experiencing respiratory complications after hospital discharge.”

In addition to Dr. Nino, Children’s National study co-authors include Awais Mansoor, Ph.D., staff scientist at the Sheikh Zayed Institute for Pediatric Surgical Innovation (SZI); Geovanny F. Perez, M.D., pediatric pulmonologist; Maria Arroyo, M.D., pulmonologist; Xilei Xu Chen, M.D., postdoctoral fellow; Jered Weinstock, pediatric pulmonary fellow; Kyle Salka, MS, research technician; Mariam Said, M.D., neonatologist, and Marius George Linguraru, DPhil, MA, MSc, SZI principal investigator and senior author. Additional co-authors include Ranniery Acuña-Cordero, Universidad Militar Nueva Granada, Bogotá, Colombia; and Monica P. Sossa-Briceño and Carlos E. Rodríguez-Martínez, both of Universidad Nacional de Colombia.

Funding for research described in this post was provided by the National Institutes of Health (NIH) under award Nos. HL145669, AI130502 and HL141237. In addition, the NIH has awarded Dr. Nino an RO1 grant to continue this research.

Laura Tosi

Technology bridges knowledge gaps in rare bone disease care

Laura Tosi

Dr. Tosi and colleagues presented on the NIH Rare Disease Day 2020 panel, Nontraditional Approaches to Improving Access for Rare Diseases.

As part of the global observance of Rare Disease Day in February, the NCATS and NIH Clinical Center hosted a special event to raise awareness about rare diseases, the people they affect and NIH research collaborations under way to address scientific challenges and advance new treatments.

This year, Children’s National Hospital orthopaedic surgeon Laura Tosi, M.D., took part in an afternoon panel, Nontraditional Approaches to Improving Access for Rare Diseases, where she outlined her work as the faculty chair of the Rare Bone Disease TeleECHO, a virtual meeting that allows care providers and experts to come together via the Zoom platform, discuss diagnosis of specific disorders and present cases for group input.

Dr. Tosi and the Rare Bone Disease Alliance have called Project ECHO Rare Bone Disease a game changer for care of these complex conditions. Rare bone disorders are only about 5% of all birth defects but include 461 skeletal disorders caused by 437 genes – making it difficult for any physician to see enough cases of any one disorder to correctly diagnose and treat it.

“Most doctors are like me, a pediatric orthopaedic surgeon. I need to know a lot of different rare diseases and it’s hard to keep everybody on the cutting edge,” Dr. Tosi says. “Even though we have found the genes for most of the disorders, the phenotypic overlaps, shortage of specialists and the multi-disciplinary needs of so many of the patients add to the challenges.”

So 7 months ago, Dr. Tosi joined together with colleagues at the Rare Bone Disease Alliance and the Osteogenesis Imperfecta Foundation to launch Project ECHO Rare Bone Disease. The now monthly telehealth meeting engages a distinguished faculty of experts from around the world and from across the spectrum of care for these rare bone disorders, including specialists in genetics, endocrinology, orthopaedics and others.

Project ECHO is a specific model for bridging distance and creating a network of professionals, with the goal of leveling the playing field for all by making vital information accessible to everyone, regardless of their location. In healthcare the model transcends traditional “telemedicine,” however. The program, launched from the University of New Mexico, self-describes itself as “telementoring, a guided practice where the participating clinician retains responsibility for the patient” but is able to discuss diagnosis and therapeutic recommendations with a set of esteemed faculty via a regular virtual meeting series.

In the case of the Rare Bone Disease TeleECHO, the ECHO’s faculty decided on two major foci for the curriculum. Half of the content is about how to make the right diagnosis and the other half shares the latest information about specific diseases. The sessions also offer free CME to attendees.

Dr. Tosi says that while finding cases to discuss can sometimes be challenging when it comes to rare bone diseases, she takes responsibility on herself to make sure the content is robust each month. So far the meetings have attracted between 40 and 90 participants per session – a great engagement rate for such a young teleECHO program.

“I believe ECHO advances knowledge of healthcare and democratizes it by offering universal accessibility across the globe,” Tosi notes.

The Rare Bone Disease Alliance, which consists of 12 organizations, experts and patient families working together, is now deciding what’s next for the Rare Bone Disease TeleECHO. They may develop disorder-specific ECHOs, are studying the frequency of the sessions and how best to improve participation for all sessions. The idea is to increase access to this expertise even further, as it could have critical impacts on patients worldwide living with these rare diseases.

In terms of key take-aways from the panel of experts at Rare Disease Day, the hope is that more disease groups might leverage this type of technology to connect people in nontraditional ways. Doing so has the potential to ensure that everyone with a rare disease receives the best support and care possible because their doctors have the knowledge they need when they need it.

Watch more sessions from the NIH’s Rare Disease Day 2020.

NICU evacuation training baby on a stretcher

Innovative NICU training lauded as ‘best article’ by national journal

NICU evacuation training baby on a stretcher

“Fires, tornadoes and other natural disasters are outside of our team’s control. But it is within our team’s control to train neonatal intensive care unit (NICU) staff to master this necessary skill,” says Lisa Zell, BSN, a clinical educator at Children’s National Hospital.

Research into how to create a robust emergency evacuation preparedness plan and continually train staff that was led by Zell was lauded by editors of The Journal of Perinatal & Neonatal Nursing. The journal named the study the “best article” for the neonatal section that the prestigious journal published in 2018-19.

“We all hope for the best no matter what the situation, but we also need to extensively plan for the worse,” says Billie Lou Short, M.D., chief of the division of neonatology at Children’s National. “I’m proud that Lisa Zell and co-authors received this much-deserved national recognition on behalf of the nation’s No. 1 NICU.”

Educators worked with a diverse group within Children’s National to design and implement periodic evacuation simulations.

In addition to Zell and Lamia Soghier, M.D., FAAP, CHSE, Children’s National NICU medical unit director, study co-authors include Carmen Blake, BSN; Dawn Brittingham, MSN; and Ann-Marie Brown, MSN.

Read more
View photos showing how disaster training occurs at Children’s National

celiac testimony on Capitol Hill

Talking on Capitol Hill about the need for increased celiac research funding

celiac testimony on Capitol Hill

Celiac Disease Program leaders joined policymakers, experts and families to make the case for additional celiac disease research funding on Capitol Hill in January 2020.

Federal funding for celiac disease has been virtually nonexistent, despite the fact that celiac is one of the most common genetic autoimmune disorders. The lack of funding directly translates into a shortage of research into better understanding celiac disease, its mechanisms and potential treatment alternatives to the strict diet that is the current standard of care.

In January, the leaders of the Celiac Disease Program at Children’s National Hospital, Dr. Benny Kerzner and Vanessa Weisbrod, gave oral testimony as part of a congressional briefing hosted by Congressman Dwight Evans (PA) on the need for significant research funding in this area. Also presenting were Jon and Leslie Bari, founders of Celiac Journey and Gluten Free Finds PA, who are parents of a child with celiac, as well as Dr. Arjunot Singh, attending physician in gastroenterology at Children’s Hospital of Philadelphia.

The briefing focused on how federal funding for celiac research could bring multi-center, large scale research projects to the study of the condition for the first time, with the goal of accomplishing the following:

  • Better understanding the immunological basis of the disease
  • Identifying celiac disease’s triggers and how to prevent them
  • Exploring potential treatments and/or cures, including those that might inhibit onset of the disease or induce tolerance of the gluten protein

In their testimony, Kerzner and Weisbrod noted that the only current treatment for celiac disease is a strict, lifelong gluten-free diet, and that there is no medication or cure for the condition. Parents and children alike struggle with managing the diet and coping with the persistent fear of increased mortality from other conditions that commonly co-occur with celiac disease, including non-Hodgkins lymphoma, liver disease, small bowel cancers and other autoimmune conditions.

Weisbrod also spoke about an existing collaborative research and care infrastructure called the Celiac Kids Network – an informal consortium of 12 pediatric hospitals with celiac programs that research together, develop tools to measure gluten exposure risks, share best practices and collaborate on difficult cases. She made the case that should federal funding significantly increase, infrastructure is already in place to manage and oversee the types of research collaborations that could really make a difference for children.

“We dream of establishing a learning health system with a coordinated patient registry that is representative of all patients with celiac disease no matter where in the country they live,” Weisbrod concluded in her testimony. “A national biorepository of patient blood and tissue samples would enable researchers from every medical discipline to join us in understanding how celiac disease affects kids. We could evaluate the biological and psychological outcomes of patients to look for interventions to improve quality of life. The sky is the limit. But to do this, we need big funding to collect big data, to make big differences.”

Vote for STAT Madness

It’s a three-peat! Children’s National again competes in STAT Madness

Vote for STAT Madness

Children’s National Hospital collects patients’ blood, extracts T-cells and replicates them in the presence of specific proteins found on cancer cells which, in essence, teaches the T-cells to target specific tumor markers. Training the T-cells, growing them to sufficient quantities and ensuring they are safe for administration takes weeks. But when patients return to the outpatient clinic, their T-cell infusion lasts just a few minutes.

For the third consecutive year, Children’s National was selected to compete in STAT Madness, an annual bracket-style competition that chooses the year’s most impactful biomedical innovation by popular vote. Children’s entry, “Immunotherapy of relapsed and refractory solid tumors with ex vivo expanded multi-tumor associated antigen specific cytotoxic T lymphocytes,” uses the body’s own immune system to attack and eliminate cancer cells in pediatric and adult patients with solid tumor malignancies.

In 2018, Children’s first-ever STAT Madness entry advanced through five brackets in the national competition and, in the championship round, finished second. That innovation, which enables more timely diagnoses of rare diseases and common genetic disorders, helping to improve kids’ health outcomes around the world, also was among four “Editor’s Pick” finalists, entries that spanned a diverse range of scientific disciplines.

An estimated 11,000 new cases of pediatric cancer were diagnosed in children 14 and younger in the U.S. in 2019. And, when it comes to disease, cancer remains the leading cause of death among children, according to the National Institutes of Health. An enterprising research team led by Children’s National faculty leveraged T-cells – essential players in the body’s immune system – to treat pediatric and adult patients with relapsed or refractory solid tumors who had exhausted all other therapeutic options.

“We’re using the patient’s own immune system to fight their cancer, rather than more traditional chemotherapy drugs,” says Catherine M. Bollard, M.D., director of the Center for Cancer & Immunology Research at Children’s National and co-senior author of the study. “It’s more targeted and less toxic to the patient. These T-cells home in on any cancer cells that might be in the body, allowing healthy cells to continue to grow,” Dr. Bollard adds.

That means patients treated in the Phase I, first-in-human trial didn’t lose their hair and weren’t hospitalized for the treatment. After a quick clinical visit for their treatment, they returned to normal activities, like school, with good energy levels.

“With our specially trained T-cell therapy, many patients who previously had rapidly progressing disease experienced prolonged disease stabilization,” says Holly J. Meany, M.D., a Children’s National oncologist and the study’s co-senior author. “Patients treated at the highest dose level showed the best clinical outcomes, with a six-month, progression-free survival of 73% after tumor-associated antigen cytotoxic T-cell (TAA-T) infusion, compared with 38% with their immediate prior therapy.”

The multi-institutional team published their findings from the study online July 29, 2019, in the Journal of Clinical Oncology.

“Our research team and our parents are delighted that some patients treated in our study continue to do well following T-cell therapy without additional treatment. In some cases, two years after treatment, patients do not appear to have active disease and are maintaining an excellent quality of life,” says Amy B. Hont, M.D., the study’s lead author. “One of these was a patient whose parents were told his only other option was palliative care. Our innovation gives these families new hope,” Dr. Hont adds.

The 2020 STAT Madness #Core64 bracket opened March 2, and the champion will be announced April 6.

In addition to Drs. Hont, Meany and Bollard, Children’s National co-authors include C. Russell Cruz, M.D., Ph.D., Robert Ulrey, MS, Barbara O’Brien, BS, Maja Stanojevic, M.D., Anushree Datar, MS, Shuroug Albihani, MS, Devin Saunders, BA, Ryo Hanajiri, M.D., Ph.D., Karuna Panchapakesan, MS, Payal Banerjee, MS, Maria Fernanda Fortiz, BS, Fahmida Hoq, MBBS, MS, Haili Lang, M.D., Yunfei Wang, DrPH, Patrick J. Hanley, Ph.D., and Jeffrey S. Dome, M.D., Ph.D.; and Sam Darko, MS, National Institute of Allergy and Infectious Diseases.

Financial support for the research described in this post was provided by the Children’s National Hospital Heroes Gala, Alex’s Army Foundation, the Children’s National Board of Visitors and Hyundai Hope on Wheels Young Investigator Grant to Support Pediatric Cancer Research, the Children’s National Research Institute Bioinformatics Unit, the Clinical and Translational Science Institute and the National Institutes of Health under award No. UL1-TR001876.

newborn in incubator

A bronchopulmonary dysplasia primer to guide clinicians and researchers

newborn in incubator

Six months in the writing, the “Bronchopulmonary Dysplasia Primer” published recently by Nature Reviews will be the gold standard review on this topic for years to come.

The term bronchopulmonary dysplasia, or BPD, was first coined in 1967 to describe a chronic lung disease of preterm newborns after treatment with supplemental oxygen via mechanical ventilation in an effort to save their lives. Back then, infants had 50-50 odds of surviving.

In the intervening years, survival has improved and the characteristics of BPD have evolved. Now, BPD is the most common complication of preterm birth for infants born at fewer than 28 weeks’ gestation, as more and more newborns survive premature birth. Hence, the primer.

“The contributing authors are some of the biggest thinkers on this topic,” says Robin H. Steinhorn, M.D., senior vice president, Center for Hospital-Based Specialties, at Children’s National Hospital and author of the section about BPD diagnosis, screening and prevention. “This document will guide clinical education and investigators in the field of BPD. I anticipate this will be the definitive review article on the subject for the next several years.”

Gestational age and low birth weight remain the most potent predictors of BPD. Some 50,000 extremely low gestational age newborns are born each year in the U.S. About 35% will develop some degree of BPD, according to the primer authors.

These newborns are introduced to life outside the womb well before their lungs are ready. Indeed, the pulmonary surfactants needed for normal lung function – a complex mixture of phospholipids that reduce surface tension within the lungs – don’t differentiate until late in pregnancy. Infants who persistently need respiratory support after the 14th day of life are at the highest risk of being diagnosed with BPD at 36 weeks, the coauthors note.

A number of complicating factors can come into play, including maternal diet; fetal exposure to maternal smoking and infection; structural issues such as pre-eclampsia; acute injury from mechanical ventilation and supplemental oxygen; as well as the body’s halting efforts to repair injured, inflamed lung tissue.

“The good news is the number of the smallest and youngest preterm infants who survive extreme preterm birth has steadily increased. Neonatal intensive care units, like our award-winning NICU, now routinely care for babies born at 22 weeks’ gestation,” Dr. Steinhorn says.

Treatment strategies include:

  • Reducing exposure to intubation and ventilation.
  • Leveraging respiratory stimulants, like caffeine.
  • Postnatal steroid therapy.

“Children’s National Hospital is the only center in our immediate region that provides comprehensive care for infants and children with severe BPD,” Dr. Steinhorn adds. “As the population of vulnerable and fragile infants has grown, we have invested in the equipment and the personnel – including at the Hospital for Sick Children Pediatric Center (HSC) – to create a very safe and supportive environment that improves survival and quality of life.”

Some preterm infants spend their first 9 to 10 months of life at Children’s National, and their days are filled with concentrated physical, occupational and speech therapy, as well as music and play therapy to hasten their rehabilitation.

Once their medical condition stabilizes, they transition to HSC to focus more intently on rehabilitation.

“We see HSC as filling a very important role in their care. When our children graduate to HSC, they are going for ongoing care of their lung disease, but also their ongoing rehabilitation. At HSC, they focus on creating the most normal life that we can possibly create and, over time, that is a life free of ventilators and tracheostomy tubes.”

In addition to Dr. Steinhorn, BPD Primer co-authors include Bernard Thébaud, Children’s Hospital of Eastern Ontario; Kara N. Goss, University of Wisconsin-Madison; Matthew Laughon, The University of North Carolina at Chapel Hill; Jeffrey A. Whitsett and Alan H. Jobe, Cincinnati Children’s Hospital Medical Center; Steven H. Abman, Children’s Hospital Colorado;  Judy L. Aschner, Joseph M. Sanzari Children’s Hospital; Peter G. Davis, The Royal Women’s Hospital; Sharon A. McGrath- Morrow, Johns Hopkins University School of Medicine; and Roger F. Soll, University of Vermont.

Financial support for the research described in this post was provided by the National Institutes of Health under grant Nos. U01HL122642, U01HL134745, RO1HL68702, R01HL145679, U01HL12118-01 and K24 HL143283; the Australian National Health and Medical Research Council; the Canadian Institute for Health Research; Stem Cell Network and the Ontario Institute for Regenerative Medicine.

Dr. Lauri Tosi examines a patient

Building patient-centered outcomes research in osteogenesis imperfecta

Dr. Lauri Tosi examines a patient

Children’s orthpaedic surgeon Laura Tosi, M.D., is the co-lead on a program to improve patient-centered outcomes research and education in osteogenesis imperfecta that recently received a Eugene Washington Engagement Award of $250,000 from the Patient-Centered Outcomes and Research Institute (PCORI).

Children’s orthpaedic surgeon Laura Tosi, M.D., is the co-lead on a program to improve patient-centered outcomes research and education in osteogenesis imperfecta (OI) that recently received a Eugene Washington Engagement Award of $250,000 from the Patient-Centered Outcomes and Research Institute (PCORI). Dr. Tosi serves as project co-lead alongside colleagues Tracy Hart, project lead, from the Osteogenesis Imperfecta Foundation (OIF) and Bryce Reeve, Ph.D., co-project lead, director of the Center for Health Measurement at Duke University.

The project, which will be housed at the Osteogenesis Imperfecta Foundation, will run for two years and seeks to:

  • Create a community of stakeholders (patients/caregivers/clinicians/researchers) who are trained or training in patient-centered outcomes research, with specific attention to priority topics identified by the OI community.
  • Expand communications and education strategies related to patient-centered outcomes research to enhance the care of the OI community.
  • Establish and extend the capacity among patients, caregivers, clinicians and researchers in OI to participate in both patient-centered outcomes research and comparative effectiveness activities.
  • Develop an OI-specific toolkit focused on disseminating evidence-based clinical care recommendations to stakeholders and care providers, based on sustainable input from the OI community.
  • Extended the reach of these activities to support other rate bone disease communities.

Osteogenesis imperfecta is a group of genetic disorders causing connective tissue dysfunction and bone fragility. It is the most common of nearly 450 rare skeletal disorders and affects an estimated 25,000 to 50,000 people in the U.S. Collecting the patient’s perspective about natural history, clinical best practices, quality of life and research priorities is challenging because, like so many rare diseases, the affected population is relatively small and  geographically dispersed.

“We hope this project will give us the ability to develop a set of best practices for care and research based on research that incorporates the patient’s point-of-view,” says Dr. Tosi. “I’m excited to work with this team and begin to change how we think about and care for OI patients and their families.”

insulin and syringes

Diabetes clinic helps undocumented children manage their chronic condition

insulin and syringes

A diabetes clinic gives undocumented children with diabetes access to the care they need to maintain their health with this chronic condition.

In 2018, Jennifer Boughton, a social worker at Children’s National Hospital, came up with the idea of starting a diabetes clinic for patients whose immigration status prevented them from qualifying for insurance. The idea came about after undocumented children were arriving in the emergency department with high blood sugar and dangerously elevated ketone levels.

Through donations and the employees, who volunteer their time, Boughton’s idea became a reality. In January of 2019, the diabetes center held its first access clinic. The clinic has been open every three months since then for undocumented children with diabetes.

Flyers for the clinic are sent to local schools and organizations to help recruit patients.

In the first year, the patient volume has quadrupled and the hbA1c levels have decreased for patients who attend.

Read more about the Diabetes Access Clinic here.

 

electronic cigarette dispenser with different flavors of nicotine

Extreme difficulty breathing and swallowing linked to teen’s vaping?

electronic cigarette dispenser with different flavors of nicotine

After a teen was transferred to Children’s National Hospital suffering from severe difficulty breathing and swallowing, a multidisciplinary team continued the detective work and surmises that vaping was to blame for her unusual symptoms.

A teenage girl with no hint of prior asthma or respiratory illness began to feel hoarseness in her throat and a feeling that she needed to clear her throat frequently. Within a few weeks, her hoarseness and throat-clearing worsened with early morning voice loss and feeling as if food were lodged in her throat. She started having trouble swallowing and began to avoid food all together.

Her pediatrician prescribed loratadine for suspected allergies to no avail. Days later, an urgent care center prescribed a three-day course of prednisone. For a few days, she felt a little better, but went back to feeling like she was breathing “through a straw.” After going to an emergency room with acute respiratory distress and severe difficulty swallowing, staff tried intravenous dexamethasone, ampicillin/sulbactam, and inhaled racemic epinephrine and arranged for transfer.

When she arrived at Children’s National Hospital, a multidisciplinary team continued the detective work with additional testing, imaging and bloodwork.

Examining her throat confirmed moderate swelling and a partially obstructed airway draped with thick chartreuse-colored mucus. The teen had no history of an autoimmune disorder, no international travel and no exposure to animals. She had no fever and had received all her scheduled immunizations.

“With epiglottitis – an inflammation of the flap found at the base of the tongue that prevents food from entering the trachea – our first concern is that an underlying infection is to blame,” says Michael Jason Bozzella, D.O., MS, a third-year infectious diseases fellow and lead author of the case report published Feb. 5, 2020, in Pediatrics. “We tested her specimens in a number of ways for a host of respiratory pathogens, including human rhino/enterovirus, respiratory syncytial virus, influenza, Epstein-Barr virus, Streptococcus and more. All negative. We also looked for more atypical infections with bacteria, like Arcanobacterium, Mycoplasma and Gonorrhea. Those were all negative as well,” Dr. Bozzella adds.

She slowly improved during a seven-day initial hospital stay, though soon returned for another six-day hospital stay after it again became excruciatingly painful for her to swallow.

Every throat culture and biopsy result showed no evidence of fungal, bacterial or viral infection, acid-fast bacilli or other malignancy. But in speaking with doctors, the teen had admitted to using candy-and fruit-flavored e-cigarettes three to five times with her friends over the two months preceding her symptoms. The last time she vaped was two weeks before her unusual symptoms began.

According to the Centers for Disease Control and Prevention, 2,668 people in the U.S. have been hospitalized for e-cigarette or vaping product use-associated lung injury, as of Jan. 14, 2020. The Children’s National case report’s authors say the increasing use of vaping products by teenagers highlights the potential for unknown health risks to continue to grow.

“This teenager’s use of e-cigarettes is the most plausible reason for this subacute epiglottitis diagnosis, a condition that can become life-threatening,” says Kathleen Ferrer, M.D., a hospitalist at Children’s National and the case report’s senior author. “This unusual case adds to a growing list of toxic effects attributable to vaping. While we normally investigate infectious triggers, like Streptococci, Staphylococci and Haemophilus, we and other health care providers should also consider e-cigarettes as we evaluate oro-respiratory complaints.”

In addition to Drs. Bozzella and Ferrer, Children’s National case report co-authors include Matthew Allen Magyar, M.D., a hospitalist; and Roberta L. DeBiasi, M.D., MS, chief of the Division of Pediatric Infectious Diseases.

people sitting in a circle holding hands

Religiousness linked to improved quality of life for people with HIV

people sitting in a circle holding hands

Adults living with HIV in Washington, D.C., were more likely to feel higher levels of emotional and physical well-being if they attended religious services regularly, prayed daily, felt “God’s presence,” and self-identified as religious or spiritual.

Adults living with HIV in Washington, D.C., were more likely to feel higher levels of emotional and physical well-being if they attended religious services regularly, prayed daily, felt “God’s presence,” and self-identified as religious or spiritual, according to research published online Jan. 29, 2020, in Psychology of Religion and Spirituality. By contrast, patients living with HIV who had the lowest levels of quality of life and more mental health challenges were privately religious, potentially eschewing organized religion due to fears about being stigmatized or ostracized.

“These findings are significant because they point to the untapped potential of encouraging patients living with HIV who are already religious to attend religious services regularly.  Scientific evidence suggests that religions that present God as all-powerful, personal, responsive, loving, just and forgiving make a difference in health-related quality of life. By contrast, belief systems and religions that see God as punishing, angry, vengeful and distant and isolate members from their families and the larger community do not have health benefits or contribute to health-related quality of life. People who identify as spiritual also benefit from improved overall health-related quality of life,” says Maureen E. Lyon, Ph.D., FABPP, a clinical health psychologist at Children’s National Hospital, and senior study author.

“In general, patients living with HIV have reported that they wished their health care providers acknowledged their religious beliefs and spiritual struggles. Additional research is needed to gauge whether developing faith-based interventions or routine referrals to faith-based programs that welcome racial and sexual minorities improve satisfaction with treatment and health outcomes,” Lyon adds.

More than 1 million people in the U.S. live with HIV, and in 2018, 37,832 people received an HIV diagnosis in the U.S., according to the Centers for Disease Control and Prevention (CDC). In 2017, the Washington, D.C., region recorded one of nation’s highest rates of new cases of HIV: 46.3 diagnoses per 100,000 people, according to the CDC.

A research team that includes current and former Children’s National faculty wanted to learn more about the degree of religiousness and spirituality reported by people living with HIV and the interplay between religion and health-related quality of life. They recruited patients to participate in a clinical trial about family-centered advance care planning and enrolled 223 patient/family dyads in this study.

Fifty-six percent of patients were male. Eighty-six percent were African American, and their mean age was 50.8. Seventy-five percent were Christian.

The researchers identified three distinct classes of religious beliefs:

  • Class 1, the highest level of religiousness/spirituality, applied to people more likely to attend religious services in person each week, to pray daily, to “feel God’s presence” and to self-identify as religious and spiritual. Thirty-five percent of study participants were Class 1 and tended to be older than 40.
  • Class 2 applied to privately religious people who engaged in religious activities at home, like praying, and did not attend services regularly. Forty-seven percent of study participants were Class 2.
  • Class 3 participants self-identified as spiritual but were not involved in organized religion. Nearly 18 percent of study participants were Class 3, the lowest overall level of religiousness/spirituality.

Class 1 religiousness/spirituality was associated with increased quality of life, mental health and improved health status.

“Being committed to a welcoming religious group provides social support, a sense of identity and a way to cope with stress experienced by people living with HIV,” Lyon says. “We encourage clinicians to capitalize on patients’ spiritual beliefs that improve health – such as prayer, meditation, reading spiritual texts and attending community events – by including them in holistic treatment programs in a non-judgmental way.”

What’s more, the research team encourages clinicians to appoint a member of the team who is responsible for handling religiousness/spirituality screening and providing referrals to welcoming hospital-based chaplaincy programs or community-based religious groups.

“This is particularly challenging for HIV-positive African American men who have sex with men, as this group faces discrimination related to race and sexual orientation. Because HIV infection rates are increasing for this group, this additional outreach is all the more important,” she adds.

In addition to Lyon, study co-authors include Biostatistician Jichuan Wang, Ph.D., and Yao I. Cheng, MS., both of Children’s National; and Lead Author Katherine B. Grill, Ph.D., the former clinical coordinator for this randomized clinical trial who is currently an adjunct professor at the California Institute of Integral Studies.

Financial support for research described in this post was provided by the National Institutes of Health under award Nos. R01NR014-052-05 and UL1RR031988.

 

Pediatric angiography

Congenital heart disease more deadly in low-income countries

Pediatric angiography

Even though mortality from congenital heart disease (CHD) has declined over the last three decades as diagnosis and treatments have advanced, the chances for a child to survive a CHD diagnosis significantly differs based on the country where he or she is born.

This eye-opening finding is drawn from the first comprehensive study of congenital heart disease across 195 countries, prepared using data from the Global Burden of Diseases, Injuries and Risk Factors Study 2017 (GBD), and recently published in The Lancet.

“Previous congenital heart estimates came from few data sources, were geographically narrow and did not evaluate CHD throughout the life course,” write the authors, known collectively as the 2017 GBD Congenital Heart Disease Collaborators. Co-lead author Meghan D. Zimmerman, M.D., worked on the study while completing her pediatric cardiology and American Heart Association Global Health Fellowships at Children’s National Hospital, and two pediatric cardiologists from Children’s National, Cardiology Associate Chief Craig Sable, M.D., and Gerard Martin, M.D., medical director of Global Services, provided leadership and oversight of this paper. The remaining collaborators are from more than 45 institutions around the world, spanning cardiology, public health and schools of medicine on every continent.

This is the first time the GBD study data was used along with all available data sources and previous publications – making it the most comprehensive study on congenital heart disease burden to date. Key differences between this study and prior estimates include:

  • Anatomic groupings of CHD by type, rather than simply categorized as moderate, severe or critical.
  • Inclusion of new data sources, including data from screening programs, congenital registries, administrative data and data sources in mortality and survival.
  • A control mechanism to account for cases of CHD that remit on their own to reduce the risk of overestimating prevalence.
  • Inclusion of all cases of congenital heart disease, including those with chromosomal or genetic anomalies such as Trisomy 21 that often co-occur.

This more comprehensive data set led to findings that showed lower predicted long-term survival, higher remission, and lower prevalence than previous studies that extrapolated evidence from studies of high-income countries. However, it also means these new estimates are a more accurate representation of the current global state of affairs. Overall, the study found:

  • A 34.5% decline in deaths from congenital disease between 1990 to 2017.
  • Nearly 70% of deaths caused by CHD in 2017 (180,624) were in infants less than one year old.
  • Most CHD deaths occurred in countries within the low and low-middle socio-demographic index (SDI) quintiles.
  • Mortality rates get lower as a country’s SDI rises.
  • Birth prevalence of CHD was not related to a country’s socio-demographic status, but overall prevalence was much lower in the poorest countries of the world. This is because children in these countries do not have access to life saving surgical services.
  • Nearly 12 million people are currently living with CHD globally, 18.7% more than in 1990.
  • The burden of CHD is not fully realized by just looking at prevalence and mortality. The measure “Years of Life Lost” provides deeper insight into the staggering burden of CHD, taking into account both absolute mortality and age at death.

“In high income countries like the United States, we diagnose some heart conditions prenatally during the 20-week ultrasound,” says Gerard Martin, M.D., a pediatric cardiologist at Children’s National Hospital who contributed to the study. “We catch others right after birth with a pulse oximetry screening for critical congenital heart disease. We can operate to correct a critical issue within the first week of life. And now our CHD kids are growing and thriving through adulthood and having families of their own.”

“For children born in middle- and low-income countries, these data draw stark attention to what we as cardiologists already knew from our own work in these countries – the lack of diagnostic and treatment tools leads to lower survival rates for children born with CHD,” adds Craig Sable, M.D., associate chief of cardiology at Children’s National, another primary contributor. “This is one of the most significant publications I have been a part of as it highlights the substantial loss of life to CHD in infancy around the globe.”

The authors write, “The UN has prioritized reduction of premature deaths from heart disease, but to meet the target of ‘ending preventable deaths of newborns and children under 5 years of age,’ health policy makers will need to develop specific accountability measures that address barriers and improve access to care and treatment.”

The study also includes a 400-page appendix breaking down each area by type of congenital anomaly, world region and country.

T2-Weighted Magnetic Resonance (MR) Imaging Brain Segmentation

Maternal mental health alters structure and biochemistry of developing fetal brain

Even when pregnant women have uncomplicated pregnancies and high socioeconomic status, when they experience elevated anxiety, stress or depression these prenatal stressors can alter the structure of the developing fetal brain and disrupt its biochemistry, according to Children’s National Hospital research published online Jan. 29, 2020, in JAMA Network Open.

The Children’s National research findings “have enormous scientific, clinical and public health implications,” Charles A. Nelson III, Ph.D.,  Boston Children’s Hospital, writes in a companion editorial.

“Previously we found that 65% of pregnant women who received a diagnosis of fetal congenital heart disease had elevated levels of stress. It’s concerning but not surprising that pregnant women who wonder if their baby will need open heart surgery would feel stress,” says Catherine Limperopoulos, Ph.D., director of the Center for the Developing Brain at Children’s National and the study’s senior author. “In this latest study, we ran the same panel of questionnaires and were surprised to find a high proportion of otherwise healthy pregnant women whose unborn babies are doing well also report high levels of stress.”

Anxiety and depression are the most common mental health problems during pregnancy. To learn more about the implications for the developing fetal brain, the Children’s National research team recruited 119 healthy volunteers with low-risk pregnancies from obstetric clinics in Washington, D.C., from Jan. 1, 2016, to April 17, 2019. The women’s mean age was 34.4 years old. All were high school graduates, 83% were college graduates, and 84% reported professional employment.

T2-Weighted Magnetic Resonance (MR) Imaging Brain Segmentation.

T2-Weighted Magnetic Resonance (MR) Imaging Brain Segmentation. Segmentation results of total brain (orange), cortical gray matter (green), white matter (blue), deep gray matter (brown), brainstem (yellow), cerebellum (light blue), left hippocampus (purple) and right hippocampus (red) on a 3-Dimensional reconstructed T2-weighted MR image of a fetus at 26.4 gestational weeks. The hippocampus plays a central role in memory and behavioral inhibition and contains high concentrations of corticosteroid receptors and, thus, this brain region is sensitive to stress. Credit: JAMA Network Open.

The team performed 193 fetal brain magnetic resonance imaging (MRI) sessions between 24-40 weeks gestation and measured the volume of the total fetal brain as well as the cortical gray matter, white matter, deep gray matter, cerebellum, brainstem and hippocampus volumes. On the same day as their MRI visit, the pregnant women completed validated questionnaires to measure maternal stress, anxiety and depression, answering questions such as “how do you feel right now,” “how do you generally feel” as well as the degree of stressful feelings they experienced the month prior.

Of the pregnant women in the study:

  • 27% tested positive for stress
  • 26% tested positive for anxiety
  • 11% tested positive for depression
  • Maternal anxiety and stress were associated with increased fetal cortical gyrification
  • Elevated maternal depression was associated with decreased creatine and choline levels in the fetal brain
  • Maternal stress scores decreased with increasing gestational age, while anxiety and depression did not

“We report for the first time that maternal psychological distress may be associated with increased fetal local gyrification index in the frontal and temporal lobes,” says Yao Wu, Ph.D., a research associate working with Limperopoulos at Children’s National and the study’s lead author. “We also found an association with left fetal hippocampal volume, with maternal psychological distress selectively stunting the left hippocampal volumetric growth more than the right. And elevated maternal depression was associated with decreased creatine and choline levels in the fetal brain,” Wu adds.

Late in pregnancy – at the time these women were recruited into the cohort study – the fetal brain grows exponentially and key metabolite levels also rise. Creatine facilitates recycling of adenosine triphosphate, the cell’s energy currency. Typically, levels of this metabolite rise, denoting rapid changes and higher cellular maturation; creatine also is known to support cognitive function. Choline levels also typically rise, marking cell membrane turnover as new cells are generated and support memory, mental focus and concentration.

“These women were healthy, and of high socioeconomic status and educational level, leading us to conclude that the prevalence of prenatal maternal psychological distress may be underestimated,” Limperopoulos adds. “While stress is an everyday reality for most of us, this is different because elevated stress during pregnancy can alter fetal brain programming. Our findings underscore the critical need to universally screen all pregnant women for prenatal psychological distress, even young mothers whose pregnancies wouldn’t otherwise raise red flags.”

In addition to Limperopoulos and Wu, Children’s National study co-authors include Yuan-Chiao Lu, Ph.D., research associate; Marni Jacobs, Ph.D., biostatistician; Subechhya Pradhan, Ph.D., research faculty; Kushal Kapse, MS, staff engineer; Li Zhao, Ph.D., research faculty; Nickie Niforatos-Andescavage, M.D., neonatologist; Gilbert Vezina, M.D., director of the neuroradiology program; and Adré  J. du Plessis, M.B.Ch.B., director, Fetal Medicine Institute. Research coordinators Catherine Lopez, MS, Kathryn Lee Bannantine, BSN, and Jessica Lynn Quistorff, MPH, assisted with subject recruitment.

Financial support for the research described in this post was provided by the National Institutes of Health under grant No. RO1 HL116585-01 and the Thrasher Research Fund under Early Career award No. 14764.

Journal Reference:
Yao Wu, Yuan-Chiao Lu, Marni Jacobs, Subechhya Pradhan, Kushal Kapse, Li Zhao, Nickie Niforatos-Andescavage, Gilbert Vezina, Adré J. du Plessis, Catherine Limperopoulos. “Association of prenatal maternal psychological distress with fetal brain growth, metabolism and cortical maturation,” JAMA Network Open, 3(1): e1919940, 2020

Schistosoma

Parasitic eggs trigger upregulation in genes associated with inflammation

Schistosoma

Of the 200 million people around the globe infected with Schistosomiasis, about 100 million of them were sickened by the parasite Schistosoma haematobium.

Of the 200 million people around the globe infected with Schistosomiasis, about 100 million of them were sickened by the parasite Schistosoma haematobium. As the body reacts to millions of eggs laid by the blood flukes, people can develop fever, cough and abdominal pain, according to the Centers for Disease Control and Prevention. Schistosomiasis triggered by S. haematobium can also include hematuria, bladder calcification and bladder cancer.

Despite the prevalence of this disease, there are few experimental models specifically designed to study it, and some tried-and-true preclinical models don’t display the full array of symptoms seen in humans. It’s also unclear how S. haematobium eggs deposited in the host bladder modulate local tissue gene expression.

To better understand the interplay between the parasite and its human host, a team led by Children’s National Hospital injected 6,000 S. haematobium eggs into the bladder wall of seven-week-old experimental models.

After four days, they isolated RNA for analysis, comparing differences in gene expression in various treatment groups, including those that had received the egg injection and experimental models whose bladders were not exposed to surgical intervention.

Using the Database for Annotation, Visualization and Integrated Discovery (DAVID) – a tool that helps researchers understand the biological meaning of a long list of genes – the team identified commonalities with other pathways, including malaria, rheumatoid arthritis and the p53 signaling pathway, the team recently presented during the American Society of Tropical Medicine and Hygiene 2019 annual meeting. Some 325 genes were differentially expressed, including 34 genes in common with previous microarray data.

“Of particular importance, we found upregulation in genes associated with inflammation and fibrosis. We also now know that the body may send it strongest response on the first day it encounters a bolus of eggs,” says Michael Hsieh, M.D., Ph.D., director of transitional urology at Children’s National, and the research project’s senior author. “Next, we need to repeat these experiments and further narrow the list of candidate genes to key genes associated with immunomodulation and bladder cancer.”

In addition to Dr. Hsieh, presentation co-authors include Lead Author Kenji Ishida, Children’s National; Evaristus Mbanefo and Nirad Banskota, National Institutes of Health; James Cody, Vigene Biosciences; Loc Le, Texas Tech University; and Neil Young, University of Melbourne.

Financial support for research described in this post was provided by the National Institutes of Health under award No. R01-DK113504.

clatharin cage viewed by electron microscopy

IPSE infiltrates nuclei through clathrin-mediated endocytosis

clatharin cage viewed by electron microscopy

IPSE, one of the important proteins excreted by the parasite Schistosoma mansoni, infiltrates human cellular nuclei through clathrin-coated vesicles, like this one.

IPSE, one of the important proteins excreted by the parasite Schistosoma mansoni infiltrates human cellular nuclei through clathrin-mediated endocytosis (a process by which cells absorb metabolites, hormones and proteins), a research team led by Children’s National Hospital reported during the American Society of Tropical Medicine and Hygiene 2019 annual meeting.

Because the public health toll from the disease this parasite causes, Schistosomiasis, is second only to malaria in global impact, research teams have been studying its inner workings to help create the next generation of therapies.

In susceptible host cells – like urothelial cells, which line the urinary tract – IPSE modulates gene expression, increasing cell proliferation and angiogenesis (formation of new blood vessels). On a positive note, neurons appear better able to fend off its nucleus-infiltrating ways.

“We know that IPSE contributes to the severity of symptoms in Schistosomiasis, which leads some patients to develop bladder cancer, which develops from the urothelial lining of the bladder. Our team’s carefully designed experiments reveal IPSE’s function in the urothelium and point to the potential of IPSE playing a therapeutic role outside of the bladder,” says Michael Hsieh, M.D., Ph.D., director of transitional urology at Children’s National and the research project’s senior author.

In addition to Dr. Hsieh, research co-authors include Evaristus Mbanefo, Ph.D.; Kenji Ishida, Ph.D.; Austin Hester, M.D.; Catherine Forster, M.D.; Rebecca Zee, M.D., Ph.D.; and Christina Ho, M.D., all of Children’s National; Franco Falcone, Ph.D., University of Nottingham; and Theodore Jardetzky, Ph.D., and Luke Pennington, M.D., Ph.D., candidate, both of Stanford University.

Financial support for research described in this post was provided by the National Institutes of Health under award No. R01-DK113504.

Hepatocytes

H-IPSE internalized by just a limited range of cells

Hepatocytes

A team led by Children’s National Hospital found that H-IPSE is internalized by just a limited range of cells, including hepatocytes.

Schistosoma mansoni is a parasite that hides out in snails, breaks free into waterways, and then infects humans, spending much of its life inside blood vessels, laying eggs and jeopardizing public health when those eggs are excreted in urine or feces. As parasitic diseases go, the ailment it causes, Schistosomiasis, is second only to malaria in global impact, according to the Centers for Disease Control and Prevention.

In order to elude the human host’s defenses, S. mansoni uses self-defense tactics that researchers are trying to better understand in order to outmaneuver the parasite. A research team led by Children’s National Hospital is trying to tease out the multiple steps that enable this parasite to reproduce and generate millions of eggs without killing its host.

The parasite’s eggs secrete a number of proteins, with IPSE as one of the most abundant, the team recently presented during the American Society of Tropical Medicine and Hygiene 2019 annual meeting. That protein binds immunoglobulin, which induces basophils and mast cells to release IL-4. After sequestering chemokines, H-IPSE infiltrates the cell nucleus (thus H-IPSE is called an infiltrin), modulating gene expression.

“H-IPSE tips the immune system balance, making it more likely to trigger a Th2 anti-inflammatory response,” says Michael Hsieh, M.D., Ph.D., director of transitional urology at Children’s National and the research project’s senior author. “It downregulates pro-inflammatory pathways, but we wanted to know more about which specific human cells it targets.”

Using Trypan Blue, a stain that selectively colors certain cells bright blue, they solved the mystery, finding that H-IPSE is internalized by just a limited range of cells. What’s more, some cell types, like urothelial cells and hepatocytes (the liver’s chief functioning cells, which activate innate immunity), are more susceptible than neurons, endothelial cells or immature dendritic cells.

In addition to Dr. Hsieh, presentation co-authors include Olivia Lamanna, Evaristus Mbanefo and Kenji Ishida, all of Children’s National; Franco Falcone, of University of Nottingham; and Theodore Jardetzky and Luke Pennington, of Stanford University.

Lataisia C. Jones on Mission Unstoppable

Getting to know the unstoppable Lataisia C. Jones, Ph.D.

Lataisia C. Jones on Mission Unstoppable

Children’s National Hospital neuroscientist Lataisia C. Jones, Ph.D., appears in the Jan. 18, 2020, edition of Mission Unstoppable, a Saturday morning show aired by CBS that spotlights cutting-edge women leaders in science, technology, engineering and math.

Budding neuroscientist Lataisia C. Jones, Ph.D., is unstoppable. For instance, using everyday items that families can pluck from their own kitchen cabinets, she walks kids through the steps of creating homemade lava lamps. In the process, the youngsters learn a bit of science, like the fact that oil and water do not mix provides the hypnotic magic behind their new lamps.

Jones’ infectious enthusiasm for science that Children’s National Hospital patients and families experience in person during weekly Young Scientist sessions she hosts will be shared nationwide as Jones appears in the Jan. 18, 2020, edition of “Mission Unstoppable.” The half-hour show aired by CBS on Saturday mornings is co-produced by the Geena Davis Institute on Gender in Media and spotlights cutting-edge women leaders in science, technology, engineering and math (STEM).

“I’m excited,” Jones says of the filming experience. “It’s going to be an amazing opportunity to show kids that there is a fun way of learning. This show is opening a lot of doors and a lot of eyes to the fact that science can be fun.”

Jones’ scientific inquiry focuses on the corpus callosum, a network of fibers centrally located in the middle of the brain that is responsible for transferring information from one lobe to another. Her current research leverages experimental models to better understand brain abnormalities associated with autism spectrum disorder. Or, as she tells CBS viewers, studying the brain helps the field better understand how information is processed in order for people to move, learn and think effortlessly.

Lataisia C. Jones on Mission Unstoppable

“I’m excited,” Jones says of the filming experience. “It’s going to be an amazing opportunity to show kids that there is a fun way of learning. This show is opening a lot of doors and a lot of eyes to the fact that science can be fun.”

In September 2019, Jones was selected to serve as an IF/THEN Ambassador by the American Association for the Advancement of Science, the world’s largest general scientific society, to inspire the next generation of women pursuing STEM careers. A postdoctoral fellow in the Center for Neuroscience Research lab run by Masaaki Torii, Ph.D., Jones now also serves as a role model for future scientists, connecting with middle school students in person, virtually and via the CBS network television show.

“A lot of my inspiration comes from individuals who I mentor, which also shows that I am learning as well. If I am able to teach science, translate it in different ways to different audiences, I am helping to fulfill my lifelong dream,” she adds. “I always say we all have an inner scientist.”

As the first African American to earn a Ph.D. from Florida State University’s College of Medicine, Department of Neuroscience, Jones has continued to acquire “first” experiences throughout her academic and professional career. But she’s also motivated to diversify the ranks of science to ensure she’s not the last.

“I am not the normal face you see in science,” she says. “Another reason for me to be stronger and to work harder and get more things done in science is so people who look like me know they can do the same things and know that they’re just as good.”

WATCH: Lataisia C. Jones, Ph.D., explains her research