Sex steroid hormones and allergic diseases in children: a pilot birth cohort study in the Japan Environment and Children's Study cohort.

BACKGROUND: Numerous studies suggest that sex steroids might play a role in sex disparity observed in allergic diseases in adults. However, whether sex hormones influence allergic diseases in children remains unclear. The aim of the present study was to examine the association of sex steroid hormones with allergic disease in Japanese children. METHODS: The present cross-sectional study included 145 6-year-old children participating in a pilot birth cohort study in the Japan Environment and Children's Study. Data on allergic diseases were obtained from questionnaires, and serum levels of sex steroid hormones and allergen-specific IgE were measured. Logistic regression was performed to evaluate the association of sex hormones with allergic diseases. RESULTS: After adjusted sex, amount of body fat at 6 years, parental history of allergic disease, and exposure to tobacco smoke, serum dehydroepiandrosterone sulfate level was significantly associated with reduced odds of any allergic disease (adjusted odds ratio, 0.58; 95% confidence interval, 0.36-0.93; P = 0.024) and serum follicle-stimulating hormone level was significantly associated with increased odds of any allergic disease (adjusted odds ratio, 2.04; 95% confidence interval, 1.01-4.11, P = 0.046). Dehydroepiandrosterone sulfate level showed a significant association with number of allergic diseases. CONCLUSIONS: The current study findings suggest that sex hormones may play an important role in the development of allergic diseases in prepubertal children.

Elective Cesarean Section during Preterm Prevents Pulmonary Hypoplasia Development in Potter Sequence.

Potter syndrome, first reported in 1946 by Edith Potter, refers to fatal cases of bilateral renal aplasia with pulmonary hypoplasia, peculiar facial features, and limb deformities. Presently, patients with oligohydramnios showing similar pathological manifestations due to oligohydramnios caused by conditions other than bilateral renal aplasia have been reported, and are known as the Potter sequence. There are limited studies and unclear guidelines on the safest delivery time and detailed postpartum management for patients with the Potter sequence. We experienced a case of Potter sequence, in which the patient was born by elective cesarean section at gestational age (GA) of 34 weeks. Fetal ultrasound at GA of 26 weeks 4 days showed oligohydramnios, multilocular cystic lesions in the left kidney, and an absent right kidney. Prenatal fetal MRI at GA of 33 weeks and 3 days showed pulmonary hypoplasia, and the ratio of fetal lung volume (FLV) to fetal body weight (FBW) was 0.0135 ml/g. We suspected that the fetal lung could not grow because of persistent oligohydramnios, which leads to a further decline in the ratio of FLV to FBW during pregnancy. We performed a cesarean section at GA of 34 weeks to prevent the exacerbation of the imbalance between lung volume and physique. We struggled to keep her condition stabilized with strict management of her respiratory condition, dialysis, and nutrition. She was discharged from the hospital at 169 days of age. Elective caesarean section in the term of premature birth prevented the progression of pulmonary hypoplasia and made it possible to save her life. Potter sequence is still relatively unknown, and it is necessary for more studies to be conducted in the future.

Procalcitonin is associated with postnatal respiratory condition severity in preterm neonate.

INTRODUCTION: Postnatal respiratory failure is common in preterm neonates and is difficult to distinguish from early-onset neonatal bacterial infection by clinical symptoms. Similar to C-reactive protein (CRP), procalcitonin (PCT) is used as a marker of bacterial infection. Recently, it has been reported that the serum PCT levels increase because of respiratory failure immediately after birth. However, there is insufficient information concerning the relationship between biological inflammation markers, such as PCT and CRP, and postnatal respiratory condition severity. METHODS: Preterm neonates were classified according to the received respiratory management as follows: nonrespiratory support (NRS), respiratory support (RS), surfactant administration therapy (STA), and STA with nitric oxide inhalation therapy (NO). The median serum PCT and CRP levels at 12-36 h postnatally were compared among the four groups. Additionally, the median serum PCT and CRP levels in the STA group were compared by STA timing and STA number. RESULTS: The PCT levels for the NRS, RS, STA, and NO groups were 1.04, 6.46, 12.93, and 86.79 µg/L, respectively; the CRP levels were 0.40, 0.80, 1.10, and 16.40 mg/L, respectively. The PCT levels were significantly lower among neonates receiving STA in the birth subgroup (4.82 µg/L) than among those receiving STA in the admission subgroup (14.71 µg/L). The PCT levels were significantly higher among the STA multiple-dose subgroup (24.87 µg/L) than among the STA single-dose subgroup (12.47 µg/L). No significant differences in the CRP levels were observed. CONCLUSION: The serum PCT levels in preterm neonates were associated with postnatal respiratory condition severity.

The Predictive Value of Procalcitonin and High-Sensitivity C-Reactive Protein for Early Bacterial Infections in Preterm Neonates.

INTRODUCTION: Evidence on the reliability of using procalcitonin (PCT) and high-sensitivity C-reactive protein (hs-CRP) as diagnostic markers for early-onset neonatal bacterial infections is still insufficient because of their physiological elevation during the early neonatal period. This study aimed to assess the respiratory influence of serum PCT and hs-CRP levels and evaluate their predictive value for bacterial infections during the first 72 h of life in preterm neonates. METHODS: The preterm neonates enrolled in this single-center retrospective cohort study were categorized into 3 groups: reference, infection-unlikely respiratory failure, and probable bacterial infection; their serum PCT and hs-CRP levels were assessed. Subsequently, age-specific 95th percentile curves were plotted and the median and cutoff PCT and hs-CRP levels for predicting bacterial infections at birth and 7-18, 19-36, and 37-72 h after birth were determined. Moreover, the analysis of PCT and hs-CRP with a neonatal sequential organ failure assessment (nSOFA) score was performed in very low birth weight neonates. RESULTS: Serum PCT levels were influenced by respiratory failure. A significant difference was found in the median PCT and hs-CRP levels among the 3 groups at each time point. PCT sensitivities for predicting bacterial infection were slightly higher than those of hs-CRP in each time frame during the first 72 h of life. In both PCT and hs-CRP, there was no significant difference between infants with nSOFA scores of >4 and those with nSOFA scores of ≤4. DISCUSSION/CONCLUSION: Age-specific evaluation showed that PCT has better predictive value than hs-CRP for early-onset bacterial infections in preterm neonates.

New reference ranges of procalcitonin excluding respiratory failure in neonates.

BACKGROUND: Existing reference data on serum procalcitonin (PCT) in neonates include the effects of respiratory disorders commonly occurring during birth. We aimed to determine new 95% reference intervals in neonates after excluding the influence of respiratory failure at birth, and to investigate the effects of gestational age (GA) and respiratory condition at birth on postnatal transient serum PCT elevation. METHODS: Samples were obtained from term and preterm neonates during the first 3 days of life. Neonates were classified into reference, respiratory failure, and bacterial infection groups. In the reference group, the correlation between PCT level and GA was investigated. RESULTS: The median PCT level within the 95% range 12-36 h after birth was 1.05 ng/mL (0.14-4.39) in term neonates (143 samples) and 1.01 ng/mL (0.15-4.44) in preterm neonates (95 samples). There was no correlation between GA and serum PCT level during 1-48 h after birth. There was a significant difference in median serum PCT level during 12-36 h after birth between the respiratory failure (9.56 ng/mL) and bacterial infection (49.82 ng/mL) groups in preterm neonates but no difference between term neonates (respiratory failure 6.83 ng/mL, and bacterial infection 7.43 ng/mL). CONCLUSIONS: Respiratory failure is the main effector for the transient elevation in serum PCT levels at 3 days of life. After excluding the influence of respiratory failure, the chronological pattern and range were very similar between term and preterm neonates. Procalcitonin can be useful for clinicians in distinguishing bacterial infection from respiratory failure, aiding decisions on appropriate antibiotic use.

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.

Neonatal methionine adenosyltransferase I/III deficiency with abnormal signal intensity in the central tegmental tract.

Methionine adenosyltransferase I/III (MAT I/III) deficiency is characterized by persistent hypermethioninemia. The clinical manifestations in cases with MAT I/III deficiency vary from a complete lack of symptoms to neurological problems associated with brain demyelination. We experienced a neonatal case with MAT I/III deficiency, in which severe hypermethioninemia was detected during the newborn screening test. The patient gradually showed hyperreflexia, foot clonus, and irritability from the age of 1 month onwards, and his brain magnetic resonance imaging scans showed abnormal signal intensity in the bilateral central tegmental tracts. His neurological manifestations improved after the S-adenosylmethionine (SAMe) treatment, deteriorated after discontinuation of SAMe, and re-improved owing to re-administration of SAMe. He achieved normal neurodevelopment through SAMe and methionine restriction therapy. Lack of SAMe as well as severe hypermethioninemia were thought to contribute towards the clinical psychophysical state. Moreover, impaired MAT I/III activity contributed to the development of neurological disorder from the early neonatal period.

Amelioration by glycine of brain damage in neonatal rat brain following hypoxia-ischemia.

BACKGROUND: Glycine protected adult brains against injury in an experimental model of stroke, but, because the ischemic response of neonatal brains differs from that of adult brains, we examined the neuroprotective efficacy of glycine and associated mechanisms in an experimental model of neonatal hypoxic-ischemic (HI) encephalopathy. METHODS: Neonatal (postnatal day 7) Wistar rats were randomly divided into an untreated group (non-HI) and two HI groups that were treated with left common carotid artery ligation and saline control or glycine. After recovery, pups that received surgery were injected i.p. with saline or glycine (800 mg/kg; optimal dose determined in pilot experiments) and were placed in a controlled 8% O2 chamber for 120 min. Brains were harvested at various times after return to normoxia (several hours-days after HI) for analysis of infarct area, glial activation, cell apoptosis, and tumor necrosis factor-α (TNF-α) expression on histology and reverse transcription-polymerase chain reaction. RESULTS: Glycine injections induced large (approx. 15-fold) but brief (approx. 2 h) increases in cerebrospinal fluid concentrations. In particular, the glycine group had a >70% decrease in infarct areas compared with controls at 7 days after HI. Glycine also significantly reduced astrocyte reactive transformation, microglia activation, and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive (apoptotic) cell numbers in peri-lesional areas at 3 days after HI, and TNF-α mRNA expression in the injured hemisphere at 12 and 24 h after HI. CONCLUSION: Glycine protected neonatal rat brains against HI, in part by inhibiting TNF-α-induced inflammation and gliosis. Hence, systemic glycine infusions may have clinical utility for the treatment of HI injury in human newborns.

Diagnosis and treatment of hereditary tyrosinemia in Japan.

Hereditary tyrosinemia is an autosomal recessive inherited disease that manifests as three types (types I-III). We conducted a nationwide survey of this disease in Japan, and here review the results in relation to prevalence, clinical characteristics, and treatment and diagnosis. A definitive diagnosis of tyrosinemia type I is difficult to obtain based only on blood tyrosine level. Detection of succinylacetone using dried blood spots or urinary organic acid analysis, however, is useful for diagnosis. In tyrosinemia type I, dietary therapy and nitisinone (Orfandin®) are effective. Prognosis is greatly affected by the complications of liver cancer and hypophosphatemic rickets; even patients that are treated early with nitisinone may develop liver cancer. Long-term survival can be expected in type I if nitisinone therapy is effective. Prognosis in types II and III is relatively good.

VLCAD deficiency in a patient who recovered from ventricular fibrillation, but died suddenly of a respiratory syncytial virus infection.

VLCAD deficiency is an autosomal recessive disorder caused by a defect of fatty acid oxidation. The phenotype is classified into three clinical forms on the basis of the onset of symptoms: a severe form with neonatal onset; a milder form with childhood onset; and a late-onset form. The neonatal form is the most common, and has a higher mortality rate than the others. We report the case of a newborn infant with VLCAD deficiency who developed ventricular fibrillation, which was successfully treated by intensive care, but who suddenly died after a respiratory syncytial virus infection. Early institution of i.v. glucose treatment and active immunization with vaccine, such as palivizumab (anti-RSV mAb), may be important to reduce the frequency and severity of life-threatening episodes.

Mutations in B3GALT6, which encodes a glycosaminoglycan linker region enzyme, cause a spectrum of skeletal and connective tissue disorders.

Proteoglycans (PGs) are a major component of the extracellular matrix in many tissues and function as structural and regulatory molecules. PGs are composed of core proteins and glycosaminoglycan (GAG) side chains. The biosynthesis of GAGs starts with the linker region that consists of four sugar residues and is followed by repeating disaccharide units. By exome sequencing, we found that B3GALT6 encoding an enzyme involved in the biosynthesis of the GAG linker region is responsible for a severe skeletal dysplasia, spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMD-JL1). B3GALT6 loss-of-function mutations were found in individuals with SEMD-JL1 from seven families. In a subsequent candidate gene study based on the phenotypic similarity, we found that B3GALT6 is also responsible for a connective tissue disease, Ehlers-Danlos syndrome (progeroid form). Recessive loss-of-function mutations in B3GALT6 result in a spectrum of disorders affecting a broad range of skeletal and connective tissues characterized by lax skin, muscle hypotonia, joint dislocation, and spinal deformity. The pleiotropic phenotypes of the disorders indicate that B3GALT6 plays a critical role in a wide range of biological processes in various tissues, including skin, bone, cartilage, tendon, and ligament.

Current status of hepatic glycogen storage disease in Japan: clinical manifestations, treatments and long-term outcomes.

Many reports have been published on the long-term outcome and treatment of hepatic glycogen storage diseases (GSDs) overseas; however, none have been published from Japan. We investigated the clinical manifestations, treatment, and prognosis of 127 hepatic GSD patients who were evaluated and treated between January 1999 and December 2009. A characteristic genetic pattern was noted in the Japanese GSD patients: most GSD Ia patients had the g727t mutation, and many GSD Ib patients had the W118R mutation. Forty-one percent (14/34) of GSD Ia patients and 18% (2/11) of GSD Ib patients of ages 13 years 4 months had liver adenoma. Among subjects aged 10 years, 19% (7/36) of the GSD Ia patients and none of the GSD Ib patients had renal dysfunction. The mean height of male GSD Ia patients aged 18 years was 160.8±10.6 cm (n=14), and that of their female counterparts was 147.8±3.80 cm (n=9). Patients with hepatic GSDs develop a variety of symptoms but can survive in the long term by diet therapy, corn starch treatment and supportive care. Liver transplantation for hepatic GSDs is an important treatment strategy and can help improve the patients'quality of life.

Animal models of tyrosinemia.

Hereditary tyrosinemia I (HT I) is a genetic disorder of tyrosine metabolism characterized by progressive liver damage from infancy and by a high risk for hepatocellular carcinoma. HT I is due to mutations in the fumarylacetoacetate hydrolase (Fah) gene, which encodes the last enzyme in the tyrosine catabolic pathway. Disturbances in tyrosine metabolism lead to increased levels of succinylacetone and succinylacetoacetate. However, the mechanisms causing liver failure, cirrhosis, renal tubular dysfunction, and hepatocarcinoma are still unknown. Lethal albino deletion c14CoS mice and mice with target-disrupted Fah are models for HT I. They die in the perinatal period, although with a different phenotype from that seen in HT I in humans. In addition, 2 mouse strains that carry N-ethyl-N-nitrosourea-induced mutations in the Fah gene have been described. Mice with a splice mutation exhibit the milder features of the clinical phenotype. In mice that carry both Fah and 4-hydroxyphenylpyruvate dioxygenase gene mutations, administration of homogentisate results in rapid apoptosis of hepatocytes. Simultaneously, renal tubular epithelial cells are injured, resulting in Fanconi syndrome. These are central features of visceral injury in patients with HT I. Apoptosis of hepatocyte and renal tubular cells is prevented by the caspase inhibitors acetyl-Tyr-Val-Ala-Asp-CHO or acetyl-Asp-Glu-Val-Asp-CHO. Apoptosis of hepatocytes and renal tubular epithelial cells are central features of this disease. Alterations in gene expression found in the liver of patients with HT I are responsible for the pathogenesis of this disease, for example, acute liver failure. Therefore, gene expression analysis allows a better understanding of the specific pathogenesis. Cell fusion of hematopoietic stem cells with hepatocytes leads to liver regeneration after liver injury. This finding was possible after using the liver injury model of HT I in Fah null mice. Thus, animal models of tyrosinemia are unique and useful tools to reveal mechanisms of interest to both clinical and basic science.