Physical growth and neurodevelopment during the first year of life: a cohort study of the Japan Environment and Children's Study.

BACKGROUND: The association between a slower physical growth and poorer neurodevelopment has been established in infants born preterm or small for gestational age. However, this association is inconsistent in term-born infants, and detailed investigations in infancy, when intervention is most beneficial for improving outcomes, are lacking. We therefore examined this association separately by sex during the first year of life in term-born infants. METHODS: Using data collected until children reached 12 months old in an ongoing prospective cohort of the Japan Environment and Children's Study, we analyzed 44,264 boys and 42,541 girls with singleton term-birth. The exposure variables were conditional variables that disentangle linear growth from weight gain relative to linear growth, calculated from the length and weight at birth and 4, 7 and 10 months old. Neurodevelopmental delay was identified using the Japanese-translated version of Ages & Stages Questionnaires, third edition. RESULTS: A reduced risk of neurodevelopmental delay at 6 months old was observed in children with a higher birth weight (adjusted relative risks [aRRs]: 0.91 and 0.93, 95 % confidence intervals [95 % CIs]: 0.87-0.96 and 0.88-0.98 in boys and girls, respectively) and increased linear growth between 0 and 4 months old (aRRs: 0.85 and 0.87, 95 % CIs: 0.82-0.88 and 0.83-0.91 in boys and girls, respectively). A reduced risk at 12 months was found in children with an increased linear growth between 0 and 4 months (aRRs: 0.92 and 0.90, 95 % CIs: 0.87-0.98 and 0.84-0.96 in boys and girls, respectively), boys with an increased relative weight gain between 0 and 4 months (aRR: 0.90, 95 % CI: 0.84-0.97), and girls with a higher birth weight (aRR: 0.89, 95 % CI: 0.83-0.96). CONCLUSIONS: These results suggest that a slow physical growth by four months old may be a predictor of neurodevelopmental delay during infancy.

Exploratory analysis of plasma cytokine/chemokine levels in 6-year-old children from a birth cohort study.

This study aimed to reveal a new dimension of allergy profiles in the general population by using machine learning to explore complex relationships among various cytokines/chemokines and allergic diseases (asthma and atopic dermatitis; AD). We examined the symptoms related to asthma and AD and the plasma levels of 72 cytokines/chemokines obtained from a general population of 161 children at 6 years of age who participated in a pilot birth cohort study of the Japan Environment and Children's Study (JECS). The children whose signs and symptoms fulfilled the criteria of AD, which are mostly based on questionnaire including past symptoms, tended to have higher levels of the two chemokine ligands, CCL17 and CCL27, which are used for diagnosis of AD. On the other hand, another AD-related chemokine CCL22 level in plasma was higher only in children with visible flexural eczema, which is one of AD diagnostic criteria but was judged on the same day of blood examination unlike other criteria. Here, we also developed an innovative method of machine learning for elucidating the complex cytokine/chemokine milieu related to symptoms of allergic diseases by using clustering analysis based on the random forest dissimilarity measure that relies on artificial intelligence (AI) technique. To our surprise, the majority of children showing at least any asthma-related symptoms during the last month were divided by AI into the two clusters, either cluster-2 having elevated levels of IL-33 (related to eosinophil activation) or cluster-3 having elevated levels of CXCL7/NAP2 (related to neutrophil activation), among the total three clusters. Future studies will clarify better approach for allergic diseases by endotype classification.

Measurement of the Estradiol Concentration in Cerebrospinal Fluid from Infants and Its Correlation with Serum Estradiol and Exosomal MicroRNA-126-5p.

Estradiol has an important role in the brain, such as in neuronal development and protection, but estradiol levels in the human brain have not been well investigated. In this study, we measured the estradiol concentration in the cerebrospinal fluid (CSF) of infants to reveal the relationships between the estradiol concentrations in the serum and the CSF and further determined exosomal microRNAs in serum. Estradiol in the CSF was strongly correlated with serum estradiol and moderately correlated with miR-126-5p in the serum exosomes. This report is the first to determine the estradiol concentration in CSF from infants and showed that the levels of miR-126-5p as well as serum estradiol can be candidates to predict brain estrogen status.

Associations Between Metal Levels in Whole Blood and IgE Concentrations in Pregnant Women Based on Data From the Japan Environment and Children's Study.

BACKGROUND: Metal exposures could possibly affect allergic responses in pregnant women, although no studies have yet shown a clear relationship between the two, and such exposures might also affect the development of allergic diseases in children. METHODS: We investigated the relationship between metal concentrations in whole blood and immunoglobulin E (IgE; total and specific) in 14,408 pregnant women who participated in the Japan Environment and Children's Study. The subjects submitted self-administered questionnaires, and blood samples were collected from them twice, specifically, during the first trimester and again during the second/third trimester. Concentrations of the metals Cd, Pb, Hg, Se, and Mn, as well as serum total and allergen-specific IgEs for egg white, house dust-mites (HDM), Japanese cedar pollen (JCP), animal dander, and moth, were measured. Allergen-specific IgE(s) were divided based on concentrations <0.35 or ≥0.35 UA/mL, and the metal levels were divided into quartiles. RESULTS: Multivariable logistic regression analysis showed that there was a significant negative correlation between HDM- and animal dander-specific IgEs and Hg and Mn concentrations. Conversely, there was a significant positive relationship between JCP-specific IgE and Hg and Se concentrations. CONCLUSIONS: Metal exposures may be related to both increases and decreases in allergen-specific IgEs in pregnant women.

Impact of sleep duration during pregnancy on the risk of gestational diabetes in the Japan environmental and Children's study (JECS).

BACKGROUND: Gestational diabetes mellitus (GDM) has serious effects on both mother and child. Like Type 2 Diabetes Mellitus, it is increasing in prevalence world-wide. In addition to obesity, sleep duration has been named an important risk factor. Using a large cohort study, including data from 48,787 participants of the Japan Environment and Children's Study (JECS), we examined the association between sleep duration and both random blood glucose levels and GDM rates during pregnancy. METHODS: Random blood glucose levels were measured during pregnancy. GDM diagnosis was based on the results of 75 g oral glucose tolerance test. Additional anthropometric data was collected from questionnaires for statistical analysis. RESULTS: Compared to mothers averaging 7 to < 10 h sleep (reference group), women receiving < 5 h or ≥ 10 h sleep exhibited significantly elevated random blood glucose levels. This was associated with an elevated risk for positive GDM screening (< 5 h sleep: OR 1.17 (0.96-1.44) p = 0.126; ≥10 h sleep: OR 1.13 (1.03-1.25) p = 0.006). Calculating the risk for GDM, women sleeping < 5 h or ≥ 10 h exhibited elevated risks of 1.31-fold and 1.21 respectively. However, this trend was not found to be significant. CONCLUSIONS: Sleep is a critical factor in glucose metabolism, with both abnormally long and short sleep duration increasing random blood glucose levels in pregnant women. Moreover, the risk for positive GDM screening increases significantly with elevated sleep, ≥10 h per night. These findings are promising because they support the idea that sleep duration is a modifiable risk factor, and can be focused upon to improve health and pregnancy outcome.

Psychometric profile of the Ages and Stages Questionnaires, Japanese translation.

BACKGROUND: This study assessed the psychometric profile of 10 questionnaires (every 6 months, from 6 to 60 months) from the Japanese translation of the Ages and Stages Questionnaires, third edition (J-ASQ-3). METHODS: Data from 439 children in a birth cohort were used to identify the J-ASQ-3 score distribution, establish cut-off scores, and calculate the instrument's internal consistency. Data were also collected from 491 outpatients to examine J-ASQ-3 test-retest reliability and concurrent validity, which was examined using the Kyoto Scale of Psychological Development (KSPD) and the Japanese version of the Denver Developmental Screening Test II (J-Denver II). Both the original and the alternative screening criteria of the ASQ-3 were used (failure in at least one and at least two domains, respectively). RESULTS: Cronbach's alpha for each J-ASQ-3 subscale on each questionnaire ranged from 0.45 to 0.89. Test-retest reliability was >0.75 for the subscales on almost all questionnaires. Concurrent validity was also adequate. In comparison with the screening results of the KSPD, the overall sensitivity and specificity were 96.0% and 48.8%, respectively, when the ASQ-3 original criterion was used, and 92.1% and 74.9%, respectively, when the alternative criterion was used. In comparison with the screening results of the J-Denver II, the overall sensitivity and specificity were 75.6% and 74.7%, respectively, when the ASQ-3 original criterion was used, and 56.3% and 93.0%, respectively, when the alternative criterion was used. CONCLUSIONS: This study quantified the psychometric profiles of the Japanese translations of 10 ASQ-3 questionnaires. We demonstrated the validity of the J-ASQ-3 and determined new cut-off scores. Further studies with larger samples from a greater range of locations are required to clarify the suitability of this tool for all Japanese children.

Associations between metal concentrations in whole blood and placenta previa and placenta accreta: the Japan Environment and Children's Study (JECS).

BACKGROUND: Placenta previa and placenta accreta associate with high morbidity and mortality for both mothers and fetus. Metal exposure may have relationships with placenta previa and placenta accreta. This study analyzed the associations between maternal metal (cadmium [Cd], lead [Pb], mercury [Hg], selenium [Se], and manganese [Mn]) concentrations and placenta previa and placenta accreta. METHODS: We recruited 17,414 women with singleton pregnancies. Data from a self-administered questionnaire regarding the first trimester and medical records after delivery were analyzed. Maternal blood samples were collected to measure metal concentrations. The subjects were classified into four quartiles (Q1, Q2, Q3, and Q4) according to metal concentrations. RESULTS: The odds ratio for placenta previa was significantly higher among subjects with Q4 Cd than those with Q1 Cd. The odds ratio for placenta previa was significantly higher for subjects with Q2 Pb than those with Q1 Pb. CONCLUSION: Participants with placenta previa had higher Cd concentrations. However, this study was cross-sectional and lacked important information related to Cd concentration, such as detailed smoking habits and sources of Cd intake. In addition, the subjects in this study comprised ordinary pregnant Japanese women, and it was impossible to observe the relationship between a wide range of Cd exposure and placenta previa. Therefore, epidemiological and experimental studies are warranted to verify the relationship between Cd exposure and pregnancy abnormalities.

Optimal protein intake during pregnancy for reducing the risk of fetal growth restriction: the Japan Environment and Children's Study.

Clinical trials show that protein supplement increases infant size in malnourished populations; however, epidemiological studies in high-income countries have reported mixed results. Although these findings suggest a non-linear relationship between maternal macronutrient intake and fetal growth, this relationship has not been closely examined. We assessed the association between maternal protein intake and fetal growth among 91 637 Japanese women with singletons in a nation-wide cohort study using validated FFQ. The respondents answered the FFQ twice, once during early pregnancy (FFQ1; 16·3 (sd 6·0) weeks), and second during mid-pregnancy (FFQ2, 28·1 (sd 4·1) weeks). Daily energy intake and percentage energy from protein, fats and carbohydrates were 7477 (sd 2577) kJ and 13·5 (sd 2·0), 29·5 (sd 6·5) and 55·3 (sd 7·8) %, respectively, for FFQ1, and 7184 (sd 2506) kJ and 13·6 (sd 2·1), 29·8 (sd 6·6) and 55·3 (sd 7·9) %, respectively, for FFQ2. The average birth weight was 3028 (sd 406) g, and 6350 infants (6·9 %) were small for gestational age (SGA). In both phases of the survey, birth weight was highest and the risk of SGA was lowest when the percentage energy from protein was 12 %, regardless of whether isoenergetic replacement was with fat or carbohydrates. Furthermore, when protein density in the maternal diet was held constant, birth weight was highest when 25 % of energy intake came from fat and 61 % came from carbohydrates during early pregnancy. We found maternal protein intake to have an inverse U-curve relationship with fetal growth. Our results strongly suggest that the effect of protein on birth weight is non-linear, and that a balanced diet fulfilling the minimum requirement for all macronutrients was ideal for avoiding fetal growth restriction.

The association between whole blood concentrations of heavy metals in pregnant women and premature births: The Japan Environment and Children's Study (JECS).

BACKGROUND: Heavy metals are widely distributed in the environment. Recent reports have demonstrated the risk of preterm birth following heavy metal exposure. Preterm births are classified as early and late, depending on the duration of pregnancy, and are associated with increased risk of congenital illnesses such as heart failure, asthma, etc. Particularly, early preterm births carry a higher risk of mortality; however, the differential effects of heavy metal exposure on early and late preterm births are unknown. OBJECTIVES: To analyze the association between maternal whole blood concentrations of heavy metals, such as cadmium (Cd), lead (Pb), mercury (Hg), selenium (Se), and manganese (Mn) that are common toxicants in Japan, and early and late preterm births. METHODS: The data of 14,847 pregnant women who were participants of the Japan Environment and Children's Study were used. Data of the self-questionnaire pertaining to the first trimester (T1), second/third trimester (T2), and medical records after delivery were analyzed. We divided preterm birth into two groups: early preterm (22 to < 34 weeks) and late preterm (34 to < 37 weeks). Maternal blood samples for measuring heavy metal concentrations were collected in T2 (pregnancy weeks: 14-39). The participants were classified into four quartiles (Q1-Q4) according to increasing heavy metal levels. RESULTS: The rate of preterm birth was 4.5%. After controlling for confounding factors, such as age, pre-pregnancy body mass index, smoking, partner's smoking, drinking habits, gravidity, parity, number of cesarean deliveries, uterine infections, household income, educational levels, and sex of infant, Cd levels were found, by multivariable logistic regression analysis, to be significantly associated with early preterm birth (p = 0.002), with odds ratio for early preterm birth of 1.91 (95% confidence interval: 1.12-3.27, P = 0.018) in subjects of Q4 compared with in subjects with term birth (≧ 37 weeks). CONCLUSION: Maternal blood Cd levels during pregnancy are positively associated with the risk of early preterm birth among Japanese women. Identification of the main source of maternal Cd exposure may contribute to the prevention of early preterm births and health maintenance of mothers and their infants in the future.

Factors associated with occupation changes after pregnancy/delivery: result from Japan Environment & Children's pilot study.

BACKGROUND: In Japan, although the number of females who continue to work after marriage has recently increased, the proportion of those working while parenting their infants is still not clearly increasing, indicating that it is still difficult for them to continue working after delivery. The present study aimed to clarify factors influencing females' continuation of work, using data obtained by continuously following up the same subjects and focusing on occupation changes, family environments, and the type of employment after pregnancy or delivery. METHODS: Based on the results of the questionnaire survey, which was conducted involving 164 participants at 4 universities, as part of the Japan Environment and Children's Pilot Study (JECS Pilot Study) led by the Ministry of Environment and the National Institute for Environmental Studies, the occupational status was compared between the detection of pregnancy (weeks 0 to 7) and 1 year after delivery. RESULTS: compared with changed their occupations significantly more frequently (OR = 5.07, 95% CI = 2.57-10.01, P < 0.001). Furthermore, on examining in detail, occupation changes were particularly marked among (OR = 12.48, 95% CI = 4.43-35.15, P < 0.001). This tendency was especially shown among < > (OR = 10.36, 95% CI = 1.59-67.38, P = 0.014) and < > (OR = 15.15, 95% CI = 2.55-90.17, P = 0.003). CONCLUSIONS: Analysis revealed that the type of employment, rather than the category of occupation, was associated with the continuation of work after pregnancy or delivery more closely, as compared with continued to work less frequently. Furthermore, on comparison of the category of occupation among , < > and < > were shown to be more likely to continue to be engaged in the same occupation after pregnancy or delivery. These differences may be related to availability of the child-care leave program and other support resources, therefore, it may be important to establish social systems that enable all females, to use these support resources if they wish, and actively work, while delivering and parenting their children.

Inability of infants to push up in the prone position and subsequent development.

BACKGROUND: During routine health screening, some infants cannot maintain the prone position with extended arm support at 6 months. Little is known, however, about the development of full-term infants with this developmental deviation. We investigated the developmental course of infants with this characteristic. METHODS: We enrolled 2,020 full-term infants who had been recruited at a regional center for the Japan Environment and Children's Study. Their development was measured using the Ages and Stages Questionnaire, third edition, at 0.5, 1, 1.5, 2, 2.5, and 3 years. The children were grouped according to their ability to stay prone on extended arms at 6 months, and their development was compared. RESULTS: A total of 1,625 infants could stay prone on extended arms and 179 could not. We excluded 212 infants who could stay prone on extended arms only sometimes, and four who did not have a questionnaire response. In the gross motor domain, significant difference in questionnaire scores was observed between the "could" and "could-not" groups at 6 months (Hedges' g, 1.83) and persisted until 3 years (Hedges' g, 0.33). Significant differences were also observed in the communication, fine motor, problem solving, and personal-social domains at 6 months (Hedges' g, 0.20-0.58) and persisted until 1, 2, 2, and 1.5 years, respectively (Hedges' g, 0.21-0.25). CONCLUSIONS: Infants who cannot maintain the prone position on extended arms lag behind those who can, although the effect sizes become relatively small after 1.5 years of age. Early intervention may be considered if delay is problematic or persistent.

Regional differences in infant 25-Hydroxyvitamin D: Pilot study of the Japan Environment and Children's Study.

BACKGROUND: In recent years, a resurgence in the number of infants with vitamin D deficiency has been noted. In addition to seasonal differences in exposure to ultraviolet (UV) rays, regional differences in dietary habits and lifestyles may affect susceptibility to vitamin D deficiency. No studies have been conducted, however, on infants in multiple regions of Japan to determine the extent of differences in vitamin D status. METHODS: 25-Hydroxyvitamin D (25OHD) was measured on radioimmunoassay in 126 infants aged 2-4 years, who participated in the Pilot Study of the Japan Environment and Children's Study (JECS) by the Ministry of Environment of Japan. A multiple regression model with 25OHD level as the outcome variable, and season and region as explanatory variables, was generated. RESULTS: Both region and season during which infants participated in this study significantly affected 25OHD level (P = 0.0087 and <0.0001, respectively; Wald test). Reflecting decreased exposure to UV rays, infants who were examined in winter had lower 25OHD than those examined in summer. Infants from both Fukuoka Prefecture (33°N) and Kumamoto Prefecture (32°N), however, had lower 25OHD than those from Tochigi Prefecture (36°N), contrary to expectations given the extent of UV exposure. CONCLUSIONS: Regional differences in daily habits and/or environmental factors affect 25OHD level in Japanese infants. The JECS is expected to identify those factors to provide guidance on preventing infantile vitamin D deficiency.

Comparative study on three different methods for arm-span measurement: the Japan environment and Children's study pilot.

BACKGROUND: Arm span is an important measure for the assessment of growth and hormone deficiency diseases. In an epidemiological survey, with a large number of subjects' indicators, it is especially valuable to establish methods which can measure both quickly and accurately. However, there are various methods, and the length of arm span may vary according to the medical institution. METHODS: The arm span of nine 6-year old subjects was measured using two institutional standard methods, A and B, and a third method C which is an improved method and has been used for the first time in this study. A, No-Wall, with heels together the child stretches the arms out to the sides. B, Wall & No-Line, the child stands against the wall with heels together and spreads the arms against the wall. C, Wall & Line, the method is the same as B except a paper with horizontal lines is placed on the wall. We measured twice by each method. RESULTS: The difference between the 1st and 2nd measurements was marginally significantly smaller by using method of C. CONCLUSION: The method C, which we improved, is the best way to measure arm span.

Relationship between hyperemesis gravidarum and small-for-gestational-age in the Japanese population: the Japan Environment and Children's Study (JECS).

BACKGROUND: Small-for-gestational-age in infancy is a known risk factor not only for short-term prognosis but also for several long-term outcomes, such as neurological and metabolic disorders in adulthood. Previous research has shown that severe nausea and vomiting in early pregnancy (NVP) and hyperemesis gravidarum, which is an extreme form of NVP, represent risk factors for small-for-gestational-age birth. However, there is no clear consensus on this association. Thus, in the present study, we investigated the correlation between hyperemesis gravidarum and NVP on the one hand, and infant birth weight on the other, using data from the Japan Environment and Children's Study (JECS). METHODS: The data utilized in the present study were obtained from the JECS, an ongoing cohort study that began in January 2011. Our sample size was 8635 parent-child pairs. The presence or absence of severe NVP, hyperemesis gravidarum, and potential confounding factors were noted. A multivariable regression analysis was used to estimate risks for small-for-gestational-age birth, and the results were expressed as risk ratios and 95 % confidence intervals. RESULTS: The risk ratios of small-for-gestational-age birth (95 % confidence interval) for mothers with severe NVP and those with hyperemesis gravidarum were 0.86 (0.62-1.19) and 0.81 (0.39-1.66), respectively, which represents a non-significant result. CONCLUSIONS: In our analysis of JECS data, neither severe NVP nor hyperemesis gravidarum was associated with increased risk for small-for-gestational-age birth.

Postal contact with participating children and its impact on response rate: Japan Environment and Children's Pilot Study.

BACKGROUND: Communication with participating children and its effect on participation outcome is one of the most important but untouched issues in birth cohort studies. The purpose of this study was to assess the effect of postal communication with the participating preschool children on the response rate to postal questionnaires. METHODS: One hundred and five mother-preschool child pairs from the Japan Environment and Children's Study (JECS) pilot cohort were included. During the 6 month study period, letters addressed to the children were enclosed with our biannual questionnaires, and the response rate transition was observed. Additionally, the participants were allocated to two groups. One of these was sent the letter with the individual name of the child at the top, and the other without it. The response rates of the two groups were compared using chi-squared test. Parents' impressions of the letters and the changes in their motivation to complete the questionnaires were surveyed using an evaluation form. RESULTS: The overall response rate was 83.8%, which was lower than the previous survey period. Response rate was not significantly different between the two letter types. The duration before questionnaire return was not changed. Despite their favorable impression based on parent evaluation, the letters were not associated with the parents' motivation to respond. CONCLUSION: Letters to participating preschool children had no effect on response rate, but the long-term impact of its favorability still remains to be evaluated. A similar trial at later ages may be more effective.

[ACTH therapy for two cases of epileptic spasms without hypsarrhythmia].

We present two patients with epileptic spasms without hypsarrhythmia (ESWoH) who were successfully treated with ACTH. One patient was an 18-month-old boy who had normal development for the first 16 months of his life. Thereafter, he experienced sudden flexion of the axial muscles, resulting in head nodings, or epileptic spasms (ES). EEG tracings showed generalized polyspikes that appeared frequently during sleep without associated hypsarrhythmia. We were thus able to diagnose him with ESWoH and treated him with ACTH, which resolved his seizures. Another patient was a 7-year-old boy. At 18 months of age, the patient began to sufferdil from sudden ES. Anti-epileptic drugs were administered individually and in combination but were proved ineffective. Like the first case, this child's EEG tracing showed generalized polyspikes during sleep without associated hypsarrhythmia. We diagnosed him with ESWoH and treated him with ACTH. His ES disappeared soon after the initiation of treatment. These two cases demonstrate the difficulty of treating ESWoH only with standard anti-epileptic drugs, we emphasize the importance of early treatment with ACTH.

Incidence and risk factors of acute encephalopathy with biphasic seizures in febrile status epilepticus.

OBJECTIVE: To clarify the incidence and risk factors of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) in pediatric patients with febrile status epilepticus (FSE). METHODS: We retrospectively surveyed patients with FSE (≥20 min and ≥40 min) who were younger than 6 years by mailing a questionnaire to 1123 hospitals in Japan. The survey period was 2 years. We then collected clinical data on patients with prolonged febrile seizures (PFS) ≥40 min and those with AESD, and compared clinical data between the PFS and AESD groups. RESULTS: The response rate for the primary survey was 42.3%, and 28.0% of hospitals which had applicable cases responded in the secondary survey. The incidence of AESD was 4.3% in patients with FSE ≥20 min and 7.1% in those with FSE ≥40 min. In the second survey, a total of 548 patients had FSE ≥40 min (AESD group, n = 93; PFS group, n = 455). Univariate analysis revealed significant between-group differences in pH, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, creatine kinase, NH3, procalcitonin (PCT), uric acid, blood urea nitrogen, creatinine (Cr), and lactate. Multivariate analysis using stratified values showed that high PCT was an only risk factor for AESD. A prediction score of ≥3 was indicative of AESD, as determined using the following indexes: HCO3- < 20 mmol/L (1 point), Cl <100 mEq/L (1 point), Cr ≥0.35 mg/dL (1 point), glucose ≥200 mg/dL (1 point), and PCT ≥1.7 pg/mL (2 points). The scoring system had sensitivity of 84.2% and specificity of 81.0%. CONCLUSION: Incidence data and prediction scores for AESD will be useful for future intervention trials for AESD.

[The ketogenic diet as an effective treatment for Ohtahara syndrome].

We here report on a male infant with Ohtahara syndrome. Tonic spasms in series appeared in an one-month-old baby, with his EEG showing a typical suppression burst pattern. We attempted these therapies in the following order; high-dose pyridoxal phosphate; anti-epileptic drugs; sodium valproate, phenobarbital, clonazepam and clobazam in various doses and combination; ACTH; TRH; and gamma-globulin. These did not, however, prove effective enough. Then we tried the ketogenic diet and brought his seizures under control. Therefore, we recommend that doctors who treat Ohtahara syndrome consider using the ketogenic diet earlier in the treatment regimen if the patient does not seem to be responding to conventional drug therapies.

[Effective cyclophosphamide pulse therapy for an young infant with severe dermatomyositis].

We herein report a 3 year-old boy, who showed proximal muscle weakness and pain at the age of one and a-half years. When he visited our hospital at the age of 1 year and 11 months, he could hardly move by himself. He also had difficulty in swallowing and suffered from multiple dermal ulcers. His blood test showed slightly elevated muscle enzyme activity, and magnetic resonance imaging suggested severe inflammation of the muscles. Radiological examination proved hypoperistalsis of the esophagus. With additional skin and muscle biopsies, we diagnosed him with juvenile dermatomyositis (JDM). Methyl-prednisolone pulse therapy was not effective enough, thus oral methotrexate, cyclosporine A and monthly cyclophosphamide pulse therapy were added. After the fourth cyclophosphamide pulse therapy, his muscular strength was restored, and the ulcers healed dramatically. Due to scarcity of severe cases, neither standardized classification nor grading system for severity in JDM has ever been established, which perplexes physicians in finding the best therapeutic strategy. Further investigation, experience and efforts are necessary to standardize an evaluating system and therapeutic strategy against JDM.