Human Neural Stem Cells: Translational Research for Neonatal Hypoxic-Ischemic Brain Injury

Neonatal hypoxic-ischemic (HI) brain injury is a major cause of neonatal mortality and long-term neurodevelopmental disabilities. Although promising neuroprotective interventions have been studied, the current management of HI brain injury has been limited to supportive measures and induced hypothermia. In addition to engrafting, migrating toward the damage sites and differentiating into multiple lineages, multipotent neural stem/progenitor cells (NSPCs) also provide trophic/immunomodulatory factors and integrate into the host neurons upon implantation into an HI-injured brain. However, NSPC-based therapies have shown poor cell survival and integration, poor differentiation or restricted differentiation into the glial lineages. Furthermore, to achieve full functional recovery following brain injury, the optimization of cell therapy is needed to recapitulate the precise migration of stem cells to the region of interest and the neural rewiring present in the brain microenvironment. Therefore, the efficacy of NSPCs in the treatment of CNS injury is currently insufficient. Human NSPCs (hNSPCs) were isolated from the forebrain of an aborted fetus at 13 weeks of gestation with full parental consent and the approval of the Institutional Review Board of the Yonsei University College of Medicine. Here, to enhance the regenerative ability of hNSPCs in HI brain injury, cells were either pretreated with pharmacological agents or engineered to serve as vehicles for gene delivery. Furthermore, when combined with a poly (glycolic acid)-based synthetic scaffold, hNSPCs provide a more versatile treatment for neonatal HI brain injury. Finally, hNSPCs transfected with zinc-doped ferrite magnetic nanoparticles for controlling both cell migration and differentiation offer a simple and smart tool for cell-based therapies.ope

Glial Cell Line-derived Neurotrophic Factor-overexpressing Human Neural Stem/Progenitor Cells Enhance Therapeutic Efficiency in Rat with Traumatic Spinal Cord Injury

Spinal cord injury (SCI) causes axonal damage and demyelination, neural cell death, and comprehensive tissue loss, resulting in devastating neurological dysfunction. Neural stem/progenitor cell (NSPCs) transplantation provides therapeutic benefits for neural repair in SCI, and glial cell linederived neurotrophic factor (GDNF) has been uncovered to have capability of stimulating axonal regeneration and remyelination after SCI. In this study, to evaluate whether GDNF would augment therapeutic effects of NSPCs for SCI, GDNF-encoding or mock adenoviral vector-transduced human NSPCs (GDNF-or Mock-hNSPCs) were transplanted into the injured thoracic spinal cords of rats at 7 days after SCI. Grafted GDNFhNSPCs showed robust engraftment, long-term survival, an extensive distribution, and increased differentiation into neurons and oligodendroglial cells. Compared with Mock-hNSPC- and vehicle-injected groups, transplantation of GDNF-hNSPCs significantly reduced lesion volume and glial scar formation, promoted neurite outgrowth, axonal regeneration and myelination, increased Schwann cell migration that contributed to the myelin repair, and improved locomotor recovery. In addition, tract tracing demonstrated that transplantation of GDNF-hNSPCs reduced significantly axonal dieback of the dorsal corticospinal tract (dCST), and increased the levels of dCST collaterals, propriospinal neurons (PSNs), and contacts between dCST collaterals and PSNs in the cervical enlargement over that of the controls. Finally grafted GDNF-hNSPCs substantially reversed the increased expression of voltage-gated sodium channels and neuropeptide Y, and elevated expression of GABA in the injured spinal cord, which are involved in the attenuation of neuropathic pain after SCI. These findings suggest that implantation of GDNF-hNSPCs enhances therapeutic efficiency of hNSPCs-based cell therapy for SCI.ope

Evaluation of Newborn Infants with Prenatally Diagnosed Congenital Pulmonary Airway Malformation: A Single-Center Experience

Purpose Congenital pulmonary airway malformation (CPAM)－a rare developmental anomaly－affects the lower respiratory tract in newborns. By comparing the reliability of diagnostic tools and identifying predictive factors for symptoms, we provide comprehensive clinical data for the proper management of CPAM. Methods We reviewed the medical records of 66 patients with prenatally diagnosed CPAM delivered at Severance Children’s Hospital between January 2005 and July 2017. Results We enrolled 33 boys and 33 girls. Their mean gestational age and birth weight were 38.8 weeks and 3,050 g, respectively. Prenatal ultrasonography and postnatal radiography, lung ultrasonography, and chest computed tomography (CT) showed inconsistent findings. Chest CT showed superior sensitivity (100%) and positive predictive value (90%). Among the 66 patients, 59 had postnatally confirmed CPAM, three had pulmonary sequestration, one had cystic teratoma, and one had a normal lung. Of the 59 patients with CPAM, 21 (35%; mean age, 23.4 months) underwent surgery, including 15 who underwent video-assisted thoracoscopy. Twenty-five and 12 patients exhibited respiratory symptoms at birth and during infancy, respectively. Apgar scores and mediastinal shift on radiography were significantly associated with respiratory symptoms at birth. However, none of the factors could predict respiratory symptoms during infancy. Conclusion Radiography or ultrasonography combined with chest CT can confirm an unclear or inconsistent lesion. Apgar scores and mediastinal shift on radiography can predict respiratory symptoms at birth. However, symptoms during infancy are not associated with prenatal and postnatal factors. Chest CT combined with periodic symptom monitoring is important for diagnosing and managing patients with prenatally diagnosed CPAM and to guide appropriate timing of surgery.ope

Epidemiological changes in cytomegalovirus end-organ diseases in a developed country: A nationwide, general-population-based study

Background: Cytomegalovirus (CMV) can cause tissue-invasive diseases in various organs after primary infection or through reactivation of latent-to-lytic switch over a lifetime. The number of individuals who are at risk of CMV diseases, such as elderly or immunocompromised patients, is constantly increasing; however, recent epidemiological changes associated with CMV disease have not been fully evaluated. Methods: We used claims data of about 50 million individuals between 2010 and 2015 from the Korean Health Insurance Review and Assessment Service nationwide database. The code for CMV end-organ diseases in the 'Relieved Co-payment Policy' program matches the ICD-10 code of B25, except for congenital CMV infection and mononucleosis. A 628 cases of CMV and 3140 controls (without CMV disease), matched for age and sex, were selected from this dataset in order to evaluate the effect of adult CMV diseases on all-cause death. Results: The overall unadjusted incidence rate (IR) of CMV end-organ diseases was 0.52/100,000 individuals. The standardized IR, adjusted for age and sex, have continuously increased from 0.32/100,000 in 2010 to 0.75/100,000 in 2015. The overall unadjusted IR in adult population was highest in 70-79 years for six years (0.96/100,000). In the model adjusted for age, sex, immunocompromised status including solid-organ or hematopoietic stem cell transplant recipients, hematologic malignancies, and human immunodeficiency virus diseases, the hazard ratio of case group was 5.2 (95% confidence interval, 3.6-7.4) for all-cause mortality. Conclusion: Nationwide data indicates that CMV end-organ disease has steadily increased in the past six years and is associated with higher mortality.ope

Successful Treatment of Neonatal Pylorospasm with Intravenous Atropine

Pylorospasm is a cause of delayed gastric emptying in young infants. As in patients with hypertrophic pyloric stenosis, most pylorospasm patients present with projectile vomiting. However, unlike that in case of hypertrophic pyloric stenosis, no persistent pyloric stenotic lesions are present. As such, follow-up using serial gastrointestinal fluoroscopy or ultrasonography can be helpful in diagnosing patients with clinical signs of gastroparesis. Most cases can be treated conservatively, but some patients require pharmacologic treatment. Antispasmodics have been proposed as a treatment for pylorospasm, but their use in neonates and infants has rarely been reported. Herein, we present a case of pylorospasm diagnosed in the neonatal period and successfully treated with intravenous atropine.ope

Growth patterns of preterm infants in Korea

With advancements in neonatal care and nutrition, the postnatal growth of preterm infants has improved; however, it remains an issue. Accurate assessments of growth using a standardized reference are needed to interpret the intrauterine and postnatal growth patterns of preterm infants. Growth in the earlier periods of life can contribute to later outcomes, and the refinement of postnatal growth failure is needed to optimize outcomes. Catchup growth occurs mainly before discharge and until 24 months of age, and very low birth weight infants in Korea achieve retarded growth later in life. Knowing an infant's perinatal history, reducing morbidity rates during admission, and performing regular monitoring after discharge are required. Preterm infants with a lower birth weight or who were small for gestational age are at increased risk of poor neurodevelopmental outcomes. Furthermore, poor postnatal growth is predictive of adverse neurodevelopmental outcomes. Careful monitoring and early intervention will contribute to better development outcomes and national public health improvements.ope

A patient with Cushing disease lateralizing a pituitary adenoma by inferior petrosal sinus sampling using desmopressin: a case report

A 14-year-old girl was referred for evaluation of the etiology of Cushing syndrome. During the previous 2 years, she had experienced weight gain, secondary amenorrhea, growth retardation, and back pain. Random serum cortisol level, 24-hour urinary free cortisol excretion, and overnight and low-dose dexamethasone suppression tests suggested Cushing syndrome. Midnight adrenocorticotropic hormone (ACTH) level and high-dose dexamethasone suppression test confirmed Cushing disease. Pituitary magnetic resonance imaging was suspicious for microadenoma. To eliminate ectopic ACTH syndrome, and lateralize the pituitary tumor, inferior petrosal sinus sampling (IPSS) was performed by desmopressin use to stimulate ACTH. Finally, the patient was diagnosed with Cushing disease due to ACTH-secreting pituitary microadenoma, lateralized to the left side; subsequently underwent transsphenoidal surgery. Here we report a case of a 14-year-old girl diagnosed with Cushing disease with a pituitary tumor lateralized by IPSS using desmopressin, which is very rare in pediatric Cushing disease.ope

Cellular Response of Ventricular-Subventricular Neural Progenitor/Stem Cells to Neonatal Hypoxic-Ischemic Brain Injury and Their Enhanced Neurogenesis

Purpose: To elucidate the brain's intrinsic response to injury, we tracked the response of neural stem/progenitor cells (NSPCs) located in ventricular-subventricular zone (V-SVZ) to hypoxic-ischemic brain injury (HI). We also evaluated whether transduction of V-SVZ NSPCs with neurogenic factor NeuroD1 could enhance their neurogenesis in HI. Materials and methods: Unilateral HI was induced in ICR neonatal mice. To label proliferative V-SVZ NSPCs in response to HI, bromodeoxyuridine (BrdU) and retroviral particles encoding LacZ or NeuroD1/GFP were injected. The cellular responses of NSPCs were analyzed by immunohistochemistry. Results: Unilateral HI increased the number of BrdU+ newly-born cells in the V-SVZ ipsilateral to the lesion while injury reduced the number of newly-born cells reaching the ipsilateral olfactory bulb, which is the programmed destination of migratory V-SVZ NSPCs in the intact brain. These newly-born cells were directed from this pathway towards the lesions. HI significantly increased the number of newly-born cells in the cortex and striatum by the altered migration of V-SVZ cells. Many of these newly-born cells differentiated into active neurons and glia. LacZ-expressing V-SVZ NSPCs also showed extensive migration towards the non-neurogenic regions ipsilateral to the lesion, and expressed the neuronal marker NeuN. NeuroD1+/GFP+ V-SVZ NSPCs almost differentiated into neurons in the peri-infarct regions. Conclusion: HI promotes the establishment of a substantial number of new neurons in non-neurogenic regions, suggesting intrinsic repair mechanisms of the brain, by controlling the behavior of endogenous NSPCs. The activation of NeuroD1 expression may improve the therapeutic potential of endogenous NSPCs by increasing their neuronal differentiation in HI.ope

Effect of Nutritional Intervention by the Nutrition Support Team on Postnatal Growth in Preterm Infants

"Purpose: Nutritional intervention by an interdisciplinary nutrition support team (NST) can potentially improve postnatal growth outcomes in preterm infants. This study aimed to measure the growth impact of a nutritional intervention package performed by an NST in a quality improvement effort in a neonatal intensive care unit (NICU). Methods: Fifty-two infants born below 2,000 g and admitted to NICU participated in the Quality Improvement (QI) program between March 2016 and February 2017. The nutritional intervention was applied according to newly established nutritional guidelines on parenteral and enteral nutrition, and an NST performed a weekly nutritional assessment. The Z-scores of weight, height, and head circumference were calculated according to the gestational age and sex. The clinical impact on postnatal growth was compared between the QI and pre-QI groups. The pre-QI group included 69 infants admitted in the same NICU between 2014 and 2015. Results: The time to the initiation of enteral nutrition decreased significantly (P＜0.001). Changes in weight (P=0.027), head circumference (P=0.003), Z-scores between birth, and 40 weeks postconceptional age (PCA) were significantly larger in the QI than the pre-QI group. The percentage of infants weighing below the 10th percentile at one month after birth and at 40 weeks PCA was higher in the pre-QI than the QI group. Conclusion: The implementation of evidence-based best practices for preterm nutrition resulted in significant improvements in the growth outcomes in preterm infants."22othe

Pulmonary Surfactant Replacement Therapy for Respiratory Distress Syndrome in Neonates: a Nationwide Epidemiological Study in Korea

Background: Pulmonary surfactant (PS) replacement therapy, as a safe and effective treatment for respiratory distress syndrome (RDS) may have further increased with the extended insurance coverage since 2011 in Korea. Thus, this study aimed to investigate the epidemiologic data of PS replacement therapy for RDS in Korea and to analyze the complications associated with RDS. Methods: We included 19,442 infants who were treated with PS and diagnosed with RDS (International Classification of Diseases-10 codes: P22.0) between 2014 and 2018 from the Health Insurance Review and Assessment database. Birth certificate data from Statistics Korea were used to estimate the incidence of RDS. Results: The average incidence of RDS within the study period was 0.99% among live births. Repeated doses of PS were administered to 1,688 infants (8.7%), ranging from 2 doses in 929 infants (4.8%) to 9 doses in 1 infant (0.01%). The incidence of RDS in term infants markedly increased over 5 years from 0.2% to 0.34%. The incidence was similarly increased among the preterm infants. The RDS mortality rate was 6.3% and showed a decreasing trend according to year. The mortality rate was significantly higher in the lower gestational age group. A decreasing trend was observed in the incidence of the complications, such as patent ductus arteriosus, intraventricular hemorrhage, and bronchopulmonary dysplasia, except for pneumothorax in term infants. The complications were also higher in the lower gestational age group and the lower birth weight group. However, pneumothorax was the most frequent complication in the term infant group and in infants with birth weight ≥ 2,500 g. Conclusion: Advancements in neonatal care and extended insurance coverage have increased the use of PS replacement therapy for RDS. This, in turn, decreased neonatal mortality and the incidence of the associated complications. The appropriate therapeutic strategy for RDS should be decided according to the gestational age and lung pathology.ope