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.

Smoking Exposure Is Associated with Serum Vitamin D Deficiency in Children: Evidence from the Japan Environment and Children's Study.

Tobacco smoke exposure is known to lower serum 25-hydroxyvitamin D (25(OH)D) concentrations. This study evaluated the association between passive smoking and vitamin D deficiency (VDD) in young children using data from the Japan Environment and Children's Study (JECS), the largest birth cohort study in Japan. Information on parental smoking status was extracted from a survey of JECS for children aged 1.5 years and data for serum 25(OH)D concentrations were obtained from blood tests in the Sub-Cohort Study of JECS performed at age 2 years. Logistic regression and linear models were fitted to evaluate the association between these variables. Data were analyzed for 4593 children. After adjusting for covariates, smoke exposure was significantly associated with increased incidence of VDD (OR 1.35; 95% CI, 1.14-1.59) according to the logistic model. The linear model indicated that passive smoking negatively predicted de-seasonalized serum 25(OH)D concentrations (ß -0.5; 95% CI -0.95 to -0.08) in children aged 2 years. The results suggest that smoke exposure is a risk factor for VDD in children. Given that VD plays a crucial role in bone metabolism and the immune system, our findings are significant for clinical and public health.

Association of Hemoglobin and Hematocrit Levels during Pregnancy and Maternal Dietary Iron Intake with Allergic Diseases in Children: The Japan Environment and Children's Study (JECS).

Few epidemiologic studies have examined the role of maternal iron status in allergic diseases in offspring and findings have been inconsistent. We used a large birth cohort in Japan to explore the association of the markers for maternal iron status (maternal hemoglobin, hematocrit and dietary iron intake during pregnancy) with allergy development in offspring during early childhood. We analyzed information on children age 0-3 years from the Japan Environment and Children's Study (JECS). We used logistic models and generalized estimating equation models to evaluate the effect of maternal hemoglobin and hematocrit levels and dietary iron intake on allergies in children. Models were also fitted with propensity score-matched datasets. Data were collected for a total of 91,247 mother-child pairs. The prevalence (95% confidence interval) of low hemoglobin and hematocrit was 14.0% (13.7-14.2%) and 12.5% (12.3-12.8%), respectively. After adjusting confounders, low hemoglobin and hematocrit during pregnancy were not associated with childhood allergic outcomes. Findings from models with propensity score-matched datasets also indicated that children born to mothers with low hemoglobin or hematocrit levels during pregnancy did not have a higher risk of developing allergic conditions at 3 years old. We found no meaningful associations between low energy adjusted maternal dietary iron intake and allergies in children. In conclusion, using birth cohort data, we found no evidence supporting an association of low maternal hemoglobin, hematocrit and low dietary iron intake with allergy symptoms during early childhood. Further studies with more suitable proxy markers for blood iron status are needed.

Determinants of Alcohol Consumption in Women Before and After Awareness of Conception.

OBJECTIVES: We examined the socio-demographic and behavioral factors associated with alcohol consumption before and after pregnancy awareness in pregnant women. METHODS: This cross-sectional study included 91,828 pregnant women in a nationwide Japanese birth cohort study from 2011 to 2014. Alcohol consumption before and after pregnancy awareness, and sociodemographic behavioral characteristics were assessed through self-reported questionnaires. Determinants of alcohol consumption were investigated using logistic regression. RESULTS: Prevalence of alcohol consumption before and after pregnancy awareness was 50.0% and 2.8%, respectively. Most women consumed low to moderate levels of alcohol. Before pregnancy awareness, high educational level (odds ratios [OR] 1.11, 95% confidence interval [CI] 1.07 to 1.15), high household income (OR 1.16, 95% CI 1.09 to 1.24), and smoking (OR 1.77, 95% CI 1.65 to 1.90) were significantly associated with increased odds of alcohol consumption. After pregnancy awareness, older age (OR 1.73, 95% CI 1.54 to 1.94) and smoking (OR 5.57, 95% CI 4.88 to 6.37) were significantly associated with increased odds of alcohol consumption, and high education level (OR 0.72, 95% CI 0.64 to 0.81) and high household income (OR 0.75, 95% CI 0.63 to 0.89) were significantly associated with decreased odds of alcohol consumption. CONCLUSION: A half of women consumed alcohol before pregnancy awareness. Guidelines recommend abstinence from alcohol consumption in pregnant women for precaution, although influence of low to moderate levels of prenatal alcohol exposure on the fetus is inconclusive. Social-demographic characteristics differed between women who consumed alcohol before pregnancy awareness and women who continued alcohol after pregnancy awareness.

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.

Elevated Soluble PD-L1 in Pregnant Women's Serum Suppresses the Immune Reaction.

Background: Programmed death-ligand 1 (PD-L1) is expressed not only on some cancer cells, but also on the outer surface of placental syncytiotrophoblasts, which is assumed to induce maternal immune tolerance to fetal tissue via programmed death-1 (PD-1) receptors on T cells. Recently, levels of soluble forms of PD-L1 (sPD-L1) were reported to be higher in the serum of pregnant women (PW) than in non-pregnant women (non-PW). However, there have been no reports of the functional significance of PW's serum containing high sPD-L1 levels. Therefore, the aim of the present study was to clarify the role of sPD-L1 in the sera of PW as an immunosuppressive molecule by in vitro assays. Methods: As a post-hoc analysis of our previous cohort study, 330 pairs of serum from PW during the third trimester and cord blood (CB) from paired offspring without major complications were examined. Serum levels of sPD-L1 and sPD-1 were measured by ELISA. On mixed lymphocyte culture (MLC), 3H-thymidine uptakes in the presence of PW's, offspring's, or non-PW's serum were compared. Peripheral blood mononuclear cells (PBMCs) were cultured in the presence of PW's serum stimulated with PHA, and then cytokine levels were measured in supernatants by multiple cytokine analysis with or without anti-PD-L1blocking antibody. Results: The median sPD-L1 level was 8.3- and 6.9-fold higher in PW than in offspring and non-PW, respectively, whereas sPD-1 levels were lower in PW and offspring than in non-PW. On MLC, 3H-thymidine uptake in the presence of autoantigen was strongly reduced by co-culture with serum of both PW and offspring, compared with serum of non-PW. In contrast, uptake in the presence of alloantigen was moderately inhibited by PW's serum, whereas it was less suppressed by offspring's serum, compared with non-PW's serum. In the culture of PBMCs, tumor necrosis factor-α, interferon gamma, interleukin (IL)-2, and IL-4 levels were significantly higher in the presence of anti-PD-L1 blocking antibody than in culture not treated with antibody (all P < 0.05) or culture treated with isotype control antibody (all P < 0.05). Conclusion: The levels of sPD-L1 are elevated in PW's serum, which may, at least in part, suppress maternal immunity.

Risky Health Behaviors of Teenage Mothers and Infant Outcomes in the Japan Environment and Children's Study: A Nationwide Cohort Study.

STUDY OBJECTIVE: Few studies have investigated the risky health behaviors and psychosocial characteristics of teenage mothers in countries with a low teenage birth rate, like Japan. We examined the differences in maternal prenatal risky health behaviors and psychosocial characteristics, and birth weight of infants between teenage and adult mothers. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: We identified 1159 teenage (age younger than 20 years) and 73,547 adult mothers (20-34 years) who participated a nationwide birth cohort study between 2011 and 2014. Behavioral and psychosocial characteristics were ascertained using questionnaires during pregnancy. Birth weight of infants was verified through medical records. Univariate and multivariable logistic regression were used to assess the association of teenage motherhood and birth weight of infants with parity, marital status, household income, maternal education, job status, preconception body mass index, gestational weight gain, psychological distress, and smoking status. RESULTS: Teenage mothers were significantly more likely to smoke and have psychological distress and less likely to use alcohol than adult mothers (9.9% vs 4.6%, P < .001; 8.9% vs 3.4%, P < .001; 1.3% vs 2.5%, P < .001, respectively). No association was found between teenage motherhood and low birth weight in infants (odds ratio 0.99; 95% confidence interval, 0.73-1.32). Further, no association was found after adjusting for covariates. CONCLUSION: A substantially greater number of Japanese teenage mothers smoked and experienced severe psychological distress than adult mothers. Our findings will be useful for future research and for developing effective policies and programs for teenage mothers and their children.

Inverse association between maternal 25OHD level and cord GLP-1/GIP concentrations.

BACKGROUND: Because vitamin D may have beneficial effects on glucose metabolism in pregnant women with gestational diabetes mellitus, we explored whether maternal 25-hydroxyvitamin D (25OHD) levels in normal pregnancy have association with diabetes-related hormone levels and glycated albumin (GA). METHODS: A prospective cohort study was performed to collect serum samples from 612 pairs of pregnant women and cord blood of their offspring. Levels of 25OHD and GA in maternal and cord blood were measured by radioimmunoassay and enzyme assay, respectively. Using cord serum, 12 diabetes-related hormones were assayed. Spearman's rank correlation coefficient was used to quantify the strength of association between biomarkers. RESULTS: A prominent association between maternal and cord 25OHD levels (r = 0.76, 95% confidence intervals (CIs): 0.73-0.79, P < 0.0001) and weak association between maternal and cord GA (r = 0.22, 95% CIs: 0.14-0.30, P < 0.0001) were shown. Among the 12 diabetes-related hormones, both maternal and cord 25OHD levels showed prominent negative associations with glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). CONCLUSIONS: These results suggest that decreased maternal 25OHD may be associated with decreased cord 25OHD and increased cord GLP-1 and GIP levels, which may be involved with the transfer of maternal glucose to the fetus.

Distinct effects of alcohol consumption and smoking on genetic alterations in head and neck carcinoma.

BACKGROUND: Tobacco and alcohol consumption are risk factors for head and neck squamous cell carcinoma (HNSCC). Recently, whole-exome sequencing clarified that smoking increased TP53 and other mutations in HNSCC; however, the effects of alcohol consumption on these genetic alterations remain unknown. We explored the association between alcohol consumption and somatic copy-number alterations (SCNAs) across the whole genome in human papillomavirus (HPV)-negative HNSCCs, and compared with the effects of smoking on genetic alterations. METHODS: SCNA and TP53 mutations in tumor samples were examined by high-resolution comparative genomic hybridization microarray 180K and by direct sequencing, respectively, and statistically analyzed for associations with alcohol consumption and smoking during the 20 years preceding diagnosis of HNSCC. Probes with a corrected p-value (=q-value) less than 0.05 and fold change greater than 1.2 or less than -1.2 were considered statistically significant. RESULTS: A total of 248 patients with HNSCC were enrolled. In the HPV-negative patients (n=221), heavy alcohol consumption was significantly associated with SCNAs of oncogenes/oncosuppressors that were previously reported to occur frequently in HNSCCs: CDKN2A (q=0.005), FHIT (q=0.005), 11q13 region including CCND1, FADD and CTTN (q=0.005), ERBB2 (HER2) (q=0.009), 3q25-qter including CCNL1, TP63, DCUN1D1 and PIK3CA (q=0.014), and CSMD1 (q=0.019). But, TP53 mutations were not affected. In contrast, smoking was associated with increased risk of TP53 mutations, but did not induce any significant SCNAs of oncogenes/oncosuppressors. CONCLUSION: These results suggest that both alcohol consumption and smoking had distinct effects on genetic alterations in HNSCCs. Heavy alcohol consumption may trigger previously known and unknown SCNAs, but may not induce TP53 mutation. In contrast, smoking may induce TP53 mutation, but may not trigger any SCNAs.

Serum vitamin D levels and survival of patients with colorectal cancer: post-hoc analysis of a prospective cohort study.

BACKGROUND: Recently, serum 25-hydroxyvitamin D (25OHD) levels were shown to be associated with the survival of patients with colorectal cancer. However, 25OHD levels were measured a median of 6 years before diagnosis or were predicted levels. In this study, we directly measured serum 25OHD levels at surgery and examined the association with survival among patients with colorectal cancer. METHODS: We started a prospective cohort study to find prognostic factors in patients with colorectal cancer from 2003 to 2008 and stored serum samples and clinical data. As part of a post-hoc analysis, serum 25OHD levels were measured by radioimmunoassay. Association between overall survival and serum 25OHD levels were computed using the Cox proportional hazard model adjusted for month of serum sampling as well as age at diagnosis, gender, cancer stage, residual tumor after surgery, time period of surgery, location of tumor, adjuvant chemotherapy and number of lymph nodes with metastasis at surgery. Unadjusted and adjusted hazard ratios (HR) and 95% confidence intervals (95% CI) were determined. RESULTS: Serum 25OHD levels were measured in 257 patients. Only 3% had sufficient levels (30 ng/ml and greater). Based on month of blood sampling, an annual oscillation of 25OHD levels was seen, with levels being lower in spring and higher in late summer. Higher 25OHD levels were associated with better overall survival under multi-variate analysis (HR, 0.91: 95% CI, 0.84 to 0.99, P = 0.027). CONCLUSIONS: These results suggest that higher 25OHD levels at surgery may be associated with a better survival rate of patients with colorectal cancer.

[Usefulness of epidural catheter with distal subcutaneous reservoir for cancer pain control in home care services].

When an effective pain relief cannot be achieved by systemic administration of analgesics, which provide adequate pain relief for up to 70 to 90 percent of patients, alternative remedies should be offered. We reported a patient with colon cancer who was effective for pain control using an epidural catheter with subcutaneous reservoir (epidural subcutaneous catheter implantation). Four other patients with an epidural catheter with subcutaneous reservoir during 2007 to 2008 also showed significant improvement in their pain level calculating by numerical rating scale (NRS). Furthermore we were able to minimize the risk of infection for homecare. However the epidural catheter with subcutaneous reservoir should be needed not only to manage dosages of epidural morphine accurately but also to prevent the incidence of catheter obstruction by general practitioners in home care service. This solution is necessary to establish the common strict guidelines between hospital doctors and general practitioners.