Faculty Profiles - TSUKAHARA Hirokazu

Papers - TSUKAHARA Hirokazu

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Older boys benefit from higher initial prednisolone therapy for nephrotic syndrome Reviewed

M Hiraoka, H Tsukahara, S Haruki, S Hayashi, N Takeda, K Miyagawa, K Okuhara, F Suehiro, Y Ohshima, M Mayumi

KIDNEY INTERNATIONAL 58 ( 3 ) 1247 - 1252 2000.9

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Background A long course of the initial prednisolone therapy has been shown to be more effective than standard-course therapy in reducing relapse rates in children with idiopathic nephrotic syndrome, but it is commonly accompanied by corticosteroid toxicities. There has been no study on prednisolone dosage for the effective treatment of nephrotic syndrome.
Methods. Sixty-eight children (42 boys and 26 girls) with an initial attack of nephrotic syndrome were randomly allocated into two different long-course treatment groups. Patients in Group 1 received a daily prednisolone dose of 60 mg/m(2) for six weeks, followed by an alternate-day dose of 40 mg/m(2) for six weeks. Patients in Group 2 had a daily dose of 40 mg/m(2) instead of 60 mg/m(2).
Results. Four children in each group did not respond within six weeks. Group 1 was associated with a significantly earlier response but more frequent corticosteroid toxicities than Group 2. Boys in Group 1 had a higher rate of sustained remission than boys in Group 2 (P = 0.0073), especially boys four years old or more (P = 0.0027), but girls did not show a significant difference (P = 0.863). Boys four years old or more in Group 1 had a course of frequent relapsing less often than those in Group 2 (2 of 13 vs. 6 of 8, P = 0.0075).
Conclusion. These findings indicate that efficient prednisolone doses may vary between sexes and ages, and that a higher initial prednisolone therapy may be of greater benefit to older boys.

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Efficacy of long-term azathioprine for relapsing nephrotic syndrome Reviewed

M Hiraoka, H Tsukahara, C Hori, Y Ohshima, T Momoi, A Seo, M Mayumi

PEDIATRIC NEPHROLOGY 14 ( 8-9 ) 776 - 778 2000.8

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER-VERLAG

Seven patients who had an initial attack of nephrotic syndrome in childhood and had frequent relapses even after cyclophosphamide therapy were given a 2-year course of azathioprine. The mean annual relapse rates decreased from 2.4 +/- 0.5 in the year preceding azathioprine to 0.4 +/- 0.8 in the 1st and 2nd years after its initiation. All six patients who were observed for more than 6 months after discontinuation of the therapy were relapse free for this period. Average doses of prednisolone could also be decreased in the 2nd and subsequent years after the therapy. There were no significant toxic effects. Long-term azathioprine therapy may be well tolerated and effective for nephrotic patients with frequent relapses.

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インフルエンザ菌による敗血症性髄膜炎に伴い急性腎不全をきたした3歳女児例

西村光敏, 塚原宏一, 平岡政弘, 木村宏輝, 大嶋勇成, 谷澤昭彦, 木川芳春, 眞弓光文

日本小児腎不全学会雑誌 20 166 - 168 2000.8

早期ステロイド補充療法

塚原宏一

日本小児呼吸器疾患学会雑誌 = Japanese journal of pediatric pulmonology 11 ( 1 ) 55 - 55 2000.6

Methylenetetrahydrofolate reductase polymorphism in Kawasaki disease Reviewed

H Tsukahara, M Hiraoka, M Saito, K Nishida, R Kobata, S Tsuchida, M Toyooka, H Kimura, F Gejyo, M Mayumi

PEDIATRICS INTERNATIONAL 42 ( 3 ) 236 - 240 2000.6

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL SCIENCE ASIA

Background: A genetic aberration in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene (677 C to T substitution) has been shown to result in reduced enzyme activity. The hypothesis tested in the present study was that a higher proportion of Kawasaki disease (KD) patients with coronary artery lesions (CAL) would have the T677 allele compared with patients without CAL and healthy subjects.
Methods: Genotypes for MTHFR were determined in 75 KD patients (male : female ratio 52:23) and 238 healthy subjects (male : female ratio, 110:128) by the polymerase chain reaction and restriction fragment length polymorphism method.
Results: The results indicated that female KD patients had a significantly higher frequency of the TT genotype compared with female control subjects. In the female population, the frequency of the TT genotype in patients with initial coronary aneurysm was significantly lower than in patients without this manifestation. Analysis of the data for the male population showed that the frequency of the TT genotype in KD patients developing coronary stenosis, occlusion or myocardial infarction was higher than that in those without these manifestations, although the difference was statistically insignificant.
Conclusions: The TT genotype may protect female KD patients against initial aneurysm formation and predispose male KD patients to severe coronary complications. Further large-scale studies may be required to confirm the contribution of homocysteine in the coronary sequelae of KD.

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Systemic inflammatory response syndrome and acute renal failure associated with Hemophilus influenzae septic meningitis Reviewed

M Nishimura, H Tsukahara, M Hiraoka, Y Osaka, Y Ohshima, A Tanizawa, M Mayumi

AMERICAN JOURNAL OF NEPHROLOGY 20 ( 3 ) 208 - 211 2000.5

Language：English Publishing type：Research paper (scientific journal) Publisher：KARGER

Sepsis is often associated with a downward spiral through a spectrum of systemic inflammatory response syndrome (SIRS) culminating in organ failure and death. Here we present a 3-year-old girl with Hemophilus influenzae septic meningitis who developed SIRS and acute renal failure. In the initial stage, the patient showed uremia, cytopenia, disseminated intravascular coagulation, elevation of tissue enzyme and ferritin values, hemophagocytosis and overproduction of nitric oxide. The serum cytokine profile revealed increased levels of soluble interleukin (IL)-2 receptor, IL-6, IL-10 and tumor necrosis factor alpha. The patient responded positively to early and intensive interventions including antibiotics, repeated exchange transfusions, dexamethasone and high-dose gamma-globulin. The above laboratory abnormalities almost normalized with clinical improvement. We consider that SIRS was probably responsible for the sequence of events resulting in renal failure in this case, and suggest that renal failure should be included among the serious complications of SIRS associated with Hemophilus influenzae septic meningitis. Copyright (C) 2000 S. Karger AG, Basel.

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インフルエンザ菌による髄膜炎に伴いsystemic inflammatory response syndrome(SIRS)及び急性腎不全をきたした1例

塚原宏一, 西村光敏, 平岡政弘, 木村宏輝, 大嶋勇成, 谷澤昭彦, 木川芳春, 眞弓光文

日本小児科学会雑誌 104 ( 3 ) 381 - 381 2000.3

Oxidative stress in childhood meningitis: measurement of 8-hydroxy-2 '-deoxyguanosine concentration in cerebrospinal fluid Reviewed

H Tsukahara, T Haruta, N Ono, R Kobata, Y Fukumoto, M Hiraoka, M Mayumi

REDOX REPORT 5 ( 5 ) 295 - 298 2000

Language：English Publishing type：Research paper (scientific journal) Publisher：W S MANEY & SONS LTD

To examine the involvement of reactive oxygen species, we measured the concentration of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of oxidative stress, in cerebrospinal fluid samples from 63 children with and without meningitis. We observed that the mean concentration of 8-OHdG in samples obtained during the early phase of bacterial meningitis, but not aseptic meningitis, was significantly higher than that in control samples. Clinical and laboratory improvement was associated with a fall in the 8-OHdG concentration in the patients with bacterial meningitis. Our findings suggest the presence of enhanced oxidative stress in the central nervous system of children with bacterial meningitis.

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シンポジウム (VI)「全身性炎症性疾患の免疫・アレルギー学的側面」

古川漸, 眞弓光文, 横田俊平, 塚原宏一, 谷内江昭宏, 松原知代, 篠原真

日本小児アレルギー学会誌 14 ( 3 ) 351 - 355 2000

Early (4-7 days of age) dexamethasone therapy for prevention of chronic lung disease in preterm infants Reviewed

H Tsukahara, Y Watanabe, M Yasutomi, R Kobata, S Tamura, K Kimura, M Hiraoka, M Mayumi

BIOLOGY OF THE NEONATE 76 ( 5 ) 283 - 290 1999.11

Language：English Publishing type：Research paper (scientific journal) Publisher：KARGER

We conducted a comparative study to evaluate whether early (4-7 days of age) tow-dose dexamethasone (DEX) therapy in preterm infa nts with surfactant-pretreated respiratory distress syndrome (RDS) would facilitate extubation and improve the clinical outcome. Twenty-six preterm infants with surfactant-pretreated RDS who were oxygen- and ventilator-dependent at 4 days of postnatal age were enrolled. Twelve infants were in the historical comparison group, and 14 infants were assigned to receive DEX 0.125 mg/kg i.v., every 12 h, for a total of 6 doses. At study entry, the two groups had a comparable clinical status. DEX therapy significantly facilitated weaning from mechanical ventilation (median interval, 6 vs. 24 days, p < 0.005) and shortened duration of oxygen supplementation (9 vs. 28 days, p < 0.05) as compared with the historical comparison group. At 28 days of age, the occurrence of chronic lung disease (CLD) was significantly lower (1/14 vs. 6/12, p < 0.05) and there was a significant decrease in the incidence of ventilator dependence (0/14 vs. 5/12, p < 0.05) in the DEX group. DEX therapy did not influence the incidence of significant complications such as infection, periventricular leukomalacia or retinopathy of prematurity. We conclude that in a selected high-risk group of preterm infants, early low-dose DEX treatment results in improvement in pulmonary outcome without significant side effects.

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Evaluation of a rapid reagent strip test for the diagnosis of childhood meningitis Reviewed

H Tsukahara, T Haruta, C Hori, M Matsuda, N Ono, M Hiraoka, Y Shigematsu, M Mayumi

PEDIATRICS INTERNATIONAL 41 ( 4 ) 443 - 446 1999.8

Voiding function study with ultrasound in male and female neonates Reviewed

M Hiraoka, C Hori, H Tsukahara, K Kasuga, F Kotsuji, M Mayumi

KIDNEY INTERNATIONAL 55 ( 5 ) 1920 - 1926 1999.5

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL SCIENCE INC

Background The neonatal period has been characterized as a time when males have a much higher incidence of urinary infection and severe ureteral reflux than females. However, little information about the voiding function in the neonatal period is available.
Methods. The bladder urine volumes, before and after voiding, and urinary how rates were determined with the use of noninvasive voiding-provocation maneuvers and ultrasound in the apparently normal neonates.
Results. There was no significant difference in the prevoid bladder urine volume between the two sexes. After they were stimulated to enhance the tension of their abdominal wall musculature, 65 of 118 females (55.1%) and 64 of 115 males (55.7%) voided. The voiding was observed in 94 (81.0%) of the 116 neonates who had had a prevoid volume above 12 ml. The residual urine expressed as a percentage of the prevoid volume was significantly higher in the males (median, 12.0% in males vs. 3.0% in females, P < 0.01), with the values being above 20% in 26 (41%) of the 64 males compared with 10 (15%) of the 65 females (P < 0.01). Urinary flow rates, determined in 52 neonates, were significantly smaller in males than in females (mean +/- so, 2.6 +/- 0.9 g/second vs. 3.8 +/- 1.3 g/second, respectively, P < 0.001).
Conclusion. This voiding function study with ultrasound using noninvasive voiding-provocation maneuvers successfully revealed that male neonates have a larger residual urine volume and smaller urinary flow rates than female neonates. This study should be useful for the diagnosis of voiding dysfunction in children with abnormal urinary symptoms.

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Assessment of bone turnover in term and preterm newborns at birth: measurement of urinary collagen crosslink excretion Reviewed

H Tsukahara, Y Watanabe, S Hirano, H Tsubokura, K Kimura, M Mayumi

EARLY HUMAN DEVELOPMENT 53 ( 3 ) 185 - 191 1999.1

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI IRELAND LTD

We measured urinary excretion of collagen crosslinks, pyridinoline and deoxypyridinoline, in term and preterm newborns at birth and evaluated the developmental changes in bone turnover. Collagen crosslink excretion in newborns was more than 10 times higher than reported adult values and several times higher than those of older children. The values were significantly higher in preterm newborns than in term newborns. In addition, a significant and inverse correlation was found between urinary collagen crosslinks and gestational age in preterm newborns. Excretion of crosslinks during this period did not correlate with beta,microglobulin, suggesting that the excretion was not directly influenced by renal function in newborns. We conclude that bone turnover assessed by measurement of collagen crosslink excretion is high at birth and that preterm newborns have higher bone turnover than term newborns. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.

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Vesicoureteral reflux in male and female neonates as detected by voiding ultrasonography Reviewed

Masahiro Hiraoka, Chikahide Hori, Hirokazu Tsukahara, Kenkou Kasuga, Yoshinori Ishihara, Fumikazu Kotsuji, Mitsufumi Mayumi

Kidney International 55 ( 4 ) 1486 - 1490 1999

Language：English Publishing type：Research paper (scientific journal) Publisher：Blackwell Publishing Inc.

Background. Vesicoureteral reflux (VUR) is assumed to be congenital, and its early diagnosis is desired in order to prevent acquired renal damage. However, the incidence of VUR in neonates remains to be revealed. Methods. Two thousand newborn babies (1048 boys and 952 girls) underwent voiding ultrasonography (an ultrasound examination of urinary tract during provoked voiding). Those who showed transient renal pelvic dilation during voiding, who had small kidneys, or who subsequently developed urinary infection underwent voiding cystourethrography. Results. Transient renal pelvic dilation was observed in 16 babies (0.8%), including one boy with small kidneys. Among the rest of the babies, one boy had a small kidney, and nine babies subsequently developed urinary infection. Voiding cystourethrography revealed VUR in 24 ureters of 16 children (11 boys and 5 girls). Dimercaptosuccinate renoscintigraphy confirmed small kidneys, with generally reduced tracer uptake in a total of three boys, all having VUR. Voiding ultrasonography detected transient renal pelvic dilation in 17 (71%) of the 24 kidneys with VUR and, strikingly, 16 of the 17 (94%) kidneys with high- grade VUR (grade III or more). Conclusion. This study effectively detected VUR in 0.8% of the neonates (mostly of high grades and predominantly in males) and voiding ultrasonography showed a decided usefulness for the detection of VUR. The male preponderance of VUR in neonates was considered to be due to the occurrence of congenitally small kidneys, with reflux found exclusively in males and easier ultrasound detection of VUR in male neonates because the majority of diagnoses are reported to be high grades of VUR.

DOI： 10.1046/j.1523-1755.1999.00380.x

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Urinary markers in neonates: Interpretation and clinical application.

Tsukahara Hirokazu

Nihon Shoni Jinzobyo Gakkai Zasshi 12 ( 1 ) 79 - 85 1999

Renal water channel expression in newborns: Measurement of urinary excretion of aquaporin-2 Reviewed

H Tsukahara, Hata, I, K Sekine, M Miura, F Kotsuji, M Mayumi

METABOLISM-CLINICAL AND EXPERIMENTAL 47 ( 11 ) 1344 - 1347 1998.11

Language：English Publishing type：Research paper (scientific journal) Publisher：W B SAUNDERS CO

Aquaporin-2 (AQP-2) encodes the vasopressin-regulated "water channels" of the renal collecting duct and is excreted in human urine. We measured urinary excretion of AQP-2 by radioimmunoassay in 15 term and 10 preterm infants on day 1 and day 4 of life to determine the molecular basis of water balance during the newborn period. AQP-2 was detectable in the urine of term and preterm newborns, but AQP-2 excretion was severalfold less than the reported level in normal adults. Urinary excretion of AQP-2 significantly decreased postnatally, in parallel with a reduction in urine osmolality and arginine vasopressin (AVP) excretion. Urinary AQP-2 correlated positively and significantly with urine osmolality on days 1 and 4 and with AVP on day 1 in both groups. No significant differences were detected in AQP-2 levels between term and preterm newborns. Our findings suggest that vasopressin-regulated water channels are expressed in the renal collecting duct of both term and preterm newborns, although to a lesser extent as compared with adults, and these channels encoded by AQP-2 contribute to the urine concentrating power of the newborn kidney. Copyright (C) 1998 by W.B. Saunders Company.

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Urinary excretion of aquaporin-2 in term and preterm infants Reviewed

H Tsukahara, Hata, I, K Sekine, M Miura, K Hata, Y Fujii, M Mayumi

EARLY HUMAN DEVELOPMENT 51 ( 1 ) 31 - 37 1998.4

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI IRELAND LTD

Aquaporin-2 (AQP-2) is a vasopressin-regulated water channel of the renal collecting duct and is excreted in human urine. We measured the urinary excretion of AQP-2 by radioimmunoassay in 14 term and 12 preterm infants aged 1 month. Excretion of AQP-2 was low compared with adults, and correlated significantly with urine osmolality in preterm infants. Our results demonstrate that AQP-2 water channels are expressed in the renal collecting duct of both term and preterm infants. (C) 1998 Elsevier Science Ireland Ltd.

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High-turnover osteopenia in preterm infants: Determination of urinary pyridinium cross-links of collagen Reviewed

H Tsukahara, M Takeuchi, K Fujisawa, M Miura, K Hata, K Yamamoto, M Mayumi

METABOLISM-CLINICAL AND EXPERIMENTAL 47 ( 3 ) 333 - 335 1998.3

Language：English Publishing type：Research paper (scientific journal) Publisher：W B SAUNDERS CO

Osteopenia is a frequent condition in preterm infants, but its pathogenesis is uncertain. In the present study, we measured longitudinal changes in the excretion of pyridinium cross-links of collagen (specific markers of bone resorption) and evaluated the relationship between collagen cross-links and other indexes of bone and renal function in preterm infants. In these infants, urinary collagen cross-links were markedly increased on day 7 and day 30 of life and at estimated full-term gestation. The values were several times higher than those of older children and almost comparable to those of healthy full-term infants. Cross-link excretion did not correlate with beta(2)-microglobulin (B2M) or N-acetyl-beta-D-glucosaminidase (NAG) activity (markers of renal function), indicating that cross-link excretion is not influenced directly by infantile renal function. High serum osteocalcin and low bone mineral density (BMD) in the lumbar spine were also observed at estimated full-term gestation, There was no significant correlation between collagen cross-link excretion and either serum osteocalcin or spine BMD. We conclude that a state of high bone turnover underlies the development of osteopenia in preterm infants. Copyright (C) 1998 by W.B. Saunders Company.

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Nitric oxide in septic and aseptic meningitis in children Reviewed

H Tsukahara, T Haruta, Hata, I, M Mayumi

SCANDINAVIAN JOURNAL OF CLINICAL & LABORATORY INVESTIGATION 58 ( 1 ) 73 - 79 1998.2

Language：English Publishing type：Research paper (scientific journal) Publisher：SCANDINAVIAN UNIVERSITY PRESS

To investigate the involvement of nitric oxide (NO) in childhood meningitis, we measured the concentrations of NO2- (a stable metabolite of NO) in serial samples of cerebrospinal fluid (CSF) from :II children with septic and 7 with aseptic meningitis and 26 control patients without meningitis. The mean concentration of NO2- in samples obtained during the early stages of septic meningitis, but not aseptic meningitis, was significantly higher than in control samples. Clinical and laboratory improvement following administration of antibiotics and dexamethasone was associated with a fall in CSF [NO2-] to normal levels in these patients. CSF [NO2-] remained almost consistently within the normal range in patients with aseptic meningitis. Our findings indicate that NO production is enhanced in the CSF compartment of children with septic meningitis and support the hypothesis that NO is involved in the pathophysiology of septic meningitis.

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Development of antigen-specific ige antibodies in atopic and non-atopic infants: Diagnostic value of low levels of ige against egg white in infants with atopic dermatitis Reviewed

M. Mayumi, M. Saito, H. Tsukahara, S. Ito, K. Katamura

Allergology International 47 ( 2 ) 129 - 136 1998

Language：English Publishing type：Research paper (scientific journal) Publisher：Japanese Society of Allergology

To analyze the development of antigen-specific IgE in infants and its clinical usefulness, the levels of IgE antibodies against egg white (f1) and cows' milk (f2) in 33 sera from cord blood, 118 sera from atopic dermatitis (AD) infants and 197 sera from non-atopic control infants were measured by using the CAP radioallergosorbent test (RAST) fluoro enzyme immunoassay (FEIA) system, which has a detection limit of 0.15 Ua/mL for fl and 0.20 Ua/mL for f2. No antigen-specific IgE was detected in cord blood, whereas in infants younger than 6 months of age, 38.5% of AD infants and 6.6% of the non-atopic controls showed IgE against f1 (≤0.70 Ua/mL) and 14.3 and 4.0%, respectively, showed low levels (0.15-0.70 Ua/mL) of the IgE. When the cut- off point for positive versus negative f1 RAST was set at 0.15 or 0.35 Ua/mL instead of 0.70 Ua/mL, the significance of the difference in f1 RAST- positive and -negative proportions between atopic and non-atopic infants did not change. Repeated examination of f1 RAST revealed later positive conversion in the majority of AD patients, with no detectable or very low levels (0.15-0.35 Ua/mL) of f1 -specific IgE. In infants at 6 months of age or older, 44.4 and 12.0% of AD patients and non-atopic controls, respectively, showed IgE against f1 (≤ 0.70 Ua/mL) and 37.1 and 22.6%, respectively, showed low levels (0.15-0.70 Ua/mL) of the IgE. These results suggest that f1 RAST at a concentration of 0.15 Ua/mL or higher has diagnostic value for egg allergy in AD infants, especially in infants younger than 6 months of age. The f1 RAST should be examined repeatedly in AD infants with low levels of IgE against f1. Similar results were obtained for f2- specific IgE, but there was a significant decrease in the specificity when the cut-off point was set at 0.20 Ua/mL.

DOI： 10.2332/allergolint.47.129

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