[Show abstract][Hide abstract] ABSTRACT: 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.
Annals of transplantation : quarterly of the Polish Transplantation Society. 02/2013; 18:63-8.
[Show abstract][Hide abstract] ABSTRACT: Neonatal alloimmune thrombocytopenia (NAIT) is a rare but clinically important etiology of intracranial hemorrhage. There have been no reported cases of intracranial hemorrhage caused by anti-group A or anti-group B antibodies. A Japanese boy weighing 1550 g was born at 37 weeks. He suffered from refractory thrombocytopenia and developed severe intracranial hemorrhage on his second day. Despite repeated platelet, red-cell and fresh-frozen-plasma transfusions, he died at day 10 of life. Serological studies and genotyping of the patient and his parents were performed. There were no incompatible genotypes of platelet antigens between the patient and the mother. Serological studies revealed that the mother had extremely high-titer anti-group A immunoglobulin G(2) (4096-fold) that reacted strongly with the father's platelets. The reaction against the father's platelets disappeared when her serum was adsorbed with group A red blood cells. Maternal anti-group A antibody was associated with NAIT and severe bilateral intracranial hemorrhage.
Journal of perinatology: official journal of the California Perinatal Association 01/2013; 33(1):79-82. · 1.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To study the effect of exchange transfusion on cytokine profiles in a patient with necrotizing enterocolitis, the levels of 12 cytokines and serum calprotectin were measured among exchange transfusion. A male extremely low birth weight infant was in non-compensated shock and diagnosed stage 3 necrotizing enterocolitis. Exchange transfusion was performed for critical condition, refractory hypotension and disseminated intravascular coagulation. After exchange transfusion, the patient's blood pressure increased and stabilized. Then an enterostomy was performed and revealed necrosis of the ascending colon. Of the cytokines examined, interleukin-8 and serum calprotectin were high before exchange transfusion and decreased after exchange transfusion.
Pediatrics International 12/2012; 54(6):931-3. · 0.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:Oxidative stress (oxidant/antioxidant imbalance) plays an important role in the pathophysiolog of neonatal sepsis. The present study evaluated whither an antisense peptide endothelin receptor antagonist ETR-P1/fl could attenuate oxidative stress in a neonatal sepsis model.Methods:Eighteen 3-day-old piglets were anesthetized and mechanically ventilated. Six piglets received cecal ligation and perforation (CLP) (CLP group) for induction of sepsis. Six piglets also received continuous infusion (0.05mg/kg/h) of ETR-P1/fl 30 minutes after CLP (ETR-P1/fl group). Six piglets received a sham operation. Serum total hydroperoxide (TH), biological antioxidant potentials (BAP), 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 6h after CLP.Results:CLP evoked a state of shock resulting in elevated TH, OSI and IL-6. ETR-P1/fl administration after CLP resulted in lower serum TH at 1 and 3h after CLP, OSI at 1 and 3h after CLP, IL-6 at 1 and 3h after CLP, and GOT at 3 and 6h after CLP compared to 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.Pediatric Research (2012); doi:10.1038/pr.2012.134.
[Show abstract][Hide abstract] ABSTRACT: Perinatal hypoxia-ischemia (HI) frequently causes white-matter injury, leading to severe neurological deficits and mortality, and only limited therapeutic options exist. The white matter of animal models and human patients with HI-induced brain injury contains increased numbers of oligodendrocyte progenitor cells (OPCs). However, the origin and fates of these OPCs and their potential to repair injured white matter remain unclear. Here, using cell-type- and region-specific genetic labeling methods in a mouse HI model, we characterized the Olig2-expressing OPCs. We found that after HI, Olig2+ cells increased in the posterior part of the subventricular zone (pSVZ) and migrated into the injured white matter. However, their oligodendrocytic differentiation efficiency was severely compromised compared with the OPCs in normal tissue, indicating the need for an intervention to promote their differentiation. Erythropoietin (EPO) treatment is a promising candidate, but it has detrimental effects that preclude its clinical use for brain injury. We found that long-term postinjury treatment with a nonerythropoietic derivative of EPO, asialo-erythropoietin, promoted the maturation of pSVZ-derived OPCs and the recovery of neurological function, without affecting hematopoiesis. These results demonstrate the limitation and potential of endogenous OPCs in the pSVZ as a therapeutic target for treating neonatal white-matter injury. STEM Cells2012;30:2234-2247.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: This retrospective case-control study aimed to examine the development of oxidative stress in asphyxiated infants delivered at more than 37 weeks of gestation.
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.
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.
This study demonstrated that hypothermia attenuated the development of systemic oxidative stress in asphyxiated newborns.
Journal of critical care 02/2012; 27(5):469-73. · 2.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Vitamin B12 deficiency in infants often presents with nonspecific hematological, gastrointestinal, and neurological manifestations. It is usually caused by inadequate intake, abnormal absorption, or congenital disorders of vitamin B12 metabolism, including transport disorders. We describe a vitamin B12-deficient infant with severe anemia who was breastfed. His mother had undiagnosed vitamin B12 deficiency having undergone total gastrectomy 18 years earlier. The infant developed normally after taking vitamin B12. It is important to suspect vitamin B12 deficiency in mothers who have undergone gastrectomy. Early diagnosis and treatment of vitamin B12 deficiency in infants is important and will help improve long-term prognosis.
Journal of Pediatric Hematology/Oncology 10/2011; 33(7):556-8. · 0.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Journal of Neuroscience Research 10/2011; 89(10):1566-74. · 2.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Oxidative stress has been suspected to influence graft survival and prognosis in pediatric recipients of living related liver transplantation (LRLT).
We determined the oxidative status of pediatric LRLT recipients during their regular outpatient follow-up visits, and looked for a relationship between oxidative status and post-liver transplantation (post-LTx) duration.
The study included 43 patients (20 males and 23 females) between the ages of 1.6 and 25.1 years (median 10.7 years) who had undergone LRLT from 5 months to 17.5 years (median 7 years) prior to the study, between the ages of 1.2 and 14.4 years (median 3.5 years).
Serum glutamic pyruvic transaminase (GPT), glutamic oxaloacetic transaminase (GOT), gamma-glutamyl transpeptidase (γ-GTP), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), direct bilirubin and choline-esterase were measured as part of the patients' regular follow-up visits. Serum total hydroperoxide (TH) and biological antioxidative potential (BAP) were measured using the free radical analytic system which requires 20 μl of serum and 10 min of processing time for each sample. Oxidative stress index (OSI) was calculated as the ratio of TH to BAP.
Serum OSI correlated positively with serum levels of GOT, GPT, LDH, ALP, γ-GTP and direct bilirubin. Serum OSI, TH, LDH, ALP and GOT correlated negatively with post-LTx duration. Serum BAP correlated positively with post-LTx duration. Serum TH correlated positively with serum GOT and γ-GTP, but negatively with serum BAP.
(1) The OSI, which can be calculated based on data acquired through a simple outpatient procedure, can serve as an index of our patients' laboratory results and oxidative status. (2) The LRLT recipients in our study were at risk for oxidative stress early in the post-operative period, but this risk subsided with time.
Pediatric Surgery International 01/2011; 27(1):17-22. · 1.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Systemic infection in the newborn (neonatal sepsis) is the most common cause of neonatal mortality. Neonatal sepsis is complicated by pulmonary hypertension. In this study, we analyzed the effect of edaravone, a free radical scavenger that is known to reduce the production of inflammatory mediators, such as tumor necrosis factor α (TNFα), on pulmonary hypertension. Experimental and sham groups were drawn from 19 three-day-old piglets; 5 underwent a modified procedure of cecal ligation and perforation (CLP) (CLP group), 8 underwent CLP followed 30 min later by edaravone intravenous administration (edaravone group), and 6 did not undergo CLP and did not receive edaravone (sham group). To evaluate the pulmonary blood pressure despite the sepsis-induced low cardiac output, mean arterial blood pressure (mABP), mean pulmonary arterial pressure (mPAP), and comparative pulmonary hypertension ratio (mPAP/mABP) were determined. Serum TNFα levels were measured before the procedure and at 1, 3, and 6 h after. The mPAP levels were higher in the CLP group at 9 h compared to the edaravone group. The mPAP/mABP ratio was lower in the edaravone and sham groups compared to the CLP group at 6 and 9 h. TNFα in the edaravone and sham groups were lower at 1 and 3 h compared to that in the CLP group. In all animals, mPAP/mABP at 6 h correlated with serum levels of TNFα at 1, 3, and 6 h. These findings suggest that edaravone ameliorates the severity of pulmonary hypertension in a neonatal sepsis model by reducing serum TNFα levels.
The Tohoku Journal of Experimental Medicine 01/2011; 223(4):235-41. · 1.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate effects of endothelin receptor antagonist ETR-P1/fl in a neonatal sepsis model.
Eighteen anesthetized and mechanically ventilated 3-day-old piglets were divided into three groups. Six piglets received cecal ligation and perforation (CLP group). Six piglets were administrated a continuous infusion of ETR-P1/fl (0.05 mg/kg/h), an antisense homology box-derived peptide with an endothelin A receptor antagonist effect, starting 30 min after CLP (ETR-P1/fl group). Six piglets acted as the sham group. Mean arterial pressure (MAP), heart rate, cardiac output, arterial blood gas, body temp (BT), serum nitrite and nitrate (NOx), tumor necrosis factor (TNF)-α, and high-mobility group box 1 (HMGB-1) were measured before CLP and at 1, 3, 6, and 9 h after CLP.
Cecal ligation and perforation exposure evoked a state of shock and showed deteriorated cardiac output, pulmonary hypertension, decreased MAP, low oxygen saturation, and base excess (BE) with elevated TNF-α, NOx, and HMGB1. ETR-P1/fl administration resulted in higher MAP at 6 and 9 h after CLP, less negative BE, lower mean pulmonary arterial pressure (mPAP)/MAP ratio at 9 h after CLP, and lower TNF-α, NOx, and HMGB-1 compared to the CLP group. BT showed no differences between the groups. Survival time in the ETR-P1/fl group was longer than in the CLP group (18.9 ± 2.3 h vs. 9.0 ± 0.8 h, p < 0.01).
ETR-P1/fl treatment significantly attenuated the elevation of NOx, TNF-α, and HMGB-1, which improved the systemic hypotension, pulmonary hypertension, and blood gases, thereby causing improvement of survival time in a progressive neonatal sepsis CLP model.
European Journal of Intensive Care Medicine 12/2010; 36(12):2132-9. · 5.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Valproate (VPA) is a simple fatty acid and a substrate for the fatty acid β-oxidation pathway. Previous data suggested that the toxicity of VPA may be provoked by carnitine deficiency and the inhibition of mitochondrial β-oxidation.
The aim of the present study was to elucidate the effect of VPA treatment on carnitine and isomer-differentiated acylcarnitine disposition, and determined the relationships between acylcarnitines and blood VPA levels in long-term treated patients with VPA and/or other antiepileptic drugs.
Serum samples were obtained from children aged 1-15 years old treated for at least 6 months with VPA alone (n=28) or VPA combined with other anticonvulsants (n=23) and untreated controls (n=23). Serum acylcarnitines were separated from their isomers and quantified using high-performance liquid chromatography-tandem mass spectrometry.
We found higher 3-hydroxyisovalerylcarnitine levels and trace amounts of valproylcarnitine in both VPA monotherapy and polytherapy patients. Other acylcarnitines, hexanoylcarnitine, C12, C14:1-carnitines and the ratio of long-chain acylcarnitine to free carnitine were also higher in VPA polytherapy individuals than in controls. VPA monotherapy does not result in decreases in free carnitine or in the accumulation of long-chain acylcarnitines. Blood VPA concentrations correlated positively with hexanoylcarnitine, C12, C14:1, C16:1, C18:1-carnitines in all VPA-treated children (n=51).
Long-term VPA treatment in pediatric patients could affect some specific acylcarnitines, which is enhanced by the concomitant use of other anticonvulsants, and the formation of valproylcarnitine alone seems insufficient to develop severe carnitine deficiency at therapeutic doses of VPA.
Brain & development 12/2010; 33(10):816-23. · 1.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: ABO-incompatible liver transplantation (LTx) is becoming more common in response to the paucity of liver allografts. Several studies have expressed concern about the effect of ABO compatibility on graft survival.
To evaluate the differences in serum cytokine levels between ABO-incompatible (ABO-i) and ABO-compatible (ABO-c; includes ABO-compatible and identical) pediatric LTx recipients during regular outpatient follow-up. Note that, in the field of organ transplantation, transplants are categorized as incompatible, compatible or identical; accordingly, these are the terms we use in the paper.
A clinical outpatient study measuring serum transforming growth factor (TGF)-β1, interferon (IFN)-γ, interleukin (IL)-2 and IL-10 in 43 living related liver transplantation (LRLT) recipients, of whom 36 received ABO-c LRLT (34 were ABO-identical and 2 were non-identical) and 7 ABO-i LRLT. Serum glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, gamma-glutamyl transpeptidase, alkaline phosphatase, lactate dehydrogenase and bilirubin were measured as part of the patients' regular follow-up visits.
There were no differences between the ABO-c and ABO-i groups in terms of recipient's age [mean 12.6 vs. 11.1 years (y)], post-LTx duration (mean 7.3 vs. 7.3 y), donor's age (mean 35.5 vs. 34.6 y), body weight (28.9 ± 2.9 vs. 27.9 ± 6.9 kg), or gender (19 female and 17 male vs. 4 female and 3 male). Serum TGF-β1, IFN-γ and IL-2 were significantly higher in the ABO-i group than in the ABO-c group. IL-10, however, did not differ between the two groups. There was a tendency toward higher γGTP levels in the ABO-i group, but this difference did not reach significance.
ABO-incompatible LRLTx patients have higher serum TGF-β1, IFN-γ and IL-2 levels as measured at regular outpatient visits. As a result, they face a higher risk of T-helper 1 cell polarization, which could make graft rejection more likely.
Pediatric Surgery International 11/2010; 27(3):263-8. · 1.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Vigabatrin (VGB) is one of the most effective anti-epileptic drugs for tonic spasms, those accompanied with tuberous sclerosis complex (TSC), but is not available in Japan. We treated 7 patients with West syndrome (WS) and TSC with VGB. In these patients, VGB treatment was started at 5-65 months of age. Six patients (86%) had complete cessation of tonic spasms. Of these, 3 patients had complete cessation within 24 hours after VGB treatment. The mean initial dosage of VGB was 36.2 mg x kg(-1) x day(-1), and the mean maintenance dosage was 38.4 mg x kg(-1) x day(-1). At the beginning of VGB treatment, 3 patients had hypsarrhythmia, 2 had focal discharge with generalization, and 2 had only focal discharge on electroencephalography. Hypsarrhythmia disappeared within 4-8 weeks after VGB treatment. Behavioral problems and sleep difficulty were observed in 6 patients. Visual field examination revealed no abnormalities in 3 patients. We hope that patients with WS and TSC can be treated with VGB as soon as possible in Japan.
No to hattatsu. Brain and development 11/2010; 42(6):444-8.
[Show abstract][Hide abstract] ABSTRACT: SUMMARY: To study the effect of exchange transfusion on cytokine profiles in a patient with transient myeloproliferative disorder and hepatic fibrosis in which cytokines were measured before and after exchange transfusion. A newborn female was diagnosed with Down syndrome phenotypically and on karyotyping. Laboratory data showed a high leukocyte count with blast cells in the peripheral blood and liver dysfunction. Exchange transfusion was performed on day 1. However, respiratory distress and multiorgan failure progressed, and she died after 16 days. Of the cytokines examined, transforming growth factor-beta1 and interleukin-7 were extremely high before exchange transfusion, and decreased after exchange transfusion.
Journal of Pediatric Hematology/Oncology 05/2010; 32(4):e164-6. · 0.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Rotavirus, one of the major causes of severe gastroenteritis in children, occasionally causes central nervous system complications. Recently several patients with acute encephalitis/encephalopathy due to rotavirus associated with cerebellar signs and symptoms have been reported. The condition is characterized by disturbances of consciousness at onset and cerebellar signs and symptoms such as hypotonia, ataxia, dysmetria, and speech disorders, including mutism, slow speech, and dysarthria at convalescence. We report two patients (3-year-old girl, 2-year-old boy) who developed acute encephalitis due to rotavirus and showed cerebellar signs and symptoms. Both patients had characteristic history of consciousness disturbances subsequent to several days of diarrhea, vomiting and fever, and cerebellar symptoms such as hypotonia, ataxia, dysmetria, and speech disorders during the recovery period. Electroencephalography showed diffuse high-voltage delta wave activity in each patient. Brain magnetic resonance imaging showed cerebellar edema in the acute phase followed by cerebellar atrophy on follow-up images in both patients. In the first patient, diffusion-weighted images (DWI) revealed high signals at the left cerebellar peduncle region and apparent diffusion coefficient (ADC) maps showed decreased ADC values of the lesion in the acute phase. The first patient had dysmetria at 1-year follow-up. However, she had normal motor and cognitive functions and could lead her daily life without impairment. In the second patient, no further symptoms were apparent at 1-year follow-up. Acute encephalitis/encephalopathy due to rotavirus with cerebellar signs and symptoms might be diagnosed on DWI, by demonstrating decreased ADC values in acute phase.
European Journal of Pediatrics 05/2010; 169(10):1287-91. · 1.98 Impact Factor