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Nobiletin (5,6,7,8,3',4'-hexamethoxyflavone) is one of the flavonoids found in shikuwasa, a popular citrus fruit in Okinawa, Japan. It exerts various pharmacological effects, such as anti-tumor, antioxidant, and anti-inflammatory activities. We herein investigated whether nobiletin attenuated lipopolysaccharide (LPS)-induced inflammatory responses in the murine microglial cell line BV-2 and neuroinflammation in mice induced by an intracerebral injection of LPS. In BV-2 cells, nobiletin significantly inhibited the LPS-induced production of nitric oxide (NO) and prostaglandin E2 (PGE2) by preventing the mRNA expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), respectively. Nobiletin also inhibited the LPS-induced mRNA expression of CCL2, CXCL1, IL-6, and TNFα. Nobiletin markedly attenuated the transcriptional activity of the NF-κB p65 subunit without affecting the degradation of IκBα or the nuclear localization of the NF-κB p65 subunit. Nobiletin also inhibited the LPS-induced activation of JNK, but not ERK or p38, in BV-2 cells. Furthermore, the administration of nobiletin significantly suppressed the accumulation of microglia and induction of the mRNA expression of CCL2, CXCL1, IL-6, and TNFα in the murine brain induced by injecting LPS into the striatum. Collectively, these results suggest the potential of nobiletin as a candidate anti-inflammatory drug for the prevention of neuroinflammation., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Rituximab is a promising option for refractory idiopathic nephrotic syndrome. However, no simple predictive markers for relapse after rituximab have been established. To determine such markers, we investigated the relationship between CD4 + and CD8 + cell counts and relapse after rituximab administration., Methods: We retrospectively investigated patients with refractory nephrotic syndrome who received rituximab followed by immunosuppressive as maintenance therapy. Patients were divided into no relapse in 2 years after rituximab treatment or relapse group. After rituximab treatment, CD4 + /CD8 + cell counts were measured monthly, at prednisolone discontinuation, and at B-lymphocyte recovery. To predict relapse, these cell counts were analyzed using receiver operating characteristic (ROC). Additionally, relapse-free survival was reevaluated based on the result of ROC analysis for 2 years., Results: Forty-eight patients (18 in the relapse group) were enrolled. At prednisolone discontinuation (52 days after rituximab treatment), the relapse-free group showed significantly lower cell counts than the relapse group (median CD4 + cell count: 686 vs. 942 cells/µL, p = 0.006; CD8 + : 613 vs. 812 cells/µL, p = 0.005). In the ROC analysis, CD4 + cell count > 938 cell/µL and CD8 + cell count > 660 cells/µL could predict relapse in 2 years (sensitivity, 56% and 83%; specificity, 87% and 70%). The patient group with both lower CD4 + and CD8 + cell counts showed significantly longer 50% relapse-free survival (1379 vs. 615 days, p < 0.001 and 1379 vs. 640 days, p < 0.001)., Conclusions: Lower CD4 + and CD8 + cell counts in the early phase after rituximab administration may predict a lower risk of relapse., (© 2023. The Author(s), under exclusive licence to The Japanese Society of Nephrology.)

Background: Glucocorticoid discontinuation, a challenge in systemic lupus erythematosus (SLE), might be achievable with the advent of new therapeutic options., Methods: This single-center study included 31 children with newly diagnosed pediatric SLE between 2002 and 2021, after the exclusion of patients who were followed for less than 1 year after treatment initiation and those lost to follow-up. Patient characteristics, clinical course including flares, treatment, glucocorticoid discontinuation, and outcomes were retrospectively analyzed., Results: Glucocorticoids could be discontinued in 19 (61%) patients during a median observation period of 105.5 (range, 17-221) months. Of these, 5 (26%), 12 (63%), and 18 (95%) patients could discontinue glucocorticoids in 3, 5, and 10 years from treatment initiation, respectively. Additionally, 18 of the 19 patients did not experience flares after glucocorticoid discontinuation during a median duration of 37.2 (7.2-106.8) months. Three of the nineteen patients achieved drug-free remission. At last follow-up, all patients achieved low disease activity with or without glucocorticoids and 19, 8, and 1 patient were receiving mycophenolate mofetil (MMF), MMF plus tacrolimus, and MMF plus ciclosporin A, respectively. Flares were observed in 15 patients during the observation period. MMF as initial immunosuppressant (P = 0.01) and shorter interval between therapy initiation and achieving maintenance prednisolone dose of 0.1-0.15 mg/kg/day (P = 0.001) were associated with significantly reduced flare risk. Femoral head necrosis was observed in two patients., Conclusion: Despite the small sample size, these results support glucocorticoid discontinuation as a therapeutic target in pediatric SLE., (© 2021. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: Risks and renal outcomes of severe acute kidney injury (AKI) in children with steroid-resistant nephrotic syndrome (SRNS), particularly those who require dialysis, have not been fully explored., Methods: This retrospective cohort study enrolled children who had been diagnosed with idiopathic nephrotic syndrome at the National Center for Child Health and Development between March 2002 and December 2018. Children with steroid-sensitive nephrotic syndrome or SRNS-related gene mutations were excluded., Results: Sixty-two children with SRNS (37 boys; median age, 3.6 years [interquartile range (IQR) 2.0-10.3]) were enrolled. Sixteen patients (25.8%) had severe AKI, including nine patients (14.5%) who received dialysis. The period from nephrotic syndrome (NS) onset to partial remission (median [IQR]) was not significantly influenced by dialysis status, but tended to be longer in the dialysis group (125 days [74-225] vs. 40 days [28-113]; p = 0.09); notably, no patient developed chronic kidney disease during the follow-up period. Infection and posterior reversible encephalopathy (PRES) were significantly associated with AKI. Patients with AKI tended to require dialysis in the presence of infection, undergo treatment with cyclosporine A, and have PRES. The period from onset of NS to AKI was significantly longer in the dialysis group (26 days [15.5-46.0] vs. 4 days [0.0-14.0]; p = 0.01)., Conclusion: Dialysis was commonly required among children with SRNS who exhibited severe AKI. The period from onset of NS to partial remission tended to be longer in patients receiving dialysis, whereas renal prognosis was satisfactory during subsequent follow-up., (© 2022. The Author(s), under exclusive licence to The Japanese Society of Nephrology.)

Background: There have been no reports on both anaphylaxis incidence rate in schools, kindergarten, and nurseries, or how teachers have treated these children. This study was a fact-finding survey aimed at determining if appropriate responses to anaphylaxis onset were implemented in Oita Prefecture, Japan., Methods: The Oita Prefectural Allergy Control Committee administered a questionnaire using Google forms to all public and private schools, public and private kindergartens, certified child-care facilities, and day-care centers in the prefecture., Results: Responses to the questionnaire were obtained from 597 institutions, of which 125 890 children were affiliated with the responding institutions. Forty-eight children developed symptoms for which an adrenaline auto-injector was recommended in an Oita guideline. Among these children, three used the adrenaline auto-injector, three were prescribed the adrenaline auto-injector but were unable to use it, 27 were unable to use it as they were not prescribed an adrenaline auto-injector, and the final 15 responded that they handled their symptoms via another method because none of the above options apply., Conclusions: Most children who developed symptoms which an adrenaline auto-injector was recommended had no prescription for an adrenaline auto-injector. There is thus a need for appropriate response training to anaphylaxis whether or not an adrenaline auto-injector was prescribed., (© 2021 Japan Pediatric Society.)

Background: Although hypotension is a life-threatening complication of nephrectomy in children, risk factors for its development remain unknown. We evaluated the incidence, clinical course, and associated risk factors of pediatric post-nephrectomy hypotension in an observational study., Methods: This retrospective observational study included the clinical data of children who underwent nephrectomy in our center between 2002 and 2020. Patients undergoing nephrectomy at kidney transplantation and those who developed hypotension before nephrectomy were excluded., Results: The study included 55 nephrectomies in 51 patients, including 42 unilateral, 4 two-stage bilateral, and 5 simultaneous bilateral nephrectomies. The diagnoses were isolated Wilms tumor, neuroblastoma, congenital nephrotic syndrome, Denys-Drash syndrome, WAGR (Wilms tumor, aniridia, genitourinary malformations, and mental retardation) syndrome, and autosomal recessive polycystic kidney disease in 24, 10, 9, 6, 1, and 1 patient, respectively. Post-nephrectomy hypotension developed in 11 (20%) patients. Two patients (3.6%) had persistent hypotension; both had their kidneys resected, and one patient (1.8%) died. Male sex, kidney disease, resection of both kidneys, low estimated glomerular filtration rate, increased left ventricular posterior wall thickness in diastole, hypertension before nephrectomy, antihypertensive use, hyperreninemia, and hyperaldosteronism were significantly associated with post-nephrectomy hypotension. Multivariate logistic regression analysis revealed that hypertension before nephrectomy was the only significant risk factor for post-nephrectomy hypotension (P = 0.04)., Conclusions: Hypertension before nephrectomy is a significant risk factor for pediatric post-nephrectomy hypotension. Life-threatening hypotension, which might occur after bilateral nephrectomy in infants, should be considered, especially in children with higher risks., (© 2021. IPNA.)

Introduction: Peritonitis due to Mycobacterium avium complex (MAC) is a rare but life-threatening complication in patients on peritoneal dialysis (PD). However, optimal therapeutic regimen, treatment duration, and appropriate timing of kidney transplantation (KT) after treatment are unknown., Symptoms: We herein report a 4-year-old boy on PD due to end-stage kidney disease resulting from bilateral hypoplastic kidneys. He was admitted for peritonitis complaining fever, abdominal pain, and cloudy peritoneal effluent on PD after accidentally biting and opening the PD catheter while in the bath. Initial treatment with vancomycin and ceftazidime for 2 weeks was successful, although peritonitis recurred 37 days after discharge., Diagnosis: Mycobacterial culture was positive 9 days after readmission, and MAC was grown in the PD culture on day 30. We diagnosed him with MAC peritonitis that occurred on PD., Interventions: Clarithromycin, ethambutol, and rifampicin were initiated. The PD catheter was removed, and hemodialysis was initiated with a cuffed catheter inserted in the internal jugular vein. Follow-up observation for 8 months after the cessation of 1-year anti-mycobacterial therapy confirmed no recurrence of MAC infection, and the patient received living-donor KT from his father., Outcomes: His renal function was stable, with no recurrence of MAC peritonitis at 2 years after the KT., Conclusion: To the best of our knowledge, this is the first report of a patient who successfully underwent KT after receiving treatment for MAC peritonitis. One-year anti-mycobacterial therapy, PD catheter removal, 8-month observation after the cessation of therapy led the successful KT, although further investigation is warranted to confirm the efficacy of this approach., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: There are two approaches for treating cytomegalovirus (CMV) infection occurring after kidney transplantation (KTx). One is preemptive therapy in which treatment is started after confirming positive CMV antigenemia using periodic antigenemia assay. The other approach is prophylactic therapy in which oral valganciclovir (VGCV) is started within 10 days after KTx and continued for 200 days. The Transplantation Society guidelines recommend prophylactic therapy for high-risk (donor's CMV-IgG antibody positive and recipient's negative) pediatric recipients. However, the adequate dose and side effects of VGCV are not clear in children, and there is no sufficient information about prophylaxis for Japanese pediatric recipients., Methods: A single-center retrospective analysis was conducted on case series of high-risk pediatric patients who underwent KTx and received oral VGCV prophylaxis at the Department of Pediatric Nephrology, Tokyo Women's Medical University, between August 2018 and March 2019. Data were collected using medical records., Results: The dose of administration was 450 mg in all the study patients (n = 5). Reduction or discontinuation was required in four of five patients due to adverse events, which included neutropenia in one patient, anemia in two patients, and neutropenia and digestive symptoms in one patient. Late-onset CMV disease occurred in all patients. No seroconversion was observed during prophylaxis., Conclusions: Our preliminary study suggests that the dosage endorsed by The Transplantation Society may be an overdose for Japanese pediatric recipients. Further studies are required to examine the safety and efficacy of VGCV prophylaxis in Japanese pediatric recipients.

Strigolactones (SLs), first identified as germination stimulants for root parasitic weeds, act as endogenous phytohormones regulating shoot branching and as root-derived signal molecules mediating symbiotic communications in the rhizosphere. Canonical SLs typically have an ABCD ring system and can be classified into orobanchol- and strigol-type based on the C-ring stereochemistry. Their simplest structures are 4-deoxyorobanchol (4DO) and 5-deoxystrigol (5DS), respectively. Diverse canonical SLs are chemically modified with one or more hydroxy or acetoxy groups introduced into the A- and/or B-ring of these simplest structures, but the biochemical mechanisms behind this structural diversity remain largely unexplored. Sorgomol in sorghum (Sorghum bicolor [L.] Moench) is a strigol-type SL with a hydroxy group at C-9 of 5DS. In this study, we characterized sorgomol synthase. Microsomal fractions prepared from a high-sorgomol-producing cultivar of sorghum, Sudax, were shown to convert 5DS to sorgomol. A comparative transcriptome analysis identified SbCYP728B subfamily as candidate genes encoding sorgomol synthase. Recombinant SbCYP728B35 catalyzed the conversion of 5DS to sorgomol in vitro. Substrate specificity revealed that the C-8bS configuration in the C-ring of 5DS stereoisomers was essential for this reaction. The overexpression of SbCYP728B35 in Lotus japonicus hairy roots, which produce 5DS as an endogenous SL, also resulted in the conversion of 5DS to sorgomol. Furthermore, SbCYP728B35 expression was not detected in nonsorgomol-producing cultivar, Abu70, suggesting that this gene is responsible for sorgomol production in sorghum. Identification of the mechanism modifying parental 5DS of strigol-type SLs provides insights on how plants biosynthesize diverse SLs., (© American Society of Plant Biologists 2021. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Rituximab is effective for maintaining remission in patients with complicated nephrotic syndrome, although a history of steroid-resistant nephrotic syndrome (SRNS) is a risk factor for early relapse. We investigated the efficacy of prophylactic rituximab treatment for maintaining remission after B cell recovery., Methods: Patients with complicated steroid-dependent or frequently relapsing nephrotic syndrome with history of SRNS who received a single dose of rituximab (375 mg/m 2 ) and continued immunosuppressive agents were enrolled in this retrospective study. Patients were divided into two groups: a prophylaxis group, which received additional rituximab treatment at B cell recovery and a non-prophylaxis group. The relapse-free period from the last rituximab infusion (the second treatment in prophylaxis group and the first treatment in non-prophylaxis group) was compared between two groups using the Kaplan-Meier method, and risk factors for early relapse were calculated using multivariate analysis by Cox proportional hazards model., Results: Sixteen patients in the prophylaxis group and 45 in the non-prophylaxis group were enrolled. Fifty-percent relapse-free survival after the last rituximab treatment was 667 days in the former and 335 days in the latter (p = 0.001). Multivariate analysis showed that additional rituximab treatment was the only significant negative factor for early relapse, with a hazard ratio of 0.40 (p = 0.02). Fifty-percent relapse-free survival after B cell recovery was much longer in the prophylaxis group (954 vs. 205.5 days, p = 0.003)., Conclusions: Additional rituximab treatment at B cell recovery can maintain prolonged remission even after B cell recovery in patients with complicated nephrotic syndrome with history of SRNS.

Background: The development of glomerulosclerosis in FSGS is associated with a reduction in podocyte number in the glomerular capillary tufts. Although it has been reported that the number of urinary podocytes in FSGS exceeds that of minimal-change nephrotic syndrome, the nature of events that promote podocyte detachment in FSGS remains elusive., Methods: In this study, we provide detailed, morphologic analysis of the urinary podocytes found in FSGS by examining the size of the urinary podocytes from patients with FSGS, minimal-change nephrotic syndrome, and GN. In addition, in urinary podocytes from patients with FSGS and minimal-change nephrotic syndrome, we analyzed podocyte hypertrophy and mitotic catastrophe using immunostaining of p21 and phospho-ribosomal protein S6., Results: The size of the urinary podocytes was strikingly larger in samples obtained from patients with FSGS compared with those with minimal-change nephrotic syndrome and GN ( P =0.008). Urinary podocytes from patients with FSGS had a higher frequency of positive immunostaining for p21 ( P <0.001) and phospho-ribosomal protein S6 ( P =0.02) than those from patients with minimal-change nephrotic syndrome. Characteristic features of mitotic catastrophe were more commonly observed in FSGS than in minimal-change nephrotic syndrome urinary samples ( P =0.001)., Conclusions: We posit that the significant increase in the size of urinary podocytes in FSGS, compared with those in minimal-change nephrotic syndrome, may be explained by hypertrophy and mitotic catastrophe., Competing Interests: All authors have nothing to disclose., (Copyright © 2021 by the American Society of Nephrology.)

Background: MIRAGE syndrome is a recently discovered rare genetic disease characterized by myelodysplasia (M), infection (I), growth restriction (R), adrenal hypoplasia (A), genital phenotypes (G), and enteropathy (E), caused by a gain-of-function mutation in the SAMD9 gene. We encountered a girl with molecularly-confirmed MIRAGE syndrome who developed steroid-resistant nephrotic syndrome., Case Presentation: She was born at 33 weeks gestational age with a birth weight of 1064 g. She showed growth failure, mild developmental delays, intractable enteropathy and recurrent pneumonia. She was diagnosed as MIRAGE syndrome by whole exome sequencing and a novel SAMD9 variant (c.4615 T > A, p.Leu1539Ile) was identified at age four. Biopsied skin fibroblast cells showed changes in the endosome system that are characteristic of MIRAGE syndrome, supporting the genetic diagnosis. Proteinuria was noted at age one, following nephrotic syndrome at age five. A renal biopsy showed focal segmental glomerulosclerosis (FSGS) with immune deposits. Steroid treatment was ineffective. Because we speculated that her nephrosis was a result of genetic FSGS, we decided not to introduce immunosuppressive agents and instead started enalapril to reduce proteinuria. Although her proteinuria persisted, her renal function was normal at age eight., Conclusions: This is the first detailed report of a MIRAGE syndrome patient with nephrotic syndrome. Because patients with MIRAGE syndrome have structural abnormalities in the endosomal system, we speculate that dysfunction of endocytosis in podocytes might be a possible mechanism for proteinuria.

Hesperetin is a natural flavonoid with robust antioxidant properties. Our previous study reported that hesperetin can prevent cataract formation. However, an important consideration regarding hesperetin consumption is the limited bioavailability due to its poor solubility. The present study investigated the anti‑cataract effects of α‑glucosyl hesperidin in vivo and in vitro using a selenite‑induced cataract model. SD rats (age, 13 days) were orally administered PBS (0.2 ml) or α‑glucosyl hesperidin (200 mg/kg) on days 0, 1 and 2. Sodium selenite was subcutaneously administered to the rats 4 h after the first oral administration on day 0. Antioxidant levels in the lens and blood were measured on day 6. In vitro, human lens epithelial cells were treated with sodium selenite (10 µM) and/or hesperetin (50 or 100 mM) for 24 h and analyzed for apoptosis markers using sub‑G1 population and Annexin V‑FITC/propidium iodide staining and DNA ladder formation. α‑glucosyl hesperidin treatment significantly reduced the severity of selenite‑induced cataract. The level of antioxidants was significantly reduced in the selenite‑treated rats compared with in the controls; however, they were normalized with α‑glucosyl hesperidin treatment. In vitro, hesperetin could significantly reduce the number of cells undergoing apoptosis induced by sodium selenite in human lens epithelial cell lines. Overall, oral consumption of α‑glucosyl hesperidin could delay the onset of selenite‑induced cataract, at least in part by modulating the selenite‑induced cell death in lens epithelial cells.

Background: The association between the clinical presentation of congenital anomalies of the kidney and urinary tract (CAKUT) and gene mutations has yet to be fully explored., Methods: In this retrospective cohort study, we examined patients with CAKUT who underwent gene analysis. The analysis was performed in patients with bilateral renal lesions, extrarenal complications, or a family history of renal disease. The data from the diagnosis, gene mutations, and other complications were analyzed., Results: In total, 66 patients with CAKUT were included. Of these, gene mutations were detected in 14 patients. Bilateral renal lesions were significantly related to the identification of gene mutations (p = 0.02), and no gene mutations were observed in patients with lower urinary tract obstruction (six patients). There was no significant difference in the rate of gene mutations between those with or without extrarenal complications (p = 0.76). The HNF1β gene mutation was identified in most of the patients with hypodysplastic kidney with multicystic dysplastic kidney (six of seven patients). There was no significant difference in the presence or absence of gene mutations with respect to the renal survival rate (log-rank test p = 0.53). The renal prognosis varied, but the differences were not statistically significant for any of the gene mutations., Conclusions: CAKUT with bilateral renal lesions were significantly related to gene mutations. We recommend that CAKUT-related gene analysis be considered in cases of bilateral renal lesions. No gene mutations were observed in patients with lower urinary tract obstruction. The renal prognosis varied for each gene mutation.

Bioconversion of GR24, the most widely used synthetic strigolactone (SL), by hydroponically grown sorghum (Sorghum bicolor) and biological activities of hydroxylated GR24 stereoisomers were studied. Analysis of extracts and exudates of sorghum roots previously fed with a racemic and diastereomeric mixture of GR24, using liquid chromatography-tandem mass spectrometry with multiple reaction monitoring (MRM), confirmed uptake of GR24 and suggested its conversion to mono-hydroxylated products. Two major GR24 metabolites, 7-hydroxy-GR24 and 8-hydroxy-GR24, were identified in the root extracts and exudates by direct comparison of chromatographic behavior with a series of synthetic mono-hydroxylated GR24 analogues. Separate feeding experiments with each of the GR24 stereoisomers revealed that the hydroxylated products were derived from 2'-epi-GR24, an evidence of sterical recognition of the GR24 molecule by sorghum. Trans-4-hydroxy-GR24 isomers derived from all GR24 stereoisomers were detected in the exudates as minor metabolites. The synthetic hydroxy-GR24 isomers induced germination of Striga hermonthica in decreasing order of C-8>C-7>C-6>C-5>C-4. In contrast the stereoisomers having the same configuration of orobanchol, irrespective of position of hydroxylation, induced germination of Striga gesnerioides. The results confirm previous reports on structural requirements of SLs and ascribe a critical role to hydroxylation, but not to the position of the hydroxyl group in the AB part of the molecule, in induction of S. gesnerioides seed germination., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Pattern formation along the anterior-posterior axis of the vertebrate limb is established upon activation of Sonic Hedgehog (SHH) in the zone of polarizing activity (ZPA). Since many mouse mutants with preaxial polydactyly show ectopic expression of Shh at the anterior margin of the limb buds, it has been thought to be a primary defect caused by these mutations. We show here that the mouse mutation luxate (lx) exhibits dose-dependent reduction in the size of the Fgf8 expression domain in the ectoderm from the initial stage of limb development. This aberration was independent of Fgf10 expression in the limb mesenchyme. Shh was induced in the mesenchyme underlying the posterior end of the Fgf8 expression domain, indicating an anterior shift of Shh expression in lx hindlimb buds. Prior to the ectopic induction of Shh, the expression domains of genes downstream from Shh, namely dHAND, Gli1, Ptc and Gre, which are normally expressed in posterior mesenchyme of limb buds, expanded anteriorly on the lx hindlimb buds. Conversely, the expression domains of anterior mesenchymal markers such as Gli3and Alx4 decreased in size. Thus, ectopic Shh is not a primary defect of the lx mutation. Rather, our results indicate that the lx mutation affects the positioning of the anteroposterior border in developing hindlimb buds.

We examined the response of neuronal nitric oxide synthase (nNOS)-containing CNS neurons in rats exposed to a unilateral hypoxic-ischemic insult at 7 days of age. Animals were sacrificed at several time points after the injury, up to and including 7 days (Postnatal Day 14). Brain regions ipsilateral to the injury (including cerebral cortex, caudate-putamen, and thalamus) exhibited delayed, focal increases in nNOS immunoreactivity. The increase in nNOS immunoreactive fiber staining was prominent in areas adjacent to severe neuronal damage, especially in the cortex and the thalamus, regions that are also heavily and focally injured in term human neonates with hypoxic-ischemic encephalopathy. In cerebral cortex, these increases occurred despite modest declines in nNOS catalytic activity and protein levels. Proliferation of surviving nNOS immunoreactive fibers highlights regions of selective vulnerability to hypoxic-ischemic insult in the neonatal brain and may also contribute to plasticity of neuronal circuitry during recovery.

A rapid perfusion of oxygen in infants at birth may cause an increase of oxidative stress. To assess this possibility, we measured levels of blood plasma antioxidants and free fatty acids in 20 normal infants at 0, 1, 3, and 5 days after birth. Plasma levels of the most reactive antioxidant, ascorbic acid, decreased daily to equilibrium values at days 3 and 5. Percentages of oxidized form of coenzyme Q-10 (%CoQ-10) in total coenzyme Q, another good marker of oxidative stress, in infants (25-31%) were significantly higher than those in healthy young adults (4.5%). Plasma levels of total free fatty acids (FFA) in normal infants were highest at day 1 and decreased rapidly thereafter. The content of polyunsaturated fatty acids (PUFA) in total FFA was lowest at day 1 and then increased. Since PUFA are susceptible to oxidation, these changes in FFA composition suggest that oxidative stress is most evident at the initial day of neonatal life. Furthermore, it appears that mono-unsaturated fatty acids such as oleic and palmitoleic acids increase in response to the oxidative loss of PUFA. Similar changes in plasma antioxidants, FFA levels, and FFA compositions were observed in 9 infants with asphyxia. Values of %CoQ-10 in infants with asphyxia were significantly greater than those in normal infants, suggesting that infants with asphyxia have elevated oxidative stress., (Copyright 1999 Academic Press.)

The influence of post-insult temperature modulation on ischemic injury in immature brain was studied in 7-day-old rats that underwent a unilateral carotid artery ligation followed by exposure to hypoxia in 8% oxygen at an ambient temperature of 36.5 degrees C. After the hypoxic exposure, the animals were separated into three groups and placed for 3 h in temperature-controlled incubators set at 32 degrees C, 35 degrees C, and 38 degrees C. In Study 1, the influence of post-insult temperature modulation was assessed after graded cerebral hypoxic-ischemic injury. Brain damage was assessed 1 week after the insult by comparison of wet weights in the cerebral hemispheres ipsilateral and contralateral to the carotid artery ligation. Rectal temperatures of the animals significantly correlated with extent of brain injury after 60 min (Spearman correlation coefficient, p = 0.44, P = 0.005) and 90 min (p = 0.46, P = 0.004) but not 120 min of hypoxia (p = 0.18, P = 0.46). In Study 2, animals were exposed to 75 min hypoxia, and injury was assessed morphometrically and histologically at 1 and 4 weeks after the injury. Rectal temperatures significantly correlated with the extent of ischemic injury in the cerebral cortex (p = 0.3, P = 0.046) and striatum (p = 0.3, P = 0.048) at 1 week, but not 4 weeks, after the insult. The findings indicate that post-insult hypothermia delayed the expression of mild to moderate brain damage by more than a week, after which the damage was as severe as in normothermic animals. The results indicate that the events that determine the final expression of a neonatal hypoxic-ischemic insult can be extended over a long interval by post-insult hypothermia.

Two patients with Sotos syndrome showed very intractable and prolonged status epilepticus, resulting in poor outcomes. Clinical seizures and EEG abnormalities in patients with Sotos syndrome are sometimes noted, but they are usually mild. These two patients showed hypoplasia of corpus callosum on MRI. We considered the mechanism of intractable seizures, and emphasized the importance of careful management for their seizures and EEG abnormalities.

Using the autoregressive model, we developed a method of illustrating significant regional differences between two records of brain electrical activity mapping. This new approach of brain electrical activity mapping analysis through a statistical taxonomy may be clinically useful for evaluation of the normal development of EEG in children and for localizing functional brain abnormality.

We applied spectral analysis through multivariant autoregressive model fitting [1] to RR interval (RRI) and respiratory (RES) oscillation obtained during quiet sleep in an infant with congenital central hypoventilation syndrome (Ondine's curse), a child with obstructive sleep apnea, and two healthy children. Power spectra, impulse response and noise contribution ratio between RRI and RES oscillation were calculated by using a minicomputer PFU-1200 (FACOM) to determine the structure of the feedback system between RRI and RES within the central nervous system. We found that the respiratory noise contribution ratio to RRI was significantly smaller in Ondine's curse (37 +/- 7.7%, at 0.23 Hz) than in obstructive sleep apnea (90 +/- 6.7%, at 0.39 Hz) and healthy subjects. We postulate that the result shows disturbance of the central autonomic control of breathing and heart rate in Ondine's curse.

Autoregressive topographic EEG analysis was used to determine topographic EEGs of the total power in quiet and active sleep stages in 33 healthy premature infants of 34 to 40 weeks conceptional age. The developmental characteristics were also examined by simultaneously referring to the autoregressive pattern discrimination of topographic EEGs between different conceptional age groups in both sleep stages. Treating 10.24 seconds of EEG as one segment, the topographic EEG of 10 segments in each of the quit and active sleep stages as well as their mean were obtained. In both sleep stages the results showed a small peak in total power in the frontal region and a large peak in the occipital region, but total power was greater in the quiet sleep. Total power decreased with increasing conceptional age. Topographic pattern discrimination between different conceptional age groups showed significant differences mainly in the frontal, temporal and occipital regions. It was concluded that regional differences in the development of EEG in premature infants could be clarified by means of topographic EEG analysis and the pattern discrimination method using the autoregressive model.

This is a case report of a newborn with congenital tracheal stenosis which was fortunately healed by surgery. A 2,650 g female infant was born at 39 wk gestation. She began having respiratory difficulty soon after birth. Prompt endotracheal intubation was attempted, but failed. She was transferred to our hospital under assisted ventilation. Chest roentgenogram and bronchoscopy demonstrated segmental narrowing of the trachea about 2 cm distal from the vocal cord. A surgical operation was performed because respiratory management would not be enough to save the infant. Through a transverse collar incision and an upper median sternotomy, a stenotic 7 mm length of the trachea was resected and anastomosed with 5-0 Dexon suture. Postoperative course was uneventful. Histologically, the stenotic segment consisted of hypoplasia of the tracheal cartilage and fibrosis of the membranous portion. Squamous metaplasia was also recognized. There was no other report of tracheal stenosis successfully operated during the period of newborn.

Autoregressive (AR) analysis and component analysis were done on EEGs during sleep stage 2 in normal and autistic children, since AR-coefficients of EEG characterize the autocovariance and power spectral density of EEG. In addition, as the generalized distance of the average AR-coefficient vector of an EEG group at one side from that at the opposite side exhibits an F-distribution, the statistical inferences were determined, as to whether there is hemispheric specialization in EEG in 21 right-handed autistic children and whether there is a difference between the AR-spectral pattern of EEG in the autistic children and that of 28 normal children of the same age range. The results obtained are as follows: 1. Significant hemispheric lateralization in EEG at the significant level of 0.01 was observed in normal children, whereas no lateralization was confirmed in autistic children. 2. Random click stimulation had cumulative effects on the hemispheric lateralization in the normal children, but not in the autistic children. On the contrary, the effects of random flash light stimulation on hemispheric asymmetry were verified in the autistic children as well as in the normal children. 3. The EEG components of autistic children were significantly different from the normal ones in the frequency range of alpha-2 component waves at bilateral frontal (Fp1 and Fp2) regions and the activity of these component waves was higher in the autistic children than in the normal ones over 5 years old. 4. These findings suggest that autistic children are not only less responsive to external stimuli, but also neurophysiologically less active in the internal regulatory mechanism.

Waking EEGs of 150 normal children aged from 20 days to 15 years were subjected to analysis. Discrete time series of an artifact free segment of the EEG record at 50 samples/sec for twenty seconds was generated and autoregressive (AR) and component analyses were carried out with a minicomputer PDP 11/40 (DEC). The results may be summarized as follows: 1) In the group of 1 year old and less, the power increased with the monthly age, whereas the bio-informing activity amount decreased. In those older than 1 year, both parameters showed maximal values at 1 year and then decreased with age, and the decreases were marked from 1 to 3 years. 2) The first- and second-order component activities of 129 and 677 waves, respectively, were obtained by applying component analysis to 152 EEG records. The frequency polygons of natural frequency of second-order component waves verified several modes, each of which was enhanced in the frequency range of the well-known delta 0, delta 1, theta 1, theta 2, alpha 1, alpha 2, beta 1, beta 2 and beta 3 waves, respectively. 3) The average percent-power of the delta wave (delta 0 + delta 1) decreased with age, especially from 1 to 3 years old, whereas those of beta- and alpha-waves increased with advancing age. That of the theta wave tended to increase from 2 to 4 years of age, and thereafter decreased gradually with increasing age. 4) With increasing age, the durations of damped oscillations were significantly lengthened in delta 1, alpha 1 and beta 3 waves, whereas that in the theta 1 wave was significantly shortened. 5) The bio-informing activity amounts of alpha waves increased from 1 to 3 years with increasing age, whereas those of delta and theta waves decreased. No significant developmental change in the parameters, however, was observed in the beta wave. The results indicate that AR-power spectral and component analyses of EEG are sensitive methods for obtaining valuable information regarding the electrical brain maturation in childhood.

Autoregressive (AR) analysis and component analysis were applied to EEGs during sleep stage 2 of normal and autistic children, since AR-coefficients of EEG characterize the autocovariance and power spectral density of EEG. In addition, as the Mahalanobis' generalized distance of the average AR coefficient vector of an EEG group at one side from that at the opposite side follows a F-distribution, the statistical inferences were carried out, whether or not there is hemispheric specialization in EEG in 21 right handed autistic children and whether there is difference between AR-spectral pattern of EEG in the autistic children and that of 28 normal children of the same age range or not. The results obtained were as follows: 1) The significant hemispheric lateralization in EEG at the significant level of 0.01 was observed in normals, whereas none of the lateralization was confirmed in autistic children. 2) The random click stimulation caused a cumulative effect on the hemispheric lateralization in the normals, but not in the autistic children. On the contrary, the effects of random flash light stimulation on hemispheric asymmetry were verified in the autistic children as well as in the normals. 3) The EEG components of autistic children were significantly different from the normal ones in frequency range of alpha-2 component wave at bilateral frontal (F1 and F2) regions and the activity of these component waves were higher in the autistic children than in the normal ones over 5 years-old. 4) These findings suggest that autistic children are not only less responsive to external stimuli, but also neurophysiologically less active in the internal regulatory mechanism.

By the use of an autoregressive (AR) model, development of beta-waves in quantitative EEG parameters was studied in 1,340 normal children aged from 3 to 12 years. The results were summarized as follows. The beta band(13.5-25 Hz) was divided into three frequency ranges; beta-1(13.5-17.4 Hz), beta-2(17.5-21.4 Hz) and beta-3 (21.5-25 Hz) waves. The average power and percent-power of the beta-1 and beta-2 waves increased with advancing age, whereas these of the beta-3 wave showed no change with advancing age. By means of EEG pattern discrimination, critical period of beta band in the developing EEG was observed at the age of 4 years in frontal region, 10 years in central region and 3 to 7 years in occipital region. Those results suggest that the development of beta activity may be faster in frontal, occipital areas and relatively slower in central area.

We developed a method of illustrating significant regional differences between two records of brain electrical activity mapping (BEAM), using pattern discrimination of autoregressive (AR) EEG analysis. In this study, the EEG data could be objectively reduced to a few AR coefficients, and this statistical method was successfully applied to discrimination of differences in BEAM among records from two or more subjects. A significant difference was illustrated at the right parietal region between two age groups, 6 years and 8 years, in normal children. It was concluded that this new approach of BEAM analysis through a statistical taxonomy was clinically useful for evaluation of the normal development of BEAM in children and for localization of functional brain abnormalities.

The records of waking state electroencephalography (EEG) of 1,340 normal children aged from 3 to 12 years were subjected to analysis using an autoregressive model. The results were summarized as follows. (1) 6,814 components of second-order activities were obtained through component analysis of the 1,218 EEG records. The frequency polygons of damping frequency of the second-order component waves verified several modes, each of which was enhanced in the eight frequency ranges. (2) The average percent-power of the alpha-1 waves decreased with increasing ages from 3 years, whereas that of the alpha-2 waves increased. That of the alpha-3 waves showed no change with ages. (3) The average damping times of alpha-2 waves increased with increasing ages. (4) Dominancy in frequency showed a course of two step increments at 3-6 and 10 years of age. The former was chiefly due to the increase in the alpha-1 wave and the latter in the alpha-2 wave. There were no significant increases of alpha-3 waves. (5) By means of EEG pattern discrimination, the differences in alpha components among different age groups were obtained as generalized (Maharanobis') distances. The alpha-1 activity showed a significant difference in amount between the age group of 3-6 years and the other age groups. The alpha-2 activity showed a significant difference in amount between the age group of 10 years and the other age groups. (6) The development of brain activity proceeds faster in the posterior areas and relatively slower in the central areas.