Human Umbilical Cord Blood Cells Ameliorate Motor Deficits in Rabbits in a Cerebral Palsy Model.
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2015-01
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Cerebral palsy (CP) has a significant impact on both patients and society, but therapy is limited. Human umbilical cord blood cells (HUCBC), containing various stem and progenitor cells, have been used to treat various brain genetic conditions. In small animal experiments, HUCBC have improved outcomes after hypoxic-ischemic (HI) injury. Clinical trials using HUCBC are underway, testing feasibility, safety and efficacy for neonatal injury as well as CP. We tested HUCBC therapy in a validated rabbit model of CP after acute changes secondary to HI injury had subsided. Following uterine ischemia at 70% gestation, we infused HUCBC into newborn rabbit kits with either mild or severe neurobehavioral changes. Infusion of high-dose HUCBC (5 × 10(6) cells) dramatically altered the natural history of the injury, alleviating the abnormal phenotype including posture, righting reflex, locomotion, tone, and dystonia. Half the high dose showed lesser but still significant improvement. The swimming test, however, showed that joint function did not restore to naïve control function in either group. Tracing HUCBC with either MRI biomarkers or PCR for human DNA found little penetration of HUCBC in the newborn brain in the immediate newborn period, suggesting that the beneficial effects were not due to cellular integration or direct proliferative effects but rather to paracrine signaling. This is the first study to show that HUCBC improve motor performance in a dose-dependent manner, perhaps by improving compensatory repair processes.
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Drobyshevsky, Alexander, C Michael Cotten, Zhongjie Shi, Kehuan Luo, Rugang Jiang, Matthew Derrick, Elizabeth T Tracy, Tracy Gentry, et al. (2015). Human Umbilical Cord Blood Cells Ameliorate Motor Deficits in Rabbits in a Cerebral Palsy Model. Developmental neuroscience, 37(4-5). pp. 349–362. 10.1159/000374107 Retrieved from https://hdl.handle.net/10161/24632.
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Charles Michael Cotten
I am involved in 4 major areas of research:
1) Neuroprotection. Working with colleagues from Cell Therapies, we have added to Duke's experience participating in pivotal trials of hypothermia for term newborns with moderate to severe hypoxic-ischemic encephalopathy (HIE) by completing, with Duke CTSI support, phase I studies of autologous cord blood cells and allogeneic cord tissue derived mesenchymal stromal cells for these infants. and developing and currently leading a multicenter, double-blind randomized clinical trial of autologous cord blood cells or placebo in term infants with moderate or severe HIE.
2) Genomics. We at Duke have been in the NICHD Neonatal Research Network (NRN) since 2001. I led the NRN's development of an Anonymized DNA bank of samples collected from 1,000 extremely low birthweight infants, with phenotype information linked to the samples. This resource has been the basis for multiple candidate gene, and genome wide scan analysis, and has identified variants associated with severe retinopathy of prematurity and necrotizing enterocolitis. We partnered with the Vermont Oxford Network-Rady Genomics collaborative to bring 48 hour turnaround Whole Genome Sequencing to patients in the Duke Intensive Care Nursery, and are continuing work with Medical Genetics faculty to keep Duke at the forefront of testing the effectiveness of applied next-gen sequencing in the NICU.
3) New Technologies: I collaborated with Drs. David Millington from Duke and Vamsee Pamula (a Duke Pratt School graduate), from BAEBIES Inc, on prototype new technology devices for use in newborn screening for lysosomal storage disease as well as multiplex chips for screening for hyperbilirubinemia and related conditions, as well as working with Dr. Pamula and Dr. Michael Freemark (Peds Endocrinology) on screening panels for hypoglycemia and hypothyroidism, and with investigators from UAB on an Acute Kidney Injury panel. I continue active collaborations with Dr. Cynthia Toth and the DARSI lab in pediatric ophthalmology, and Pratt School investigators to develop and apply use of optical coherence tomography (OCT) for retinal imaging that will assess associations between retinal neurovascular development, brain development, and neurodevelopmental outcomes. We continue with a comparative trial of the value and effectiveness of utilization of OCT compared with the current standard indirect ophthalmoscopy for ROP screening in the NICU.
4)Microbiome in Micropreemies and health outcomes of periviable infants. I have worked with multiple epidemiology researchers to assess practice variation within our center, and within the Neonatal Research Network centers, to identify how variation in practice can influence outcomes, with a particular focus on antibiotic use. This work demonstrated strong associations between high empirical antibiotic use in infants with sterile cultures and subsequent morbidities and mortality. This discovery has led to strong collaborations and new initiatives by early career faculty leading studies of the evolving microbiome, leading to hypothesis generation re: the microbiome and optimal growth in extremely preterm infants.

Ronald Norman Goldberg
1. Perinatal asphyxia and neuroprotection - use of umbilical cord blood transfusion
2. Persistent Pulmonary hypertension - use of ethyl nitrite
3. The extremely low-birth-weight infant.
4. Newborn screening - use of digital microfluidics
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