Impact of maternal dyslipidemia on infant neurodevelopment: The Japan Environment and Children's Study.

BACKGROUND: Various genetic and environmental influences have been studied for developmental disorders; however, the precise cause remains unknown. This study assessed the impact of maternal serum total cholesterol (TC) level in early pregnancy on early childhood neurodevelopment. METHODS: The fixed data of 31,797 singleton births from a large national birth cohort study that commenced in 2011 were used to identify developmental disorders as estimated by Ages and Stages Questionnaire, third edition (ASQ-3) scores of less than -2 standard deviations at 12 months of age. Multiple logistic regression analysis was employed to search for correlations between possibility of developmental disorders and maternal TC levels in early pregnancy classified into 4 groups based on quartile (Q1-Q4) values. RESULTS: After controlling for potential confounding factors in 27,836 participants who ultimately underwent multivariate analysis, we observed that elevated TC levels were significantly associated with a higher risk of screen positive status for communication (Q4: adjusted odds ratio [aOR] 1.20, 95% confidence interval [CI] 1.05-1.37) and gross motor (aOR 1.13, 95% CI 1.03-1.25) ASQ-3 domain scores. CONCLUSION: This large nationwide survey revealed a possible deleterious effect of hypercholesterolemia in early pregnancy on infant neurodevelopment and age-appropriate skill acquisition at 12 months age.

Insufficient maternal gestational weight gain and infant neurodevelopment at 12 months of age: the Japan Environment and Children's Study.

Abnormal maternal gestational weight gain (GWG) increases the risk of obstetric-related complications. This investigation examined the impact of GWG on infant neurodevelopmental abnormalities at 12 months of age using the data of a nationwide Japanese cohort study. Questionnaire data were obtained from the ongoing Japan Environment and Children's Study cohort study. Maternal GWG was subdivided as below, within, or above the reference values of the Institution of Medicine pregnancy weight guidelines. The Ages and Stages Questionnaire, third edition (ASQ-3) is a parent-reported developmental screening instrument for children across five domains: communication, gross motor, fine motor, problem-solving, and personal-social. Multiple logistic regression analysis was employed to identify correlations between GWG and developmental delay defined as ASQ-3 scores of less than two standard deviations below the mean. A total of 30,694 mothers with singleton live births and partners who completed the questionnaire were analyzed. The prevalence of mothers below, within, and above the GWG guidelines was 60.4% (18,527), 32.1% (9850), and 7.5% (2317), respectively. We recorded 10,943 infants (35.7%) who were outliers in at least one ASQ-3 domain. After controlling for covariates, GWG below established guidelines was associated with a significantly higher risk of developmental delay for the communication (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.09-1.34), gross motor (OR 1.14, 95% CI 1.05-1.24), fine motor (OR 1.13, 95% CI 1.04-1.24), problem-solving (OR 1.09, 95% CI 1.01-1.18), and personal-social (OR 1.15, 95% CI 1.07-1.24) domains.Conclusion: This large survey revealed a possible deleterious effect of insufficient maternal GWG on infant neurodevelopment.Trial registration: The Japan Environment and Children's Study (JECS) was registered in the UMIN Clinical Trials Registry on January 15, 2018 (number UMIN000030786). What is Known: • Inappropriate maternal gestational weight gain may cause obstetric complications and adverse birth outcomes. • Excess maternal weight gain may result in gestational diabetes, hypertension, eclampsia, caesarean delivery, and macrosomia, while insufficient maternal weight gain has been associated with pre-term birth and small for gestational age. What is New: • This study provides important information on a possible adverse effect of insufficient maternal gestational weight gain on offspring neurodevelopment at 12 months of age. • Our findings indicate a need to reconsider the optimal body mass index and gestational weight gain for women desiring pregnancy.

Successful treatment of congenital myasthenic syndrome caused by a novel compound heterozygous variant in RAPSN.

BACKGROUND: Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous neuromuscular disorder characterized by muscle weakness and caused by mutations in more than 35 different genes. This condition should not be overlooked as a subset of patients with CMS are treatable. However, the diagnosis of CMS is often difficult due to the broad variability in disease severity and course. CASE REPORT: A five-year-old boy without remarkable family history was born with marked general muscle hypotonia and weakness, respiratory insufficiency, anomalies, and multiple joint contractures. Congenital myopathy was suspected based upon type 1 fiber predominance on muscle biopsy. However, he was diagnosed with CMS at age 4 years when his ptosis and ophthalmoplegia were found to be improved by edrophonium chloride and repetitive nerve stimulation showed attenuation of compound muscle action potentials. An exome sequencing identified a compound heterozygous missense variant of c.737C > T (p.A246V) and a novel intronic insertion c.1166 + 4_1166 + 5insAAGCCCACCAC in RAPSN. RT-PCR analysis which showed the skipping of exon 7 in a skeletal muscle sample confirmed that the intronic insertion was pathogenic. His myasthenic symptoms were remarkably improved by pyridostigmine. CONCLUSION: The patient's diagnosis of CMS was confirmed by exome sequencing, and RT-PCR revealed that the skipping of exon 7 in RAPSN was caused by a novel intronic insertion. The genetic information uncovered in this case should therefore be added to the collection of tools for diagnosing and treating CMS.

Maternal alcohol consumption and risk of offspring with congenital malformation: the Japan Environment and Children's Study.

BACKGROUND: The association between fetal exposure to alcohol and congenital structural disorders remains inconclusive. The present study searched for relationships between maternal alcohol consumption during pregnancy and the risk of congenital malformations. METHODS: We evaluated the fixed dataset of a large national birth cohort study including 73,595 mothers with a singleton live birth. Information regarding the alcohol consumption of mothers was obtained from self-reported questionnaires. Physicians assessed for 6 major congenital malformations (congenital heart defects [CHDs], male genital abnormalities, limb defects, cleft lip and/or cleft palate [orofacial clefts (OFC)], severe brain abnormalities, and gastrointestinal obstructions) up to 1 month after birth. Multiple logistic regression analysis was performed to identify associations between maternal alcohol consumption during pregnancy and each malformation. RESULTS: The prevalence of maternal drinking in early pregnancy and until the second/third trimester was 46.6% and 2.8%, respectively. The onset of CHD was inversely associated with mothers who quit drinking during early pregnancy (OR 0.85, 95% CI 0.74-0.98). There was no remarkable impact of maternal drinking habit status on the other congenital malformations after adjustment for covariates. CONCLUSIONS: Maternal alcohol consumption during pregnancy, even in early pregnancy, displayed no significant adverse impact on congenital malformations of interest. IMPACT: This large-scale Japanese cohort study revealed that no teratogenic associations were found between maternal retrospective reports of periconceptional alcohol consumption and congenital malformations after adjustment for covariates. This is the first nationwide birth cohort study in Japan to assess the effect of maternal alcohol consumption during pregnancy on major congenital malformations. Our finding indicated that maternal low-to-moderate alcohol consumption during pregnancy, even in early pregnancy, displayed no significant adverse impact on congenital heart defects, male genital abnormalities, limb defects, orofacial clefts, severe brain abnormalities, or gastrointestinal obstructions.

Association between pesticide usage during pregnancy and neonatal hyperbilirubinemia requiring treatment: the Japan Environment and Children's Study.

BACKGROUND: Maternal exposure to pesticides during pregnancy may cause oxidative hemolysis leading to neonatal hyperbilirubinemia. This investigation examined for associations between maternal use of pesticides or repellents during pregnancy and neonatal hyperbilirubinemia requiring phototherapy. METHODS: We used the dataset from the Japan Environment and Children's Study, a large national birth cohort study registered from January 31, 2011 to March 31, 2014. The fixed data of 61,751 live births were used to evaluate the presence of neonatal hyperbilirubinemia and potential confounding factors. We employed multiple logistic regression analysis to identify correlations between the frequency of maternal pesticide or repellent use during pregnancy and clinically relevant neonatal hyperbilirubinemia. RESULTS: After controlling for confounding factors, there were significant associations between neonatal hyperbilirubinemia necessitating phototherapy and the frequent use of indoor insecticide spray (OR 1.21, 95% CI 1.05-1.38). For spray- or lotion-type insect repellents, an opposite relationship was observed (more than a few times a week: OR 0.70, 95% CI 0.61-0.81, up to a few times a month: OR 0.84, 95% CI 0.78-0.91). CONCLUSION: The frequent use of indoor insecticide spray during pregnancy showed an increased risk of neonatal hyperbilirubinemia requiring phototherapy, which was absent for spray- or lotion-type insect repellents. IMPACT: The frequent use of indoor insecticide spray during pregnancy showed an increased risk of neonatal hyperbilirubinemia requiring phototherapy, which was absent for spray- or lotion-type insect repellents. This is the first study examining the effects of maternal exposure to pesticides or repellents on clinically relevant neonatal hyperbilirubinemia using a dataset from a nationwide birth cohort study. This large-scale Japanese cohort study revealed that the frequent use of indoor insecticide spray during pregnancy may increase the risk of neonatal hyperbilirubinemia requiring treatment.

The Preventive Effect of Lactoferrin-Containing Yogurt on Gastroenteritis in Nursery School Children-Intervention Study for 15 Weeks.

To evaluate the effects of bovine lactoferrin (LF)-containing yogurt on gastroenteritis in nursery school children during the winter season, we conducted a randomized prospective study. A total of 1296 children were randomized into a group in which LF was provided in yogurt (LF group, n = 661) and a non-LF consumption group (control group, n = 635). The LF group was given LF-containing yogurt (100 mg/day) on all 5 weekdays for approximately 15 weeks, and the control group consumed fruit jelly instead of the yogurt. The final totals of 578 children as the LF group and 584 as the control group were analyzed. The total number of children who were absent from school due to vomiting was significantly lower in the LF group compared to the control, accounting for ≥3 days in any week: 10/234 (4.3%) vs. 49/584 (8.4%), respectively; p = 0.04. Regarding the relationship between absences due to vomiting and the consumption of the LF-containing yogurt, the adjusted odds ratio for absence due to vomiting was 2.48 (95% CI: 1.19-5.14) in the LF children who consumed LF-containing yogurt ≤2 days/week compared to the LF children who consumed the yogurt ≥ 3 days/week. The consumption of LF-containing yogurt (100 mg/day) for ≥3 days/week might help alleviate the symptom of vomiting in nursery school children during the winter.

Effects of Lactoferrin on Subjective Skin Conditions in Winter: A Preliminary, Randomized, Double-Blinded, Placebo-Controlled Trial.

OBJECTIVE: To investigate the effects of lactoferrin (LF) on subjective skin conditions in winter. DESIGN: A preliminary, randomized, double-blinded, placebo-controlled trial. SETTING AND SUBJECTS: Healthy adults in Japan. INTERVENTIONS: Intake of placebo, 200 mg, or 600 mg of LF for 12 weeks in winter. ENDPOINTS: Changes in the scores of subjective skin conditions. RESULTS: Three hundred and forty-six subjects were randomized. Nine subjects (placebo, n=0; 200 mg, n=5; 600 mg, n=4) withdrew consent, and 7 subjects (placebo, n=4; 200 mg, n=2; 600 mg, n=1) were lost to follow-up, resulting in 330 for a full analysis set. OUTCOMES: Changes in the scores of moisture were greater in the 600 mg group than in the placebo group. Changes in the scores of moisture were greater in the 200 mg and 600 mg groups, and of texture were greater in the 600 mg group than in the placebo group in female subjects. CONCLUSION: Intake of LF may improve moisture or texture of skin in winter.

Maternal Exposure to Housing Renovation During Pregnancy and Risk of Offspring with Congenital Malformation: The Japan Environment and Children's Study.

There have been no large, nationwide, birth cohort studies in Japan examining the effects of house renovation during pregnancy on congenital abnormality. This study examined the impact of (1) prenatal exposure to house renovation and (2) maternal occupational exposure to organic solvents and/or formaldehyde on the incidence of congenital abnormality. The fixed data of 67,503 singleton births from a large national birth cohort study that commenced in 2011 were used to evaluate the presence of congenital abnormalities and potential confounding factors. We employed multiple logistic regression analysis to search for correlations between maternal exposure to house renovation or organic solvents and/or formaldehyde during pregnancy and such congenital abnormalities as congenital heart disease, cleft lip and/or palate, male genital abnormality, limb defect, and gastrointestinal obstruction. After controlling for potential confounding factors, we observed that house renovation was significantly associated with male genital abnormality (OR 1.81, 95% CI 1.03-3.17, P = 0.04) when stratified by congenital abnormality, with no other remarkable relations to house renovation or occupational use of organic solvents and/or formaldehyde during pregnancy. There were also significant correlations for maternal BMI before pregnancy, history of ovulation induction through medication, maternal diabetes mellitus/gestational diabetes mellitus, and hypertensive disorder of pregnancy with an increased risk of congenital abnormality. In conclusion, this large nationwide survey provides important information on a possible association of house renovation during pregnancy with congenital male genital abnormality which needs confirmation in future studies.

Alcohol Consumption During Pregnancy and Risk of Placental Abnormality: The Japan Environment and Children's Study.

There have been no large nationwide birth cohort studies examining for the effects of maternal alcohol use during pregnancy on placental abnormality. This study searched for associations between alcohol consumption and the placental abnormalities of placenta previa, placental abruption, and placenta accreta using the fixed dataset of a large national birth cohort study commencing in 2011 that included 80,020 mothers with a singleton pregnancy. The presence of placental abnormalities and potential confounding factors were recorded, and multiple logistic regression analysis was employed to search for correlations between maternal alcohol consumption during pregnancy and placental abnormalities. The overall rate of prenatal drinking until the second/third trimester was 2.7% (2,112). The prevalence of placenta previa, placental abruption, and placenta accreta was 0.58% (467), 0.43% (342), and 0.20% (160), respectively. After controlling for potential confounding factors, maternal alcohol use during pregnancy was significantly associated with the development of placenta accreta (OR 3.10, 95%CI 1.69-5.44). In conclusion, this large nationwide survey revealed an association between maternal drinking during pregnancy and placenta accreta, which may lead to excessive bleeding during delivery.

Concentrations of various forms of vitamin B6 in ginkgo seed poisoning.

A 2-year-old girl required medical attention for a sudden onset of repetitive tonic-clonic convulsions after ingesting 20-30 ginkgo seeds. Concentrations of the major forms of circulating vitamin B6, pyridoxal-5'-phosphate (PLP), pyridoxal (PL), and 4-pyridoxic acid, as well as the known ginkgo seed toxin 4'-O-methylpyridoxine (MPN) were measured in the serum and cerebrospinal fluid (CSF). PLP is an active form of vitamin B6 and necessary for γ-aminobutyric acid (GABA) production. High MPN concentrations were observed in both the serum and CSF. As the PLP to PL ratio was markedly decreased in serum and CSF examinations, we suspected the ratio to be important in GABA production. This case report provides novel information on the metabolism of vitamin B6 in humans as a result of ginkgo seed poisoning.

Early prognostic factors for acute encephalopathy with reduced subcortical diffusion.

OBJECTIVE: The aim of this study was to determine the prognostic factors for acute encephalopathy with reduced diffusion (AED) during the acute phase through retrospective case evaluation. METHODS: The participants included 23 patients with AED. The diagnosis of AED was based on their clinical course and radiological findings. We divided the patients into severe and non-severe groups based on the neurodevelopmental outcome. The severe group included seven patients (median age, 21 months; range, 6-87 months) and the non-severe group included 16 patients (19 months, 9-58 months). Clinical symptoms, laboratory data and electroencephalogram (EEG) findings within 48 h from the initial seizure onset were compared between the two groups to identify neurological outcome predictors. RESULTS: The incidence of coma 12-24 h after onset, serum creatinine (Cr) levels within 2 h after onset, maximum aspartate aminotransferase (AST) levels within 24 h after onset, and the rate of electrographic seizures in EEG were significantly higher in the severe group (Coma, 80%; Cr, 0.40 mg/dl, 0.37-0.73; AST, 363 IU/L, 104-662; electrographic seizures, 80%) than the non-severe group (Coma, 0%; Cr, 0.29 mg/dL, 0.19-0.45; AST, 58.5 IU/L, 30-386; electrographic seizures, 0%). CONCLUSIONS: Coma 12-24 h after onset, elevation of Cr levels within 2 h after onset, elevation of AST levels within 24 h after onset, and non-convulsive status epileptics (NCSE) in comatose patients were early predictors of severe AED. Patients in a coma after a febrile seizure should be checked for NCSE signs in EEG to terminate NCSE without delay.

Cross-sectional observation of the relationship of depressive symptoms with lifestyles and parents' status among Japanese junior high school students.

OBJECTIVES: Students' depressive symptoms might be related to their own risk factors and to their parents' status. The objective of this cross-sectional study was to examine the relationship of depressive symptoms with lifestyle variables and parents' psychological and socio-demographic status among Japanese junior high school students. METHODS: Of 477 students and their parents, 409 (85.7 %) students and 314 (65.8 %) parents participated in the study. Students answered self-reported questionnaire on depressive symptoms, their heights and weights, subjective stress, body dissatisfaction, lifestyles including sleep duration and extracurricular physical activity in school and other physical activity outside the school, and nutritional intake. Parents responded to questionnaire on depressive symptoms and socio-demographic status. RESULTS: The prevalence of depressive symptoms was 24.9 %. Students with depressive symptoms were more likely to have stress. Students in shorter and longer sleep duration groups were more likely to have depressive symptoms. The students with depressive symptoms had smaller amount of energy intake than did those without depressive symptoms. Multiple logistic regression analysis revealed significant relationships between students' depressive symptoms and some independent variables. Sex, subjective stress, "almost-never"-categorized extracurricular physical activity in school and other physical activity outside the school, and having a parent with depressive symptoms were significantly associated with students' depressive symptoms. CONCLUSION: Reducing mental stress and taking care of lifestyles, especially, "almost-everyday"-categorized extracurricular physical activity in school and other physical activity outside the school, may have benefits for students' mental health, and having a parent with depressive symptoms may be associated with students' depressive symptoms.

[Efficacy of visual cognitive function tests in health examinations of five-year-old children].

OBJECTIVE: Health examination programs for five-year-old children are aimed at effectively detecting developmental disorders, such as attention deficit/hyperactivity disorders (AD/HD), learning disorders (LD), higher functioning autistic spectrum disorders (HFASD), and other abnormalities. Tests usually include a questionnaire and observation of group playing, verbal communication, and soft neurological signs; however, it is often difficult to detect children who have LD with visual cognitive dysfunctions through such conventional examination techniques. Here, we analyzed the efficacy of using a battery of visual cognitive function tests to identify such cases. METHODS: We employed four simple tests to evaluate visual cognitive function in addition to a standard health examination for five-year-old between April 2008 and March 2010. To analyze visual cognitive function tests, the results were scored and the applicability of these tests was verified by comparisons with established tests. RESULTS: A total of 653 five-year-old children underwent health examinations, and 48 children were referred to the hospital for further examinations. As a result, 34 children were newly diagnosed with developmental disorders, including HFASD, AD/HD, LD, and mild intellectual disturbances. Strong correlations were seen between the scores of these four examinations and those of other established tests, such as the performance intelligence score, the perceptual organization index of WISC-III, and the Frostig visual development test score. An additional benefit of our method was that parents could easily recognize developmental disorders in their children through direct observation of these examinations. CONCLUSIONS: We concluded that the battery of visual cognitive function tests was simple and useful for detecting developmental disorders in the health examinations of five-year-old children.

[A 6-year-old girl who exhibited residual reading disorder during the course of acute encephalopathy].

We assessed a 6-year-old girl who developed status epilepticus and exhibited transient aphasia during the course of acute encephalopathy with late reduced diffusion, and who had a residual reading disorder in the recovery period. The aphasia appeared to be fluent aphasia and anomia, suggesting that the reading disorder during the recovery process was due to impairment of the phonological process. There were no biphasic seizures during the course of the patient's illness, but this case was acute encephalopathy with febrile convulsive status epilepticus (AEFCSE) from the standpoint of the characteristic imaging findings. Lesions in the left parietal and temporal lobes were detected on MRI diffusion-weighted images and by SPECT and MRS, and they appeared to be the lesions responsible for the aphasia and residual reading disorder. This case appears to be important from the standpoint of assessing the pathophysiology and the treatment of coexisting illness observed in acute encephalopathy.

Reduction-oxidation poise regulates the sign of phototaxis in Chlamydomonas reinhardtii.

In many phototrophic microorganisms and plants, chloroplasts change their positions relative to the incident light to achieve optimal photosynthesis. In the case of motile green algae, cells change their swimming direction by switching between positive and negative phototaxis, i.e., swimming toward or away from the light source, depending on environmental and internal conditions. However, little is known about the molecular signals that determine the phototactic direction. Using the green alga Chlamydomonas reinhardtii, we found that cellular reduction-oxidation (redox) poise plays a key role: Cells always exhibited positive phototaxis after treatment with reactive oxygen species (ROS) and always displayed negative phototaxis after treatment with ROS quenchers. The redox-dependent switching of the sign of phototaxis may contribute in turn to the maintenance of cellular redox homeostasis.

Reflex seizures induced by micturition and defecation, successfully treated with clobazam and phenytoin.

We report a six-year-old girl with seizures induced by both micturition and defecation. Several days after unprovoked generalised tonic-clonic seizures, she developed reflex seizures characterised by the extension of both arms and rhythmic jerking of her upper body. No abnormal findings were noted on brain magnetic resonance imaging. Interictal electroencephalography (EEG) showed spike-and-wave activity on central electrode recording, and rhythmic fast activity was recorded by central electrodes during the ictal EEG upon micturition. The combination of clobazam and phenytoin was effective for both unprovoked and reflex seizures. Although some previous reports have described reflex seizures triggered by either micturition or defecation, this is the first case report of reflex seizures induced by both micturition and defecation in the same patient. Based on a comparison with previous cases of reflex seizures induced either by micturition or defecation, the neuronal pathway from the pelvic base musculature to the supplementary motor area may be responsible for the condition in our patient.

[Two cases of symptomatic West syndrome suffering from severe respiratory syncytial virus-induced bronchiolitis].

We report two cases of symptomatic West syndrome with severe respiratory syncytial virus (RSV)-induced bronchiolitis: one was a 9-month-old boy who was hospitalized for shock, and the other was a 15-month-old boy in pre-shock condition. Both cases needed mechanical ventilation for approximately 2 weeks. Seizures from the primary disease worsened in both patients during the infection, and both needed long periods of hospitalization, which resulted in a considerable reduction in their quality of life and that of their families. According to a one-year epidemiological survey of RSV infection conducted in 2004-2005 in Nagano prefecture, 7 of 238 hospitalized RSV cases were found to have basic neuromuscular disorders. Compared to patients with chronic lung disease or other primary diseases, they were older, had higher incidence of mechanical ventilation, and required longer hospitalization. Neuromuscular disorders may thus be an important risk factor for severe forms of RSV infection. Although children with such disorders should be protected from RSV, they are currently excluded from the indication for palivizumab administration as passive immunization against RSV in Japan.

Vitamin D(3) induces expression of human cathelicidin antimicrobial peptide 18 in newborns.

Bactericidal activities of neutrophils occur by two distinctive mechanisms that are oxygen-dependent and -independent. Human cathelicidin antimicrobial peptide 18 (hCAP18), also known as LL-37/FALL-39, is a neutrophil-specific granule protein. We compared the content of hCAP18 and neutrophil gelatinase-associated lipocalin (NGAL), another neutrophil-specific granule protein, in neutrophils of both neonates and adults by flow cytometry. The percentage as well as fluorescence intensity ratio of hCAP18 and NGAL expression in neonate neutrophils were significantly lower than in adults. Expression of hCAP18 in monocytes, however, was not significantly different between neonates and adults. Both hCAP18 and NGAL expression increased in an age-dependent fashion. Plasma concentration of these peptides measured by enzyme-linked immunosorbent assay was not significantly different between neonates and adults. Oral intake of 1alpha hydroxy vitamin D(3) (1alpha(OH)D(3)) in rickets patients for 4 weeks significantly increased hCAP18 expression in neutrophils compared to age-matched healthy controls without 1alpha(OH)D(3), indicating the potential of vitamin D(3) as a regulator of the innate immune response of neonates.