Eun Sun Kim

Intratracheal transplantation of human umbilical cord blood-derived mesenchymal stem cells attenuates Escherichia coli-induced acute lung injury in mice

BackgroundHuman umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) attenuate hyperoxic neonatal lung injury primarily through anti-inflammatory effects. We hypothesized that intratracheal transplantation of human UCB-derived MSCs could attenuate Escherichia coli (E. coli)-induced acute lung injury (ALI) in mice by suppressing the inflammatory response.MethodsEight-week-old male ICR mice were randomized to control or ALI groups. ALI was induced by intratracheal E. coli instillation. Three-hours after E. coli instillation, MSCs, fibroblasts or phosphate-buffered saline were intratracheally administered randomly and survival was analyzed for 7 days post-injury. Lung histology including injury scores, myeloperoxidase (MPO) activity, and protein levels of interleukin (IL)-1α, IL-1β, IL-6, tumor necrosis factor (TNF)-α, and macrophage inflammatory protein (MIP)-2 as well as the wet-dry lung ratio and bacterial counts from blood and bronchoalveolar lavage (BAL) were evaluated at 1, 3, and 7 days post-injury. Levels of inflammatory cytokines in the lung were also profiled using protein macroarrays at day 3 post-injury which showed peak inflammation.ResultsMSC transplantation increased survival and attenuated lung injuries in ALI mice, as evidenced by decreased injury scores on day 3 post-injury and reduced lung inflammation including increased MPO activity and protein levels of IL-1α, IL-1β, IL-6, TNF-α, and MIP-2 on day 3 and 7 post-injury. Inflammatory cytokine profiles in the lungs at day 3 post-injury were attenuated by MSC transplantation. MSCs also reduced the elevated lung water content at day 3 post-injury and bacterial counts in blood and BAL on day 7 post-injury.ConclusionsIntratracheal transplantation of UCB-derived MSCs attenuates E. coli-induced ALI primarily by down-modulating the inflammatory process and enhancing bacterial clearance.

Long-Term (Postnatal Day 70) Outcome and Safety of Intratracheal Transplantation of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells in Neonatal Hyperoxic Lung Injury

Purpose This study was performed to evaluate the long-term effects and safety of intratracheal (IT) transplantation of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) in neonatal hyperoxic lung injury at postnatal day (P)70 in a rat model. Materials and Methods Newborn Sprague Dawley rat pups were subjected to 14 days of hyperoxia (90% oxygen) within 10 hours after birth and allowed to recover at room air until sacrificed at P70. In the transplantation groups, hUCB-MSCs (5×105) were administered intratracheally at P5. At P70, various organs including the heart, lung, liver, and spleen were histologically examined, and the harvested lungs were assessed for morphometric analyses of alveolarization. ED-1, von Willebrand factor, and human-specific nuclear mitotic apparatus protein (NuMA) staining in the lungs and the hematologic profile of blood were evaluated. Results Impaired alveolar and vascular growth, which evidenced by an increased mean linear intercept and decreased amount of von Willebrand factor, respectively, and the hyperoxia-induced inflammatory responses, as evidenced by inflammatory foci and ED-1 positive alveolar macrophages, were attenuated in the P70 rat lungs by IT transplantation of hUCB-MSCs. Although rare, donor cells with human specific NuMA staining were persistently present in the P70 rat lungs. There were no gross or microscopic abnormal findings in the heart, liver, or spleen, related to the MSCs transplantation. Conclusion The protective and beneficial effects of IT transplantation of hUCB-MSCs in neonatal hyperoxic lung injuries were sustained for a prolonged recovery period without any long-term adverse effects up to P70.

Trends in epidemiology of neonatal sepsis in a tertiary center in Korea: a 26-year longitudinal analysis, 1980-2005.

There were many reports of longitudinal changes in the causative organisms of neonatal sepsis in Western countries but few in Asia. We aimed to study longitudinal trends in the epidemiology of neonatal sepsis at Seoul National University Childrens Hospital (SNUCH), a tertiary center in Korea, and compared the results to previous studies of Western countries. The medical records of all of the neonates who were hospitalized at SNUCH from 1996 to 2005 with positive blood cultures were reviewed. We also compared the findings to previous 16-yr (1980-1995). One hundred and forty-nine organisms were identified in 147 episodes from 134 infants. In comparison with the previous 16-yr studies, there was a decrease in the number of Escherichia coli infections (16.2% vs 8.7%: odds ratio [OR] 0.495; 95% confidence interval [CI], 0.255-0.962; P = 0.035), but an increase in Staphylococcus aureus (16.6% vs 25.5%: OR 1.720; 95% CI, 1.043-2.839; P = 0.033) and fungal infections (3.3% vs 18.7%: OR 6.740; 95% CI, 2.981-15.239; P < 0.001), predominantly caused by Candida species. In conclusion, the incidence of sepsis caused by E. coli decreases, but S. aureus and fungal sepsis increases significantly. Compared with Western studies, the incidence of sepsis caused by S. aureus and fungus has remarkably increased.

Neutralization of Ocular Surface TNF-α Reduces Ocular Surface and Lacrimal Gland Inflammation Induced by In Vivo Dry Eye

PURPOSE The purpose of this study was to investigate the effectiveness of tumor necrosis factor (TNF)-α blocker for treatment of dry eye (DE)-induced inflammation and determine a more effective method to suppress lacrimal gland inflammation. Efficacy of topical versus systemic administration of TNF-α blockers was determined using a murine dry eye (DE) model. METHODS The TNF-α blocker HL036 was developed by modification of the TNF receptor I. Protein purity, binding affinity, and clearance of TNF-α was compared with etanercept. Using DE-induced C57BL/6 mice, corneal erosion and goblet cell counts were measured after subcutaneous or topical treatment with etanercept or HL036. Inflammatory cytokines in cornea and lacrimal glands were determined by quantitative RT-PCR and ELISA. RESULTS HL036 showed TNF-α binding affinity comparable to etanercept, as measured by surface plasmon resonance. HL036 concentration was significantly higher in cornea and anterior segment than etanercept and effectively eliminated TNF-α on ocular surfaces. Etanercept was preferentially concentrated in the posterior segment. Corneal erosion and goblet cell counts were improved only with topically applied etanercept and HL036. Ocular surface IFN-γ, IL-6, and IL-21 were significantly decreased by topical HL036. DE-induced lacrimal gland IFN-γ and IL-6 expression was effectively suppressed by topical etanercept and HL036. CONCLUSIONS Topical TNF-α blockers effectively suppressed lacrimal gland and corneal inflammation by suppressing IFN-γ, IL-21, and IL-6. Differences in TNF-α affinity, clearance, and local concentration of blockers may account for the anti-inflammatory effects in different ocular regions.

Continuous renal replacement therapy in neonates weighing less than 3 kg

Purpose Continuous renal replacement therapy (CRRT) is becoming the treatment of choice for supporting critically ill pediatric patients. However, a few studies present have reported CRRT use and outcome in neonates weighing less than 3 kg. The aim of this study is to describe the clinical application, outcome, and complications of CRRT in small neonates. Methods A retrospective review was performed in 8 neonatal patients who underwent at least 24 hours of pumped venovenous CRRT at the Samsung Medical Center in Seoul, Korea, between March 2007 and July 2010. Data, including demographic characteristics, diagnosis, vital signs, medications, laboratory, and CRRT parameters were recorded. Results The data of 8 patients were analyzed. At the initiation of CRRT, the median age was 5 days (corrected age, 38+2 weeks to 23 days), and the median body weight was 2.73 kg (range, 2.60 to 2.98 kg). Sixty-two patient-days of therapy were reviewed; the median time for CRRT in each patient was 7.8 days (range, 1 to 37 days). Adverse events included electrolyte disturbances, catheter-related complications, and CRRT-related hypotension. The mean circuit functional survival was 13.9±8.6 hours. Overall, 4 patients (50%) survived; the other 4 patients, who developed multiorgan dysfunction syndrome, died. Conclusion The complications of CRRT in newborns are relatively high. However, the results of this study suggest that venovenous CRRT is feasible and effective in neonates weighing less than 3 kg under elaborate supportive care. Furthermore, for using potential benefit of CRRT in neonates, efforts are required for prolonging filter survival.

Permissive Hypotension in Extremely Low Birth Weight Infants (≤1000 gm)

Purpose We performed this study to evaluate the safety of permissive hypotension management in extremely low birth weight infants (ELBWIs). Materials and Methods Medical records of all inborn ELBWIs admitted to Samsung Medical Center from January 2004 to December 2008 were reviewed retrospectively. Of a total of 261 ELBWIs, 47 (18%) required treatment for hypotension (group T), 110 (42%) remained normotensive (group N), and 104 (40%) experienced more than one episode of hypotension without treatment (group P) during the first 72 hours of life. Treatment of hypotension included inotropic support and/or fluid loading. Results Birth weight and Apgar scores were significantly lower in the T group than the other two groups. In the N group, the rate of pathologically confirmed maternal chorioamnionitis was significantly higher than other two groups, and the rate was higher in the P group than the T group. After adjusting for covariate factors, no significant differences in mortality and major morbidities were found between the N and P groups. However, the mortality rate and the incidence of intraventricular hemorrhage (≥stage 3) and bronchopulmonary dysplasia (≥moderate) were significantly higher in the T group than the other two groups. Long term neurodevelopmental outcomes were not significantly different between the N and P groups. Conclusion Close observation of hypotensive ELBWIs who showed good clinical perfusion signs without intervention allowed to avoid unnecessary medications and resulted in good neurological outcomes.

A novel PRF1 gene mutation in a fatal neonate case with type 2 familial hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) occurs in the primary form (genetic or familial) or secondary form (acquired). The familial form of HLH (FHL) is a potentially fatal autosomal recessive disorder that occurs because of constitutional defects in cell-mediated cytotoxicity. Here, we report a fatal neonatal case of type 2 FHL (FHL2) that involved a novel frameshift mutation. Clinically, the newborn presented with severe sepsis-like features and required mechanical ventilation and continuous venovenous hemodiafiltration. Flow cytometry analysis showed marked HLH and complete absence of intracytoplasmic perforin expression in cytotoxic cells; therefore, we performed molecular genetic analyses for PRF1 mutations, which showed that the patient had a compound heterozygous mutation in PRF1, that is, c.65delC (p.Pro22Argfs*2) and c.1090_1091delCT (p.Leu364Glufs*93). Clinical and genetic assessments for FHL are required for neonates with refractory fever and progressive multiple organ failure, particularly when there is no evidence of microbiological or metabolic cause.

Outcomes of small for gestational age micropremies depending on how young or how small they are.

Purpose The outcomes of small for gestational age (SGA) infants especially in extremely low birth weight infants (ELBWIs) are controversial. This study evaluated the mortality and morbidity of ELBWIs, focusing on whether or not they were also SGA. Methods The medical records of 415 ELBWIs (birth weight <1,000 g), who were inborn and admitted to the Samsung Medical Center neonatal intensive care unit from January 2000 to December 2008, were reviewed retrospectively. Mortality and morbidities were compared by body size groups: very SGA (VSGA), birth weight ≤3rd percentile; SGA, 3rd to 10th percentile; and appropriate for gestational age (AGA) infants, >10th percentile for gestational age. For gestational subgroup analysis, groups were divided into infants with gestational age ≤24+6 weeks (subgroup I), 25+0 to 26+6 weeks (subgroup II), and ≥27+0 weeks (subgroup III). Results Gestational age was 29+2±2+6 weeks in the VSGA infants (n=49), 27+5±2+2 weeks in the SGA infants (n=45), and 25+4±1+4 weeks in AGA infants (n=321). Birth weight was 692±186.6 g, 768±132.9 g, and 780±142.5 g in the VSGA, SGA, and AGA groups, respectively. Cesarean section rate and maternal pregnancy-induced hypertension were more common in the VSGA and SGA than in AGA pregnancies. However, chorioamnionitis was more common in the AGA group. The mortalities of the lowest gestational group (subgroup I), and also of the lower gestational group (subgroup I+II) were significantly higher in the VSGA group than the SGA or AGA groups (P=0.020 and P=0.012, respectively). VSGA and SGA infants showed lower incidence in respiratory distress syndrome, ductal ligation, bronchopulmonary dysplasia, intraventricular hemorrhage than AGA group did. However, by multiple logistic regression analysis of each gestational subgroup, the differences were not significant. Conclusion Of ELBWIs, extremely SGA in the lower gestational subgroups, had an impact on mortality, which may provide information useful for prenatal counseling.

Sequential magnetic resonance spectroscopic changes in a patient with nonketotic hyperglycinemia

Nonketotic hyperglycinemia (NKH) is a rare inborn error of amino acid metabolism. A defect in the glycine cleavage enzyme system results in highly elevated concentrations of glycine in the plasma, urine, cerebrospinal fluid, and brain, resulting in glycine-induced encephalopathy and neuropathy. The prevalence of NKH in Korea is very low, and no reports of surviving patients are available, given the scarcity and poor prognosis of this disease. In the current study, we present a patient with NKH diagnosed on the basis of clinical features, biochemical profiles, and genetic analysis. Magnetic resonance spectroscopy (MRS) allowed the measurement of absolute glycine concentrations in different parts of the brain that showed a significantly increased glycine peak, consolidating the diagnosis of NKH. In additional, serial MRS follow-up showed changes in the glycine/creatinine ratios in different parts of the brain. In conclusion, MRS is an effective, noninvasive diagnostic tool for NKH that can be used to distinguish this disease from other glycine metabolism disorders. It may also be useful for monitoring NKH treatment.

Idiopathic severe hypermagnesemia in an extremely low birth weight infant on the first day of life

A preterm female infant born at 27 weeks of gestation with a birth weight of 990 g developed acute hypotonia, apnea, hypotension and bradycardia mimicking septic shock syndrome at 14h after birth. Laboratory tests indicated a severe hypermagnesemia of 45 mg/dL. The renal function, complete blood count and maternal blood concentrations of magnesium were normal, and the blood cultures were negative. The patient recovered with treatment including exchange transfusion. However, the etiology of the severe hypermagnesemia remains unknown.