Tatenobu Goto

Endogenous erythropoietin from astrocyte protects the oligodendrocyte precursor cell against hypoxic and reoxygenation injury

The hypoxia‐responsive cytokine erythropoietin (EPO) provides neuroprotective effects in the damaged brain during ischemic events and neurodegenerative diseases. The purpose of the present study is to evaluate the EPO/EPO receptor (EPOR) endogenous system between astrocyte and oligodendrocyte precursor cell (OPC) under hypoxia. We report here elevated EPO mRNA levels and protein release in cultured astrocytes following hypoxic stimulation by quantitative RT‐PCR and ELISA. Furthermore, the EPOR gene expressions were detected in cultured OPCs as in astrocytes and microglias by quantitative RT‐PCR. Cell staining revealed the EPOR expression in OPC. To evaluate the protective effect of endogenous EPO from astrocyte to OPCs, EPO/EPOR signaling was blocked by EPO siRNA or EPOR siRNA gene silencing in in vitro study. The suppression of endogenous EPO production in astrocytes by EPO siRNA decreased the protection to OPCs against hypoxic stress. Furthermore, OPC with EPOR siRNA had less cell survival after hypoxic/reoxygenation injury. This suggested that EPO/EPOR signaling from astrocyte to OPC could prevent OPC damage under hypoxic/reoxygenation condition. Our present finding of an interaction between astrocytes and OPCs may lead to a new therapeutic approach to OPCs for use against cellular stress and injury.

Edaravone, a novel free radical scavenger, reduces high-mobility group box 1 and prolongs survival in a neonatal sepsis model.

Free radicals play an important role in the inflammatory process of sepsis. We hypothesized that edaravone, a novel free radical scavenger, can suppress pathophysiological events and prolong survival in a neonatal sepsis cecal ligation and perforation (CLP) model. Of 32 3-day-old anesthetized and mechanically ventilated piglets, 11 received CLP only, 10 received CLP and edaravone treatment starting 30 min after CLP, and 11 constituted a sham (control) group. Mean arterial pressure (MAP), heart rate, cardiac output, arterial blood gas, serum total hydroperoxide, nitrite and nitrate, TNF-&agr;, and high-mobility group box 1 (HMGB1) were measured before CLP and at 1, 3, and 6 h after CLP. Compared with the CLP group, the edaravone group showed higher MAP at 6 h, lower heart rate at 1 and 3 h, lower total hydroperoxide at 1 h, lower nitrite and nitrate at 3 and 6 h, and higher (although not significantly so) mean cardiac output at 1, 3, and 6 h. TNF-&agr; elevation was delayed from 1 h in the CLP group to 3 h in the edaravone group. In the edaravone group, HMGB1 did not change significantly at any time, whereas in the CLP group, it increased at 6 h. Survival times were longer in the edaravone group than in the CLP group (15.4 ± 1.4 vs. 10.2 ± 1 h; P < 0.005). In addition, each of the serial dilutions of edaravone had a higher biological antioxidant potential than tempol does. In conclusion, edaravone suppressed free radicals, delayed the TNF-&agr; surge, and prevented HMGB1 elevation, thereby maintaining MAP and prolonging survival time in a neonatal sepsis CLP model.

High cerebrospinal fluid antioxidants and interleukin 8 are protective of hypoxic brain damage in newborns

Abstract The objective was to explain the discrepancy in the development of hypoxic ischemic brain injury (HIE) in some asphyxiated newborns rather than others. Forty newborns were classified according to their cerebrospinal neuron-specific-enolase (CSF-NSE) levels on their 5th-day of life; group 1 with low-NSE (n = 25). The remaining 15 newborns had high-NSE and were further divided into a group with no HIE (n = 10, group 2) and another with HIE (n = 5, group 3). CSF-NSE, totalhydroperoxide (TH), biological-antioxidant-potentials (BAPs), 12 cytokines and Erythropoietin (EPO) were measured. The TH/BAP gave the oxidative-stress-index (OSI). The BAPs of serial dilutions of three types of EPO were tested. CSF-NSE and TH and mean OSIs were higher in group 3. IL-8 and mean BAPs were higher in group 2 than in group 1. EPO was less detected in group 3. Serial EPO dilutions correlated with their BAPs. Compensatory antioxidants and IL-8 elevation could be protective of perinatal asphyxic brain injury. Antioxidative effect of EPO could be neuroprotective.

Children undergoing liver transplantation for treatment of inherited metabolic diseases are prone to higher oxidative stress, complement activity and transforming growth factor-β1.

BACKGROUND Main indications for liver transplantation in the pediatric population include biliary atresia and inherited metabolic diseases. The present study evaluated whether there are differences between pediatric patients undergoing living-related liver transplantation due to the two diseases in terms of their oxidative and immunological status during their regular outpatient follow-up visits. MATERIAL AND METHODS A clinical outpatient study measuring serum oxidative stress index (calculated as serum oxidant/antioxidant ratio, in the form of serum total hydroperoxide/serum biological antioxidative potential), serum terminal complement component 5a, as an indicator of complement activity and immunological status, and transforming growth factor-ß1, as a marker of liver fibrosis, in 16 patients (6 males and 10 females, 2.5-15 years old) who received living-related liver transplantation due to inherited metabolic diseases (n=6; in the form of propionic acidemia [n=1], methylmalonic acidemia [n=1], arginase deficiency [n=1], tyrosinemia [n=2], and glycogen storage disease type 1b [n=1], with an age range of 2.4-14.6 years old) and due to biliary atresia ([n=10], with an age range of 2.9-14.5 years old). RESULTS Serum oxidative stress index, complement component-5a, and transforming growth factor-ß1 were significantly higher in the inherited metabolic diseases group than in the biliary atresia group. In all patients, serum oxidative stress index correlated positively with complement component-5a and transforming growth factor-ß1. CONCLUSIONS Patients who receive living-related liver transplantation due to inherited metabolic diseases are prone to higher oxidative stress, complement activity, and serum transforming growth factor-ß1.

Neonatal Central Diabetes Insipidus Caused by Severe Perinatal Asphyxia

We describe three rare cases of neonatal central diabetes inspidus (CDI) caused by severe perinatal asphyxia. In these cases, hypernatremia, high plasma osmolality and hyposthenuria, with polyuria occurred after one week of age. CDI in one case might be due to the temporal dysfunction of hypothalamic-neurohypophyseal axis and the other two cases to permanent dysfunction. Although these cases are rare, early diagnosis and treatment of CDI are indispensable. Follow-up of serum sodium, serum and urine osmolality is necessary after acute phase to maintain water and electrocyte homeostasis in severe perinatal asphyxia.

Periventricular leukomalacia is decreasing in Japan.

Periventricular leukomalacia is recognized as the leading cause of cerebral palsy in preterm infants. To clarify the prevalence of periventricular leukomalacia and cerebral palsy in Japan, a nationwide survey was performed. The prevalence of periventricular leukomalacia in the group of surviving preterm infants of gestational ages less than 33 weeks born in 2007 was 2.7% (78/2883) on ultrasound diagnosis, and 3.3% (92/2824) on magnetic resonance imaging. The prevalence of cerebral palsy was 4.3% (125/2883) on clinical diagnosis. In our previous study, the prevalences of periventricular leukomalacia in 1990-1991, 1993-1994, 1996, and 1999 were 4.8%, 4.9%, 4.9%, and 5.3% on ultrasound, and 7.9%, 7.7%, 6.9%, and 7.3% on magnetic resonance imaging, respectively. The prevalence of periventricular leukomalacia has decreased significantly in Japan.

Endothelin receptor antagonist attenuates oxidative stress in a neonatal sepsis piglet model

Background:Oxidative stress (oxidant–antioxidant imbalance) plays an important role in the pathophysiology of neonatal sepsis. This study evaluated whether an antisense peptide endothelin receptor antagonist, ETR-P1/fl, could attenuate oxidative stress in a neonatal sepsis model.Methods:A total of 18 3-d-old piglets were anesthetized and mechanically ventilated. Six piglets received cecal ligation and perforation (CLP group) for induction of sepsis. Six piglets also received continuous infusion (0.05 mg/kg/h) of ETR-P1/fl 30 min after CLP (ETR-P1/fl group). Six piglets received a sham operation. Serum total hydroperoxide (TH), biological antioxidant potentials (BAPs), oxidative stress index (OSI, calculated as TH/BAP), interleukin (IL)-6, serum glutamic oxaloacetic transaminase (GOT), and creatinine were measured before CLP and at 1, 3, and 6 h after CLP.Results:CLP evoked a state of shock resulting in elevated TH, OSI, and IL-6 levels. ETR-P1/fl administration after CLP resulted in lower serum TH at 1 and 3 h after CLP, OSI at 1 and 3 h after CLP, IL-6 at 1 and 3 h after CLP, and GOT at 3 and 6 h after CLP as compared with the CLP group.Conclusion:ETR-P1/fl treatment significantly attenuated the elevation of serum oxidative stress markers (TH and OSI), IL-6, and GOT in a progressive neonatal sepsis CLP model.

Hypothermia attenuates the severity of oxidative stress development in asphyxiated newborns

PURPOSE This retrospective case-control study aimed to examine the development of oxidative stress in asphyxiated infants delivered at more than 37 weeks of gestation. MATERIAL AND METHODS Thirty-seven neonates were stratified into 3 groups: the first group experienced hypothermia (n = 6); the second received hypothermia cooling cup treatment for 3 days, normothermia (n = 16); and the third was the control group (n = 15). Serum total hydroperoxide (TH), biological antioxidant potential, and oxidative stress index (OSI) (calculated as TH/biological antioxidant potential) were measured within 3 hours after birth. RESULTS Serum TH and OSI levels gradually increased after birth in hypothermia and normothermia cases. At all time points, serum TH and OSI levels were higher in hypothermia and normothermia cases than in control cases. Serum TH and OSI levels were higher in normothermia cases than in hypothermia cases at days 3, 5, and 7. CONCLUSION This study demonstrated that hypothermia attenuated the development of systemic oxidative stress in asphyxiated newborns.

Fatal Tension Pneumopericardium in an Extremely Low Birth Weight Infant to Identify the Perforation Site of the Pericardium

A pneumopericardium is a very rare condition and is the least common form of air leak in neonates. A tension pneumopericardium is associated with very high mortality. Neonatal pneumopericardium is usually a complication of mechanical ventilation in premature infants with respiratory distress syndrome. The mechanism of this rare condition and the perforation site of the pericardium have largely been speculative. This case report documents an extremely low birth weight infant who developed fatal tension pneumopericardium, and the autopsy revealed airflow into the pericardial sac through a perforation site of the pericardium near the ostia of the right pulmonary vein. This is a valuable case in which the perforation site of the pericardium was confirmed.

Viral Load Before and After Exchange Transfusion in a Neonate with Hyperbilirubinemia and Congenital Cytomegalovirus Infection

Introduction: Cytomegalovirus is the most common cause of intrauterine infection in developed countries. Between 10% and 15% of infants infected with congenital cytomegalovirus exhibits the clinically apparent or symptomatic form of the disease. Exchange transfusion is an established therapy for hyperbilirubinemia and severe anemia. However, to the best of our knowledge, the viral load of cytomegalovirus before and after exchange transfusion has not been previously reported. Case report: A Japanese female was delivered at 36 weeks of gestation to a 29-year-old gravida 3 para 3 by emergency Cesarean section because of non-reassuring fetal status. Hepatomegaly, splenomegaly, generalized petechiae, leptocephaly, and jaundice were noted at birth. On admission, her total bilirubin was 14.2 mg/dL, cytomegalovirus immunoglobulin M was positive (4.63 mg/dL), and her head ultrasound and computed tomography showed left intraventricular calcification and bilateral ventriculomegaly. Toxoplasma, rubella, and herpes simplex virus serologies were negative. The exchange transfusion was performed for the treatment of early onset hyperbilirubinemia, not for the treatment of congenital cytomegalovirus infection. The cytomegalovirus viral load before and after exchange transfusion was investigated by real-time polymerase chain reaction, and the plasma viral load of cytomegalovirus was not significantly decreased from before (8.7×105/mL) to after (4.3×105/mL) exchange transfusion. Conclusion: Exchange transfusion did not reduce the viral load of cytomegalovirus in severe congenital cytomegalovirus infection.