• Clinical and Experimental Pediatrics
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• 제64권8호
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• pp.422-429
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• 2021

Background: Carnosine has antioxidative and neuroprotective properties against hypoxic-ischemic (HI) brain injury. Hypothermia is used as a therapeutic tool for HI encephalopathy in newborn infants with perinatal asphyxia. However, the combined effects of these therapies are unknown. Purpose: Here we investigated the effects of combined carnosine and hypothermia therapy on HI brain injury in neonatal rats. Methods: Postnatal day 7 (P7) rats were subjected to HI brain injury and randomly assigned to 4 groups: vehicle; carnosine alone; vehicle and hypothermia; and carnosine and hypothermia. Carnosine (250 mg/kg) was intraperitoneally administered at 3 points: immediately following HI injury, 24 hours later, and 48 hours later. Hypothermia was performed by placing the rats in a chamber maintained at 27℃ for 3 hours to induce whole-body cooling. Sham-treated rats were also included as a normal control. The rats were euthanized for experiments at P10, P14, and P35. Histological and morphological analyses, in situ zymography, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assays, and immunofluorescence studies were conducted to investigate the neuroprotective effects of the various interventional treatments. Results: Vehicle-treated P10 rats with HI injury showed an increased infarct volume compared to sham-treated rats during the triphenyltetrazolium chloride staining study. Hematoxylin and eosin staining revealed that vehicle-treated P35 rats with HI injury had decreased brain volume in the affected hemisphere. Compared to the vehicle group, carnosine and hypothermia alone did not result in any protective effects against HI brain injury. However, a combination of carnosine and hypothermia effectively reduced the extent of brain damage. The results of in situ zymography, TUNEL assays, and immunofluorescence studies showed that neuroprotective effects were achieved with combination therapy only. Conclusion: Carnosine and hypothermia may have synergistic neuroprotective effects against brain damage following HI injury.

• Pediatric Gastroenterology, Hepatology & Nutrition
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• 제17권3호
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• pp.162-169
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• 2014

Purpose: To study temporal pattern of serum liver enzymes levels in newborns with hepatic injury associated with birth asphyxia (BA). Methods: Singleton term newborns with BA and ${\leq}72$ hours of age admitted to neonatal intensive care unit were prospectively enrolled. Term newborns with physiological jaundice and without BA were studied as controls. Serum liver enzymes were measured at <24 hours, 24-72 hours, and at 6-12 days of age for cases and at 1-6 days of age for controls. BA was defined by 1 minute Apgar score <7 or delayed or absent cry with hypoxic ischemic encephalopathy. BA-associated liver injury was defined as serum alanine aminotransferase (ALT) elevation beyond +2 standard deviation (ALT > +2 SD) above the mean of control subjects at any of the three time points. Results: Sixty controls and 62 cases were enrolled. Thirty-five cases (56%) developed BA-associated liver injury (ALT>81 IU/L). They had higher serum levels of ALT, aspartate aminotransferase, lactate dehydrogenase than the control infants, with peak at 24-72 hours. In controls, serum liver enzyme levels were significantly higher in appropriate-for-date (AFD) babies than small-for-date (SFD) babies. Serum enzyme pattern and extent of elevation were comparable between SFD and AFD babies. Degree of serum liver enzyme elevation had no relationship with severity of hypoxic encephalopathy. Conclusion: Serum liver enzyme elevation is common in BA; it peaks at 24-72 hours followed by a sharp decline by 6-12 days of age. Pattern and extent of enzyme elevation are comparable between SFD and AFD babies.

• Clinical and Experimental Pediatrics
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• 제60권6호
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• pp.181-188
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• 2017

Purpose: Hypoxic-ischemic encephalopathy is a significant cause of neonatal morbidity and mortality. Erythropoietin (EPO) is emerging as a therapeutic candidate for neuroprotection. Therefore, this study was designed to determine the neuroprotective role of recombinant human EPO (rHuEPO) and the possible mechanisms by which mitogen-activated protein kinase (MAPK) signaling pathway including extracellular signal-regulated kinase (ERK1/2), JNK, and p38 MAPK is modulated in cultured cortical neuronal cells and astrocytes. Methods: Primary neuronal cells and astrocytes were prepared from cortices of ICR mouse embryos and divided into the normoxic, hypoxia (H), and hypoxia-pretreated with EPO (H+EPO) groups. The phosphorylation of MAPK pathway was quantified using western blot, and the apoptosis was assessed by caspase-3 measurement and terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Results: All MAPK pathway signals were activated by hypoxia in the neuronal cells and astrocytes (P<0.05). In the neuronal cells, phosphorylation of ERK-1/-2 and apoptosis were significantly decreased in the H+EPO group at 15 hours after hypoxia (P<0.05). In the astrocytes, phosphorylation of ERK-1/-2, p38 MAPK, and apoptosis was reduced in the H+EPO group at 15 hours after hypoxia (P<0.05). Conclusion: Pretreatment with rHuEPO exerts neuroprotective effects against hypoxic injury reducing apoptosis by caspase-dependent mechanisms. Pathologic, persistent ERK activation after hypoxic injury may be attenuateed by pretreatment with EPO supporting that EPO may regulate apoptosis by affecting ERK pathways.

• Neonatal Medicine
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• 제16권1호
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• pp.10-17
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• 2009

The immature neonatal brain is susceptible to the development of seizures. Seizures occur in 1% to 5% of infants during the neonatal period. Neonatal seizures are most commonly associated with serious acute illnesses, such as hypoxic-ischemic encephalopathy, birth trauma, metabolic disturbances, or infections. Thus, newborn infants with seizures are at risk for neonatal death and survivors are at risk for neurologic impairment, developmental delay, and subsequent epilepsy. Experimental data have also raised concerns about the potential adverse effects of the currently used anticonvulsants in neonates on brain development. Therefore, in the management of neonatal seizures, confirmatory diagnosis and optimal, but shorter, duration of anticonvulsant therapy is essential. Nevertheless, there has been substantial progress in understanding the developmental mechanisms that influence seizure generation and responsiveness to anticonvulsants. The currently used therapies have limited efficacy and the treatment of neonatal seizures has not significantly changed in the past several decades, This review includes an overview of current approaches to the treatment of neonatal seizures.

• 한국임상약학회지
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• 제27권2호
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• pp.63-68
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• 2017

Neonates have large inter-individual variability in pharmacokinetic parameters of many drugs due to developmental differences. The aim of this study was to investigate the factors affecting the pharmacokinetic parameters of drugs, which are commonly used in critically ill neonates. Factors that reflect physiologic maturation such as gestational age, postnatal age, postconceptional age, birth weight, and current body weight were correlated with pharmacokinetic parameters in neonates, especially preterm infants. Comorbidity characteristics affecting pharmacokinetics in critically ill neonates were perinatal asphyxia, hypoxic ischemic encephalopathy, patent ductus arteriosus (PDA), and renal dysfunction. Administration of indomethacin or ibuprofen in neonates with PDA was associated with the reduced clearance of renally excreted drugs such as vancomycin and amikacin. Therapeutic hypothermia and extracoporeal membrane oxygenation were influencing factors on pharmacokinetic parameters in critically ill neonates. Dosing adjustment and careful monitoring according to the factors affecting pharmacokinetic variability is required for safe and effective pharmacotherapy in neonatal intensive care unit.

• 대한자기공명의과학회:학술대회논문집
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• 대한자기공명의과학회 2003년도 제8차 학술대회 초록집
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• pp.99-99
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• 2003

To exhibit our clinical experience of diffusion-weighted (DW) MR imaging for various brain pathologies and to determine its role in characterizing brain pathologies in children. DW images in 177 children (M：F＝96：81, mean age, 4.7 years) with various brain pathologies were retrospectively collected over past 3 years. DW images (b value： 1000 s/mm) were reviewed along with corresponding apparent diffusion coefficient (ADC) maps. Brain pathologies included cystic or solid brain tumor (n = 55), cerebral infarct (n = 32), cerebritis with or without brain abscess (n = 21), metabolic or toxic brain disorder (n = 19), demyelinating disease (n = 16), hypoxic-ischemic encephalopathy (n = 16), intracerebral hemorrhage including traumatic brain lesion (n = 15), and posterior reversible leukoencephalopathy (n = 3). We reviewed whether DW images and ADCmaps contribute to further characterization of brain pathologies by defining a chronological age of lesions, the presence of cytotoxic edema in lesions, and the nature of cystic lesions.

• Childhood Kidney Diseases
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• 제11권1호
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• pp.32-40
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• 2007

목적 : 급성신부전은 질식 신생아의 사망률과 신경학적 예후와 관련이 있는 것으로 알려져 있다. 이에 본 저자들은 신생아 질식 환아에서 급성신부전의 발생률을 알아보고, 질식과 저산소성 허혈 뇌증의 정도와 급성신부전과의 연관성을 알아보고자 이번 연구를 시행하였다. 방법 : 신생아 질식으로 진단 받은 환아 33명과 임신 기간과 출생체중으로 짝지어진 환아 33명의 의무기록을 후향적으로 검토하였다. 5분 아프가 점수에 의해 신생아 질식의 정도를 경증(6 또는 7), 중등도(4 또는 5), 중증(3 이하)으로 세분하였으며, Sarnat and Sarnat stage에 의해 저산소성 허혈 뇌증의 단계를 분류하였다. 생후 3일에 측정한 혈청 크레아티닌, 혈액요소질소, 전해질 수치와 소변배출량, 혈뇨와 단백뇨 유무에 대한 기록을 검토하였다. 영상 검사를 통해 진단 받은 뇌실 내 출혈의 유무와 정도를 비교하였다. 결과 : 질식군 8명(24.2%)에서 급성신부전이 발생하였다. 이 중 3명(37.5%)이 감뇨성 급성신부전을 보였다. 경증 질식 1명(10.0%), 중등도 질식 2명(18.2%), 중증 질식 5명(41.7%)에서 급성 신부전이 발생하였다(P>0.05). 뇌증 1단계 1명(25%), 뇌증 2단계 4명(50%), 뇌증 3단계 3명(75%)에서 급성신부전이 발생하였다(P<0.01). 5분 아프가 점수에 의한 질식의 정도와 저산소성 허혈뇌증 단계와의 통계학적 연관성은 없었다. 뇌실내 출혈 1단계 1명(7.7%), 2단계 0명, 3단계 2명(66.7%), 4단계 2명(100%)에서 급성신부전이 발생하였다(P<0.01). 급성신부전이 발생한 집단에서 발생하지 않은 집단보다 사망률이 더 높았다. (P<0.05). 감뇨성과 비감뇨성 급성신부전 간의 차이는 없었다. 결론 : 저산소성 허혈 뇌증이 심할수록 급성신부전 발생률이 높았으며, 급성신부전 발생 집단에서 예후가 더 좋지 않았다. 저산소성 허혈 뇌증환아에서 급성신부전을 조기에 진단하여 적절한 수액 및 전해질 공급을 하여야겠다.

• Clinical and Experimental Pediatrics
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• 제56권7호
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• pp.271-274
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• 2013

Brain insults, including neurotrauma, infection, and perinatal injuries such as hypoxic ischemic encephalopathy, generate inflammation in the brain. These inflammatory cascades induce a wide spectrum of cytokines, which can cause neuron degeneration, have neurotoxic effects on brain tissue, and lead to the development of seizures, even if they are subclinical and occur at birth. Cytokines are secreted by the glial cells of the central nervous system and they function as immune system mediators. Cytokines can be proinflammatory or anti-inflammatory. Interleukin (IL)-$1{\beta}$ and IL-8 are proinflammatory cytokines that activate additional cytokine cascades and increase seizure susceptibility and organ damage, whereas IL-1 receptor antagonist and IL-10 act as anti-inflammatory cytokines that have protective and anticonvulsant effects. Therefore, the immune system and its associated inflammatory reactions appear to play an important role in brain damage. Whether cytokine release is relevant for the processes of epileptogenesis and antiepileptogenesis, and whether epileptogenesis could be prevented by immunomodulatory treatment should be addressed in future clinical studies. Furthermore, early detection of brain damage and early intervention are essential for the prevention of disease progression and further neurological complications. Therefore, cytokines might be useful as biomarkers for earlier detection of brain damage in high-risk infants.

• Investigative Magnetic Resonance Imaging
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• 제12권1호
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• pp.49-54
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• 2008

목적 : 저산소성-허혈성 뇌증(HIE)의 확산강조영상(DWI) 소견을 알아보고자 하였다. 대상 및 방법 : 심폐기능 정지에 의한 뇌손상으로 심폐소생술을 통하여 소생된 6명의 환자를 대상으로 하였으며 뇌손상 후 MR검사까지의 시간 간격은 4일에서부터 32일까지 평균 11.8일 이었다. 전 예에서 T1 및 T2강조영상, FLAIR, DWI 및 현성확산계수영상을 얻었다. 병변의 분포, 각 영상에서의 신호 강도를 분석하였으며, T2 및 FLAIR영상과 비교한 DWI에서의 병변의 명확도를 분석하였다. 결과 : 전 예에서 T2, FLAIR 및 DWI에서 기저핵에 양측으로 대칭적인 고신호 강도의 병변을 볼 수 있었다. 현성확산계수영상에서는 이중 4예가 저신호 강도를, 2예는 동등신호 강도를 보였다. 병변의 명확도는 6예 중 4예에서 T2 및 FLAIR영상과 비교하여 DWI에서 뚜렷한 고신호 강도를 보였고, 2예에서는 비슷하였다. 대뇌 피질과 피질하 백질의 경우 6예 중 5예에서 T2, FLAIR 및 DWI에서 양측으로 대칭적인 고신호 강도를 보였고, 그 중 3예에서는 T2 및 FLAIR 영상과 비교하여 DWI에서 명확하게 보였다. 현성확산계수영상에서는 3예가 저신호 강도를, 나머지는 동등신호 강도를 보였다. 대뇌 심부백질의 경우 6예 중 4예에서 T2, FLAIR 및 DWI에서 양측으로 대칭적인 고신호 강도를 보였고, 그 중 1예에서만 T2 및 FLAIR 영상과 비교하여 DWI에서 명확하게 보였다. 결론 : HIE의 DWI 소견은 기저핵 및 대뇌 피질과 백질의 대칭적인 고신호 강도가 특징이며, T2 및 FLAIR영상보다 명확하였다.

• Clinical and Experimental Pediatrics
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• 제51권11호
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• pp.1205-1210
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• 2008

목 적: 뇌자기공명영상에서 정상소견을 보인 신생아와 뇌실주위 백질연화증을 보인 보인 미숙아와 저산소성 뇌손상 소견이 보이는 만삭아의 뇌량 크기를 비교하고 양적으로 분석하여 뇌량의 크기가 신생아시기에 신경학적 경과에 유용한 지표가 될 수 있는가에 대한 평가를 하고자 하였다. 방 법: 2002년 9월부터 2005년 2월까지 원광대학교병원에서 출생한 신생아에서 경련, 주산기 가사, 소두증, 늘어지는 영아증후군(floppy infant syndrome) 등 신경학적인 이상이 의심되어 뇌자기공명영상을 시행 후 정상소견을 보인 15명의 신생아와 이상소견을 보인 27명의 환아 등 총 42명 신생아의 뇌량 크기를 비교하였다. 선천적인 뇌 기형이 동반된 경우와 염색체 이상, 대사 이상, 신경계 감염이 동반된 예는 연구대상에서 제외 하였다. 각 군의 뇌자기공명 영상에서 시상의 정중면에서 보이는 뇌량 전후의 최장 길이와 뇌량슬부의 수평 최장 두께, 체부의 수직 최장 두께, 팽대부의 수평 최장 두께를 원광대학교병원 영상 분석 시스템의 자동 측량 방법으로 기록하였고 이렇게 얻어진 각 부위의 두께를 다시 뇌량 전후의 최장 길이로 나누어서 뇌량 전후 길이에 대한 뇌량슬, 체부, 팽대부의 두께에 대한 비율을 계산하여 얻어진 측정치를 정상소견을 보인 신생아의 수치와 저산소성 허혈성 뇌증 소견이 보이는 만삭아 19명과 뇌실주위 백질연화증이 있는 미숙아 8명의 뇌량 전후 길이에 대한 뇌량 각 부위 두께의 비를 비교 분석하였다. 결 과: 뇌량 전후의 길이에 대한 뇌량슬부와 팽대부 두께의 비는 정상 소견을 보인 대조군과의 비교에서 저산소성 허혈성 뇌증 소견이 보이는 만삭아와 뇌실주위 백질연화증 소견이 보이는 미숙아에서 각각 통계학적인 의의가 있는 차이는 보이지 않았다. 그러나 뇌량 전후의 길이에 대한 뇌량체부 두께의 비는 P value가 저산소성 허혈성 뇌증 소견이 보이는 만삭아의 경우에서는 0.042, 뇌실주위 백질연화증 소견이 보이는 미숙아의 경우에서는 0.017로 정상소견을 보인 대조군과는 통계적으로 의의 있는 차이를 보였다. 결 론: 뇌량의 크기나 모양은 대뇌백질의 부피나 백질의 수초화 정도를 나타내는 좋은 지표이므로 뇌자기공명영상에서 뇌량의 크기를 양적으로 측정하는 것은 뇌발달의 평가 및 출생 전후의 뇌손상의 정도와 범위를 평가하는데 유용할 뿐만 아니라 뇌성마비나 정신발달지체 등 향후 신경학적인 예후를 추정하는 데에도 큰 도움이 될 수 있을 것으로 생각된다.