Tag Archive for: Hoffman

Baby on ventilator

Autonomic markers of extubation readiness in premature infants

Baby on ventilator

Premature infants often require a breathing tube and mechanical ventilation as a mainstay in their therapy. It can be difficult to predict when these patients are ready to come off the ventilator (extubate).

Premature infants often require a breathing tube and mechanical ventilation as a mainstay in their therapy. It can be difficult to predict when these patients are ready to come off the ventilator (extubate). In a study from Pediatric Research, experts from Children’s National Hospital describe a model to predict the success of extubation using markers of autonomic tone (rest and digest versus fight or flight response). This study was led by Suma Hoffman, M.D., neonatologist and co-authored by Adré J. du Plessis, M.B.Ch.B., M.P.H., division chief of Prenatal Pediatrics Institute, Sarah Schlatterer, M.D., prenatal and neonatal neurologist, and Rathinaswamy B. Govindan, Ph.D.

The team deployed a study of 89 infants less than 28 weeks. Heart rate variability (HRV) metrics 24 hours prior to extubation were compared for those with and without extubation success within 72 hours. Receiver-operating curve analysis was conducted to determine the predictive ability of each metric and a predictive model was created.

Conclusions show that extubation success is associated with HRV. The authors demonstrate an autonomic imbalance with low sympathetic and elevated parasympathetic tone in those who failed. α1, a marker of sympathetic tone, was noted to be the best predictor of extubation success especially when incorporated into a clinical model.

Learn more about the study in Pediatric Research.

2019 National Maternal & Infant Health Summit

Children’s National Hospital participated in the second annual National Maternal & Infant Health Summit which highlights the District’s approaches to ensure the health of women, babies and families. From L to R are: Sahira Long, M.D., Jessica Nash, M.D., Hope Rhodes, M.D., and Kofi Essel, M.D.

Children’s National Hospital participated in the second annual National Maternal & Infant Health Summit hosted by Mayor Muriel Bowser. The summit was built upon highlighting the District’s approaches to ensure the health of women, babies and families, while also seeking to increase public awareness and interest on these topics.

“I enjoyed the summit as a mother, parent, physician and presenter,” said Jessica Nash, M.D., a pediatrician at Children’s National. “I am excited about the future conversations about infant and maternal mortality and the strides needed in the District.”

Nash led a panel titled “Maternal and Infant Mental Health Landscape: Taking Steps to Improve Practice and Policy,” with Hope Rhodes, MD, MPH, Dominique Charlot-Swilley, Ph.D., Leandra Godoy, Ph.D. and Sarah Barclay Hoffman. The discussion identified infant and early childhood mental health resources available in the District, the current state of infant and early childhood mental health, future potential policy changes and the collaborative model that places HealthySteps DC within a child’s primary care medical home.

Children’s National Hospital’s Saharia Long, M.D., discusses the local efforts to improve healthy food access for families.

The day-long summit covered many topics including The Role of Food Policy, Access, and Nutrition in Supporting Positive Outcomes for Families, which focused on national and local efforts to improve healthy food access for families, breastfeeding and babies’ first foods. The discussion was a direct response to feedback on the absence of information about breastfeeding and nutrition during last year’s summit. Sahira Long, M.D., and Kofi Essel, M.D.  served as panelists.

“According to the Centers for Disease Control and Prevention (CDC), low rates of breastfeeding add $3 billion a year to medical costs for mothers and children in the U.S.” said Dr. Long. “Breastfeeding is more than an infant feeding choice, it’s a public health decision due to its impact on maternal and infant health.”

The Maternal and Infant Health Summit brings together residents of the District, elected officials, health and education officials and community-based partners to collaborate and explore strategies that will improve perinatal health and address racial disparities in birth outcomes.

Biomarkers sensitive to daily corticosteroid use

Using a mass spectrometer, Yetrib Hathout, Ph.D., is able to quantify 3,000 to 4,000 proteins from a tissue sample to identify proteins associated with cancer.

Using a Somascan proteomics assay – which simultaneously analyzes 1,129 proteins in a small volume of serum – a team led by Children’s National Health System researchers identified 21 biomarkers that respond to corticosteroids taken daily by children with Duchenne muscular dystrophy (DMD) and inflammatory bowel disease.

Corticosteroids are commonly prescribed to treat inflammatory conditions. High daily doses of corticosteroids are considered the standard of care for DMD, a type of muscular dystrophy characterized by worsening muscle weakness that affects 1 in 3,600 male infants. However, depending on the age of the child and drug dosage, chronic use is associated with such side effects as changes in bone remodeling that can lead to stunted growth, weight gain, facial puffiness caused by fat buildup, mood changes, sleep disturbances, and immune suppression. The research team sought to identify blood biomarkers that could be leveraged to create a fast, reliable way to gauge the safety and efficacy of corticosteroid use by children. The biomarkers also could guide development of a replacement therapy with fewer side effects.

“Ten pro-inflammatory proteins were elevated in untreated patients and suppressed by corticosteroids (MMP12, IL22RA2, CCL22, IGFBP2, FCER2, LY9, ITGa1/b1, LTa1/b2, ANGPT2 and FGG),” Yetrib Hathout, Ph.D., Proteomic Core Director at Children’s National, and colleagues write in the journal Scientific Reports. “These are candidate biomarkers for anti-inflammatory efficacy of corticosteroids.”

The blood biomarkers sensitive to corticosteroids fit into three broad groups, according to the authors. The children taking corticosteroids were matched with children of the same age who had never taken the medicine. Five biomarkers significantly increased in this corticosteroid-naïve group and decreased in kids prescribed corticosteroids. The biomarkers generally were inflammatory proteins and included chemokine, insulin-like growth factor binding protein 2, and integrin alpha-I/beta-1 complex.

The second group of biomarkers included nine proteins associated with macrophage and T-lymphocytes that were significantly reduced in concentration in kids taking corticosteroids. According to the study, this finding hints at corticosteroids blunting the ability of the immune system’s most able fighters to respond to infection.

In the third group were five proteins that were significantly increased by corticosteroid treatment in DMD and included matrix metalloproteinase 3, carnosine dipeptidase 1, angiotensinogen, growth hormone binding protein, insulin, and leptin, a hormone linked to appetite.

What researchers learned with this study will help them more accurately design the next phase of the work, Hathout says.

“We are the first team to report a number of novel discoveries, including that growth hormone binding protein (GHBP) levels increase with corticosteroid use. This represents a candidate biomarker for stunted growth. In order to use that new information effectively in drug development, the next studies must corroborate the role of serum GHBP levels as predictors of diminished stature,” he adds. “The study finding that four adrenal steroid hormones are depressed in kids taking corticosteroids raises additional questions about the broader impact of adrenal insufficiency, including its role in the delay of the onset of puberty.”

This work was supported by National Institutes of Health grants (R01AR062380, R01AR061875, P50AR060836, U54HD071601, K99HL130035, and R44NS095423) and Department of Defense CDMRP program grant W81XWH-15-1-0265. Additional support was provided by AFM-Telethon (18259) and the Muscular Dystrophy Association USA (MDA353094).

Why subtle cellular changes can result in dramatically different genetic disorders

cellular_changes

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What’s Known
One single gene, lamin A/C, is to blame for a multitude of genetic disorders, such as premature aging and problems with nerves, the heart, and muscles. Uncertainties linger in the scientific and medical community about why subtle changes of this gene cause such dramatically different disorders, such as Emery-Dreifuss muscular dystrophy, a condition that can lead to progressive muscle weakness in childhood and heart problems by adulthood.

What’s New
The nuclear envelope is where attached regions are pulled from genetic circulation never to be used again. The process of attachment signals which parts of the genome the cell no longer considers useful. Discarding superfluous DNA keeps the cell focused on what matters more: Its future role. Proper cell differentiation hinges on “the coordinated execution of three key cellular programs,” the study authors write. Pluriopotency programs, which give primitive cells the remarkable ability to generate any cell type in the body, are inactivated. Exit from the cell cycle occurs, and cells stop dividing. Myogenesis is induced, ushering in formation of muscle tissue. Mutations in lamin A/C can disrupt this careful choreography with the cumulative effect of slowing exit from cell cycle, slowing exit from pluripotency programs, and poorly coordinating induction of terminal differentiation programs.

Questions for Future Research
Q: What are the regions of human genome that become attached to the nuclear envelope during the development of tissues other than muscle (such as fat, nerve, and heart)?
Q: Can medicines that influence epigenetic pathways help to reverse the inappropriate DNA-lamin associations in Emery-Dreifuss muscular dystrophy?
Q: Can the new knowledge of DNA-lamin associations during muscle cell differentiation help to inform stem cell therapies?

Source: “Laminopathies Disrupt Epigenomic Developmental Programs and Cell Fate.” J. Perovanovic, S. Dell’Orso, V.F. Gnochi, J. K. Jaiswal, V. Sartorelli, C. Vigouroux, K. Mamchaoui, V. Mouly, G. Bonne, and E. P. Hoffman. Science Translational Medicine. April 20, 2016.