Evaluating Novel SP-B and SP-C Synthetic Analogues for Pulmonary Surfactant Efficacy.

Pulmonary surfactants, a complex assembly of phospholipids and surfactant proteins such as SP-B and SP-C, are critical for maintaining respiratory system functionality by lowering surface tension (ST) and preventing alveolar collapse. Our study introduced five synthetic SP-B peptides and one SP-C peptide, leading to the synthesis of CHAsurf candidates (CHAsurf-1 to CHAsurf-5) for evaluation. We utilized a modified Wilhelmy balance test to assess the surface tension properties of the surfactants, measuring spreading rate, surface adsorption, and ST-area diagrams to comprehensively evaluate their performance. Animal experiments were performed on New Zealand white rabbits to test the efficacy of CHAsurf-4B, a variant chosen for its economic viability and promising ST reduction properties, comparable to Curosurf®. The study confirmed that higher doses of SP-B in CHAsurf-4 are associated with improved ST reduction. However, due to cost constraints, CHAsurf-4B was selected for in vivo assessment. The animal model revealed that CHAsurf-4B could restore alveolar structure and improve lung elasticity, akin to Curosurf®. Our research highlights the significance of cysteine residues and disulfide bonds in the structural integrity and function of synthetic SP-B analogues, offering a foundation for future surfactant therapy in respiratory disorders. This study's findings support the potential of CHAsurf-4B as a therapeutic agent, meriting further investigation to solidify its role in clinical applications.

Birth Rate Transition in the Republic of Korea: Trends and Prospects.

BACKGROUND: In Korea, the birth rate is declining at an alarming pace. This study aimed to investigate the changes and trends in the population count, number of births, and birth rate in Korea, in the past and future. METHODS: Data regarding the total number of births, crude birth rate, and total fertility rate were collected from the "Statistics Korea Census" of the national statistical portal, census report, and Statistics Korea's "2020 Population Trend Survey for 1981-2020, provisional results of birth and death statistics." We used the Organisation for Economic Co-operation and Development 2019 Family Database for the TFR. To develop a better understanding of the data in this study, we classified it according to the modern history of Korea. RESULTS: The changes and trends in the number of births and fertility rate in Korea, after liberation, were due to the birth control policy that restricted births. In Korea's low fertility society, which began in the mid-2000s, the fertility rate dropped to below 0.84 in 2020, despite policies to improve the quality of the population. The death toll has reached 300,000, entering an era of population decline. CONCLUSION: As we enter the era of population decline, we are in a direction that will cause various socioeconomic problems, from demographic problems to future population decline.

Trends in Birth Weight and the Incidence of Low Birth Weight and Advanced Maternal Age in Korea between 1993 and 2016.

BACKGROUND: As the aging society progresses, the average age of mothers is also increasing. Advanced maternal age has been known to be associated with perinatal outcomes, as well as birth weight (BW). In this study, we aimed to investigate the perinatal factors associated with low birth weight infants (LBWIs) using birth statistics of the Korean population. METHODS: Birth statistics between 1993 and 2016 from the Korean Statistical Information Service were reviewed. We investigated 12,856,614 data points, which included the number of births, BWs, percentage of preterm births and LBWIs, multiple pregnancies, and maternal age. RESULTS: The proportion of LBWIs delivered by mothers of advanced maternal age has gradually increased since 1993. In addition, the proportion of older mothers (≥ 35 years old) giving birth to LBWIs has increased over the years. Average BW has a negative correlation with the ratio of preterm births, LBW, multiple births, and advanced maternal age. The mean BW also has a negative correlation with maternal age. CONCLUSION: This study shows that the average BW continues to decline, and the incidence of LBWIs is increasing in Korea since 1993. This study also revealed that several perinatal factors, including percentage of preterm births, LBWIs, multiple births, and maternal age influence the mean BW. Although this study did not investigate the effects of decreasing mean BW on perinatal health, future research is worth discussing.

History of Pulmonary Surfactant Replacement Therapy for Neonatal Respiratory Distress Syndrome in Korea.

Neonatal respiratory distress syndrome (RDS) is a disease that is unique to newborn infants. It is caused by a deficiency of pulmonary surfactant (PS), which is usually ready to be activated around the perinatal period. Until RDS was more clearly understood, it was not known why premature infants died from respiratory failure, although pathology revealed hyaline membranes in the alveoli. Surprisingly, the era of PS replacement therapy began only relatively recently. The first clinical trial investigating neonatal RDS was conducted in 1980. Since then, newborn survival has improved dramatically, which has led to significant advances in the field of neonatology. The present comprehensive review addresses PS, from its discovery to the application of artificial PS in newborns with RDS. It also reviews the history of PS in Korea, including its introduction, various commercial products, present and past research, newborn registries, and health insurance issues. Finally, it describes the inception of the Korean Society of Neonatology and future directions of research and treatment.

Association of Surfactant Protein with Expression of Hoxa5 and Hoxb5 in Rabbit Fetal Lung.

Hox genes regulate organ formation and identity of the embryo, and expressed in specific temporo-spatial patterns in the developing embryo. We compared the expression levels of the Hoxa5, Hoxb5, surfactant protein (SP)-A, and SP-B genes in immature and mature rabbit fetal lung tissues, and to uncover roles for Hoxa5, Hoxb5, SP-A, and SP-B. Cesarean sections were performed after rabbits were divided into two groups of 30-31 days of gestation (term group, n = 24) and 26-27 days of gestation (preterm group, n = 24). mRNA levels of Hoxa5, Hoxb5, SP-A, and SP-B were compared by quantitative reverse transcriptase polymerase chain reaction, and protein expression of Hoxa5 and Hoxb5 was compared by western blot analysis. Fetal lung tissue histology was observed by hematoxylin and eosin (H&E) staining. The relative expression ratios of SP-A and SP-B mRNA in the term to preterm groups were 2.45:1 and 2.94:1, respectively. Hoxb5 mRNA and protein levels decreased in the term group, with a relative expression ratio of 0.48:1 and 0.50:1, however, Hoxa5 mRNA and protein levels increased in the term group with a relative expression ration of 2.99:1 and 2.33:1, respectively, for the term to preterm groups. Moreover, a significant positive correlation was found between the expression of Hoxa5 and SP-A, SP-B in the term group. Hoxa5 gene may be essential for the expression of SP-A and SP-B in term rabbits. The Hoxb5 gene may be an important factor for lung maturation in preterm rabbits.

Improvement in the Survival Rates of Very Low Birth Weight Infants after the Establishment of the Korean Neonatal Network: Comparison between the 2000s and 2010s.

The survival rate (SR) of very low birth weight infants (VLBWIs) and extremely low birth weight infants (ELBWIs) is a health indicator of neonatal intensive care unit (NICU) outcomes. The Korean Neonatal Network (KNN) was established in 2013, and a system has been launched to manage the registration and quality improvement of VLBWIs. The SR of the VLBWIs significantly increased to 85.7% in the 2010s compared with 83.0% in the 2000s. There was also a significant increase in the SR of the ELBWIs from 66.1% to 70.7%. The equipment, manpower, and assistance systems of NICUs also improved in quantity and quality. In the international comparison of the SRs of VLBWIs, the SRs were 93.8%, 92.2%, 90.2%, 89.4%, 86.4%, 85.1%, and 80.6% in Japan, Australia and New Zealand, Canada, Europe, Korea, Taiwan, and United States, respectively. In conclusion, the SRs of the VLBWIs and ELBWIs improved in the 2010s compared with those in the 2000s in Korea. This improvement is considered to have been related to the role of the KNN built in 2013. However, the latest VLBWI and ELBWI SRs in 2015 are still low compared with those in Japan, Australia and New Zealand, Canada, and Europe. In the future, we must establish and develop the tasks that are presented as future tasks in this review.

Comparison of the Birth Statistics between Multi-cultural and Korean Families in Korea (2015).

Since 2002, the number of marriages, births, and family members among multi-cultural families (MCFs) has increased. Beginning in 2006, the government initiated a planned management for such families and has implemented the MCF policy basic plan since 2010. In 2015, with multiple socio-economic and medical support initiatives for MCF being available, we analyzed the statistics for several factors related to birth, to determine whether there are significant adverse birth outcomes in MCF. We analyzed the birth data of MCFs in 2015, from Statistics Korea. This study compared the birth data of MCF and Korean families (KF) by geography, neonatal birth weight (BW), gestational age (GA), birth order of the neonates, place of delivery, cohabitation period of parents before the first child, and parental education level. The distribution of BW and the prevalence of low BW (< 2,500 g) or very low BW (< 1,500 g) were similar between both groups. The incidence of preterm birth was lower in the MCF group (6.5% vs. 7.0%, P = 0.015) than in the KF group. In the MCF group, parental education level was lower, and incidence of out-of-hospital births was higher than that of the KF group. Adverse birth outcomes, such as preterm birth and low BW in MCF are similar or better than KF. This study could be a good basis to present the status of MCF birth and newborn care in 2015.

Percentile Distributions of Birth Weight according to Gestational Ages in Korea (2010-2012).

The Pediatric Growth Chart (2007) is used as a standard reference to evaluate weight and height percentiles of Korean children and adolescents. Although several previous studies provided a useful reference range of newborn birth weight (BW) by gestational age (GA), the BW reference analyzed by sex and plurality is not currently available. Therefore, we aimed to establish a national reference range of neonatal BW percentiles considering GA, sex, and plurality of newborns in Korea. The raw data of all newborns (470,171 in 2010, 471,265 in 2011, and 484,550 in 2012) were analyzed. Using the Korean Statistical Information Service data (2010-2012), smoothed percentile curves (3(rd)-97(th)) by GA were created using the lambda-mu-sigma method after exclusion and the data were distinguished by all live births, singleton births, and multiple births. In the entire cohort, male newborns were heavier than female newborns and singletons were heavier than twins. As GA increased, the difference in BW between singleton and multiples increased. Compared to the previous data published 10 years ago in Korea, the BW of newborns 22-23 gestational weeks old was increased, whereas that of others was smaller. Other countries' data were also compared and showed differences in BW of both singleton and multiple newborns. We expect this updated data to be utilized as a reference to improve clinical assessments of newborn growth.

The Experience of Human Milk Banking for 8 Years: Korean Perspective.

Human milk banks are a solution for mothers who cannot supply their own breast milk to their sick or hospitalized infants; premature infants, in particular, are unable to receive a full volume of breast milk for numerous reasons. As of December 2015, there was only one milk bank in a university hospital in Korea. We reviewed the basic characteristics of donors and recipients, and the amounts and contamination of breast milk donated at the Human Milk Bank in Kyung Hee University Hospital at Gangdong in Korea from 2008 to 2015. The donor pool consisted of 463 first-time donors and 452 repeat donors who made 1,724 donations. A total of 10,820 L of breast milk was collected, and 9,541.6 L were processed. Detectable bacteria grew in 12.6% after pasteurization and 52.5% had cytomegalovirus DNA before pasteurization in donated milk. There were 836 infant and 25 adult recipients; among new infant recipients, 48.5% were preterm; the groups received 8,009 and 165.7 L of donor milk, respectively. There was an increase in the percentage of preterm infants among new infant recipients in 2015 (93.1%) compared to 2008 (8.5%). Based on the number of premature infants in Korea, the number of potential recipients is not likely to diminish anytime soon, despite efforts to improve the breastfeeding rate. Sustainability and quality improvement of the milk bank need long-term financial support by health authorities and a nationwide network similar to blood banking will further contribute to the progress of milk banking.

Changes in Survival Rate for Very-Low-Birth-Weight Infants in Korea: Comparison with Other Countries.

Recently the Korean Neonatal Network (KNN) was established in order to enhance treatment outcomes further through the registration of very-low-birth-weight infants (VLBWI) data. The present study was conducted on 2,606 VLBWI, 2,386 registered and 220 un-registered, in the KNN participating centers, with the objective of reporting on recent survival rates of VLBWI in Korea and verifying the changing trends in survival rates with data from the 1960s and beyond. The study also aimed to compare the premature infants' survival rate in Korea with those reported in neonatal networks of other countries. The recent survival rate of VLBWI increased more than twice from 35.6% in the 1960s to 84.8%, and the survival rate of the extremely low birth weight infants (ELBWI) increased by more than 10 times, indicating improvement of the survival rate in premature infants with lower birth weight and gestational age. Comparison of VLBWI between countries showed improved survival rates according to each birth weight group in Canada, Australia-New Zealand, and European countries with Japan at the head, but in terms of comparison based on gestational age, differences, except for Japan, have been reduced. Efforts to increase the survival rate of premature infants in Korea with low birth rate are inevitable, and they should be the foundation of academic and clinical development based on its network with advanced countries.

Reference intervals of serum cystatin C/creatinine ratio of 30 postnatal days in neonates.

BACKGROUND: A number of recent reports have suggested that the cystatin C/creatinine (CysC/Cr) ratio might be a useful biomarker of renal function in pediatric patients. In this study we investigated the reference intervals of the serum CysC/Cr ratio for neonates including very low birth weight infants. CASE-DIAGNOSIS/TREATMENT: A total of 883 blood samples were collected from 246 neonates during the first 30 days of life for the concurrent measurement of serum CysC and Cr levels. Infants with symptoms or signs of acute kidney injury, systemic illness, congenital anomaly, or renal pathology were excluded. The association between serum CysC/Cr ratio and the subgroups of patients was also analyzed. Reference intervals of serum CysC/Cr ratio were determined according to the postnatal age and post-conceptional age (PCA). CysC/Cr ratio level increased according to PCA, except in the first three postnatal days. The serum CysC/Cr ratio correlated positively with gestational age at birth, birth weight, postnatal age, and PCA, and negatively with serum CysC and Cr (P < 0.001). CONCLUSIONS: Reference levels of serum CysC/Cr ratio were determined according to postnatal age and PCA. As the serum CysC/Cr ratio is dependent on several clinical parameters, these should be considered when assessing the serum CysC/Cr ratio in neonates.

Duplicate publication rate decline in Korean medical journals.

The purpose of this study was to examine trends in duplicate publication in Korean medical articles indexed in the KoreaMed database from 2004 to 2009, before and after a campaign against scientific misconduct launched by the Korean Association of Medical Journal Editors in 2006. The study covered period from 2007 to 2012; and 5% of the articles indexed in KoreaMed were retrieved by random sampling. Three authors reviewed full texts of the retrieved articles. The pattern of duplicate publication, such as copy, salami slicing (fragmentation), and aggregation (imalas), was also determined. Before the launching ethics campaign, the national duplication rate in medical journals was relatively high: 5.9% in 2004, 6.0% in 2005, and 7.2% in 2006. However, duplication rate steadily declined to 4.5% in 2007, 2.8% in 2008, and 1.2 % in 2009. Of all duplicated articles, 53.4% were classified as copies, 27.8% as salami slicing, and 18.8% as aggregation (imalas). The decline in duplicate publication rate took place as a result of nationwide campaigns and monitoring by KoreaMed and KoreaMed Synapse, starting from 2006.

Changes in the cesarean section rate in Korea (1982-2012) and a review of the associated factors.

Although Cesarean section (CS) itself has contributed to the reduction in maternal and perinatal mortality, an undue rise in the CS rate (CSR) has been issued in Korea as well as globally. The CSR in Korea increased over the past two decades, but has remained at approximately 36% since 2006. Contributing factors associated with the CSR in Korea were an improvement in socio-economic status, a higher maternal age, a rise in multiple pregnancies, and maternal obesity. We found that countries with a no-fault compensation system maintained a lower CSR compared to that in countries with civil action, indicating the close relationship between the CSR and the medico-legal system within a country. The Korean government has implemented strategies including an incentive system relating to the CSR or encouraging vaginal birth after Cesarean to decrease CSR, but such strategies have proved ineffective. To optimize the CSR in Korea, efforts on lowering the maternal childbearing age or reducing maternal obesity are needed at individual level. And from a national view point, reforming health care system, which could encourage the experienced obstetricians to be trained properly and be relieved from legal pressure with deliveries is necessary.

Early prophylactic versus late selective use of surfactant for respiratory distress syndrome in very preterm infants: a collaborative study of 53 multi-center trials in Korea.

Pulmonary surfactant (PS) therapy was proven to be highly successful for the treatment of respiratory distress syndrome in premature infants. As a results, early prophylactic (EP) PS therapy has been introduced recently in Europe, the US and Korea. However, no multi-center study was compared EP and late selective (LS) PS therapies in Korea. We performed a retrospective multi-center study to compare the outcomes of EP and LS PS therapies in very preterm infants. We analyzed clinical morbidity and mortality for 1,291 infants in 2010 (LS group) and 1,249 infants in 2011 (EP group); the infants were born <30 weeks of gestation and had birth weight ≤1,250 g, and were chosen from 53 neonatal intensive care units in Korea. Compared to the LS group (22.5%), the overall mortality was better in the EP group (19.9%) and there was no increased need for retreatment.There were additional benefits in the EP group such as fewer associated complications. To the best of knowledge, our study is the first nationwide Korean study to compare the outcomes of EP and LS therapies, and it provides evidences that EP PS therapy is important in very preterm infants to improve for survival and reduce morbidities.

Serum cystatin C during 30 postnatal days is dependent on the postconceptional age in neonates.

BACKGROUND: Cystatin C (CysC) is a promising endogenous marker for renal function. However, the reference serum CysC level is not sufficiently studied in neonates. This study was conducted to investigate the reference level of serum CysC for neonates, including very low birth weight infants according to the postconceptional age (PCA). METHODS: Serum CysC levels were measured in 883 blood samples (246 neonates including 127 premature infants). Infants with symptoms or signs of acute kidney injury, systemic illness, congenital anomaly, or renal pathology were excluded. CysC levels were analyzed for association between subgroups dichotomized by postnatal age and PCA. RESULTS: Reference ranges of serum CysC were determined and a decreasing trend of CysC levels was observed as PCA increased, except for the first 3 postnatal days. CysC levels were negatively correlated with gestational age at birth, and PCA (P < 0.001), while positively correlated with postnatal age and serum creatinine (P < 0.001). CONCLUSION: The reference level of serum CysC was determined according to postnatal age and PCA. As the reference CysC level was dependent on gestational age and PCA, consideration of these parameters is warranted when assessing CysC levels in neonates.

Trends of breastfeeding rate in Korea (1994-2012): comparison with OECD and other countries.

Breastfeeding has numerous benefits both for infants and mothers. WHO, UNICEF, and OECD report the breastfeeding rate (BR) and exclusive breastfeeding rate (EBR) at 3, 4, and 6 months of age for the international comparison. This article investigates the nationwide changes in BR and EBR in Korea from 1994 to 2012. EBR declined from 1994 to 2000, however progressively increased untill 2012. The latest data in 2012 revealed EBRs at 3, 4, and 6 months were 50.0%, 40.5%, and 11.4% respectively. The exclusive formula feeding rate (EFR) was highest in 2000 and gradually declined thereafter. In 2012, the EFRs at 3, 4 and 6 months were 21.7%, 26.5%, and 10.1%. In 2009, the EBRs at 3 and 6 months in the United States were 36.0% and 16.3% compared to 50.0% and 11.4% in Korea. In England, the EBRs were 17% and 12% in 2010. Amongst OECD countries, Hungary ranked highest EBRwith 95%, and Iceland, Norway, Slovak Republic, Australia, New Zealand followed. In conclusion, BRs were lowest in 2000, and there have been remarkable increases in BRs over the past 10 yr in Korea. Although BRs have been increasing, further efforts to increase BRs should be made continuously.

Ghrelin suppresses tunicamycin- or thapsigargin-triggered endoplasmic reticulum stress-mediated apoptosis in primary cultured rat cortical neuronal cells.

Ghrelin functions as a neuroprotective agent and rescues neurons from various insults. However, the molecular mechanisms underlying ghrelin neuroprotection remains to be elucidated. An accumulation of unfolded proteins in the endoplasmic reticulum (ER) leads to ER stress and then induces ER stress-mediated cell death. Here, we report that acylated ghrelin inhibited tunicamycin- or thapsigargin-triggered ER stress-induced apoptotic cell death in primary rat cortical neurons. An analysis using a specific inhibitor of phosphatidylinositol-3-kinase (PI3K), LY294002, showed that ghrelin prevented apoptosis via the activation of PI3K signaling pathway. Ghrelin suppressed tunicamycin- or thapsigargin-induced upregulation and nuclear translocation of C/EBP homologous protein (CHOP). Ghrelin also inhibited tunicamycin or thapsigargin induction of PRK-like ER kinase (PERK), eukaryotic translation initiation factor-2α (eIF2α) and activating transcription factor (ATF) 4. Exposure of cells to tunicamycin or thapsigargin resulted in nuclear translocation of forkhead box protein O1 (Foxo1), which was reduced by pretreatment with ghrelin. The protective effect of ghrelin was accompanied by an increased phosphorylation of Akt and glycogen synthase kinase (GSK)-3ß. Furthermore, ghrelin phosphorylated and inactivated pro-apoptotic BAD and Foxo1. In addition, phospho-Akt was translocated to the nucleus in response to ghrelin and PI3K inhibition by LY294002 prevented ghrelin-induced effect on phospho-Akt localization. Our study suggests that suppression of CHOP activation via the inhibition of PERK/eIF2α/ATF4 pathway and prevention of Foxo1 activation and nuclear translocation may contribute to ghrelin-mediated neuroprotection during ER stress responses. Our data also suggest that PI3K/Akt-mediated inactivation of GSK-3ß, BAD and Foxo1 may be associated with the anti-apoptotic effect of ghrelin.

Novel compound heterozygous mutations in the vitamin D receptor gene in a Korean girl with hereditary vitamin D resistant rickets.

Hereditary vitamin D resistant rickets (HVDRR) is a rare genetic disorder caused by a mutation of vitamin D receptor (VDR) gene. A number of cases had been reported in many countries but not in Korea. We examined a three-year old Korean girl who had the typical clinical features of HVDRR including rickets, hypocalcemia, hypophosphatemia, elevated serum calcitriol level and secondary hyperparathyroidism. The girl and her father were both heterozygous for the 719C-to-T(I146T)---> c.437C > T(p.T1461) [corrected] mutation in exon 4, whereas she and her mother were both heterozygous for 754C-to-T (R154C)---> c.472 > T(p.R158C) [corrected] mutation in exon 5 of the VDR gene. In this familial study, we concluded that the girl had compound heterozygous mutations in her VDR gene which caused HVDRR. This is the first report of a unique mutation in the VDR gene in Korea.

Recent trends in neonatal mortality in very low birth weight Korean infants: in comparison with Japan and the USA.

With regard to the outcome of intensive neonatal care, one of the most important concerns in neonatology is the mortality rate of very low birth weight infants (VLBWI; birth weight < 1,500 g) and extremely low birth weight infants (ELBWI; birth weight < 1,000 g). The present study was conducted to analyze and compare the mortality of VLBWI and ELBWI and neonatal care among Korean, Japanese, and American newborns. In Korea, the survival rates of VLBWI have increased significantly; they were 31.8% in the early 1960s, 65.8% in the early 1990s, 77.5% in 2002, 84.7% in 2007, and 85.7% in 2009. The survival rates of ELBWI have also increased; they were 8.2% in the early 1960s, 37.4% in the early 1990s, 56.1% in 2002, 67.7% in 2007, and 71.8% in 2009. The survival rates of VLBWI and ELBWI have significantly improved over the past 50 yr in Korea. However, the Korean survival rates of VLBWI and ELBWI are still lower than for similar groups in Japan and the USA. To achieve better outcomes that reach the level of these countries, the organization of perinatal care centers, nationwide neonatal perinatal research networks, and regionalization are needed in Korea.

Decreasing trends of neonatal and infant mortality rates in Korea: compared with Japan, USA, and OECD nations.

Neonatal mortality rate (NMR) and infant mortality rate (IMR) are two of the most important indices reflecting the level of public health of a country. In this review, we investigated changes in NMR and IMR in Korea and compared the results with those of Japan, USA, and OECD nations. During the past 20 yr, NMR and IMR have lowered remarkably from 6.6 and 9.9 in 1993 to 1.7 and 3.2 in 2009, respectively, in Korea. It is an impressive finding that Korean IMR (3.2 in 2009) is lower than the average of OECD nations (4.7 in 2008), and USA (6.3 in 2009), although higher than Japanese IMR (2.8 in 2009). The proportion of NMR among the IMR calculation decreased from 66.7% in 1993 to 53.1% in 2009. The reason the value of Korea was higher than Japan but lower than USA was speculated to be an aspect of the health care service system. Several suggestions in perinatal, neonatal and infantile health care such as establishment of perinatal care center, research network system, regionalization, and new policies for care of pre-term and high risk pregnancy, are elucidated to achieve further improvement on NMR and IMR in Korea.