Association between Cesarean section delivery and increased risk of childhood Kawasaki disease.

AIM: Cesarean section delivery is associated with microbiota disruption and immuno-dysregulation during childhood, but the association with Kawasaki disease remains uncertain. We aimed to evaluate the association between Cesarean section and Kawasaki disease. METHODS: We examined the association between Kawasaki disease between six and eighteen months and Cesarean section within a birth cohort of 15,796 mother-infant pairs in Taiwan. The associations were assessed with Poisson regression in the study population, in the 1:2 propensity score-matched subpopulation, and compared with febrile convulsion, trauma and accidents during the same interval as negative control outcomes. RESULTS: Cesarean section was found to increase the risk of Kawasaki disease among overall population (adjusted relative risk [aRR]: 2.22, 95 % confidence interval (CI): 1.14-4.34) and the matched subpopulation (aRR: 2.29, 95 % CI: 1.14-4.68 in PS-matched subpopulation). Meanwhile, there was no association between Cesarean section and the clinic visits for febrile convulsion, trauma and accidents. CONCLUSION: In conclusion, this study identified a potential association between Cesarean section delivery and a higher risk of Kawasaki disease during six-to eighteen months of the prospective birth cohort in Taiwan.

The global response: How cities and provinces around the globe tackled Covid-19 outbreaks in 2021.

Background: Tackling the spread of COVID-19 remains a crucial part of ending the pandemic. Its highly contagious nature and constant evolution coupled with a relative lack of immunity make the virus difficult to control. For this, various strategies have been proposed and adopted including limiting contact, social isolation, vaccination, contact tracing, etc. However, given the heterogeneity in the enforcement of these strategies and constant fluctuations in the strictness levels of these strategies, it becomes challenging to assess the true impact of these strategies in controlling the spread of COVID-19. Methods: In the present study, we evaluated various transmission control measures that were imposed in 10 global urban cities and provinces in 2021- Bangkok, Gauteng, Ho Chi Minh City, Jakarta, London, Manila City, New Delhi, New York City, Singapore, and Tokyo. Findings: Based on our analysis, we herein propose the population-level Swiss cheese model for the failures and pitfalls in various strategies that each of these cities and provinces had. Furthermore, whilst all the evaluated cities and provinces took a different personalized approach to managing the pandemic, what remained common was dynamic enforcement and monitoring of breaches of each barrier of protection. The measures taken to reinforce the barriers were adjusted continuously based on the evolving epidemiological situation. Interpretation: How an individual city or province handled the pandemic profoundly affected and determined how the entire country handled the pandemic since the chain of transmission needs to be broken at the very grassroot level to achieve nationwide control. Funding: The present study did not receive any external funding.

Absence of the lectin-like domain of thrombomodulin reduces HSV-1 lethality of mice with increased microglia responses.

BACKGROUND: Herpes simplex virus 1 (HSV-1) can induce fatal encephalitis. Cellular factors regulate the host immunity to affect the severity of HSV-1 encephalitis. Recent reports focus on the significance of thrombomodulin (TM), especially the domain 1, lectin-like domain (TM-LeD), which modulates the immune responses to bacterial infections and toxins and various diseases in murine models. Few studies have investigated the importance of TM-LeD in viral infections, which are also regulated by the host immunity. METHODS: In vivo studies comparing wild-type and TM-LeD knockout mice were performed to determine the role of TM-LeD on HSV-1 lethality. In vitro studies using brain microglia cultured from mice or a human microglia cell line to investigate whether and how TM-LeD affects microglia to reduce HSV-1 replication in brain neurons cultured from mice or in a human neuronal cell line. RESULTS: Absence of TM-LeD decreased the mortality, tissue viral loads, and brain neuron apoptosis of HSV-1-infected mice with increases in the number, proliferation, and phagocytic activity of brain microglia. Moreover, TM-LeD deficiency enhanced the phagocytic activity of brain microglia cultured from mice or of a human microglia cell line. Co-culture of mouse primary brain microglia and neurons or human microglia and neuronal cell lines revealed that TM-LeD deficiency augmented the capacity of microglia to reduce HSV-1 replication in neurons. CONCLUSIONS: Overall, TM-LeD suppresses microglia responses to enhance HSV-1 infection.

Integrin-Linked Kinase Reduces H3K9 Trimethylation to Enhance Herpes Simplex Virus 1 Replication.

Histone modifications control the lytic gene expression of herpes simplex virus 1 (HSV-1). The heterochromatin mark, trimethylation of histone H3 on lysine (K) 9 (H3K9me3), is detected on HSV-1 genomes at early phases of infection to repress viral gene transcription. However, the components and mechanisms involved in the process are mostly unknown. Integrin-linked kinase (ILK) is activated by PI3K to phosphorylate Akt and promote several RNA virus infections. Akt has been shown to enhance HSV-1 infection, suggesting a pro-viral role of ILK in HSV-1 infection that has not been addressed before. Here, we reveal that ILK enhances HSV-1 replication in an Akt-independent manner. ILK reduces the accumulation of H3K9me3 on viral promoters and replication compartments. Notably, ILK reduces H3K9me3 in a manner independent of ICP0. Instead, we show an increased binding of H3K9 methyltransferase SUV39H1 and corepressor TRIM28 on viral promoters in ILK knockdown cells. Knocking down SUV39H1 or TRIM28 increases HSV-1 lytic gene transcription in ILK knockdown cells. These results show that ILK antagonizes SVU39H1- and TRIM28-mediated repression on lytic gene transcription. We further demonstrate that ILK knockdown reduces TRIM28 phosphorylation on serine 473 and 824 in HSV-1-infected cells, suggesting that ILK facilitates TRIM28 phosphorylation to abrogate its inhibition on lytic gene transcription. OSU-T315, an ILK inhibitor, suppresses HSV-1 replication in cells and mice. In conclusion, we demonstrate that ILK decreases H3K9me3 on HSV-1 DNA by reducing SUV39H1 and TRIM28 binding. Moreover, our results suggest that targeting ILK could be a broad-spectrum antiviral strategy for DNA and RNA virus infections, especially for DNA viruses controlled by histone modifications.

Microglia Reduce Herpes Simplex Virus 1 Lethality of Mice with Decreased T Cell and Interferon Responses in Brains.

Herpes simplex virus 1 (HSV-1) infects the majority of the human population and can induce encephalitis, which is the most common cause of sporadic, fatal encephalitis. An increase of microglia is detected in the brains of encephalitis patients. The issues regarding whether and how microglia protect the host and neurons from HSV-1 infection remain elusive. Using a murine infection model, we showed that HSV-1 infection on corneas increased the number of microglia to outnumber those of infiltrating leukocytes (macrophages, neutrophils, and T cells) and enhanced microglia activation in brains. HSV-1 antigens were detected in brain neurons, which were surrounded by microglia. Microglia depletion increased HSV-1 lethality of mice with elevated brain levels of viral loads, infected neurons, neuron loss, CD4 T cells, CD8 T cells, neutrophils, interferon (IFN)-ß, and IFN-γ. In vitro studies demonstrated that microglia from infected mice reduced virus infectivity. Moreover, microglia induced IFN-ß and the signaling pathway of signal transducer and activator of transcription (STAT) 1 to inhibit viral replication and damage of neurons. Our study reveals how microglia protect the host and neurons from HSV-1 infection.

Associations Between Infant Developmental Delays and Secondhand Smoke Exposure Modified by Maternal Prepregnancy Overweight and Obesity Status.

INTRODUCTION: Secondhand smoke exposure during pregnancy has long been associated with adverse health outcomes in children, but only a few studies have examined its effect modifiers. In this study, we applied effect modification analysis for maternal prepregnancy weight status on detrimental neurodevelopmental effect of secondhand smoke exposure during pregnancy and infancy in a nationwide representative population. AIMS AND METHODS: Term singleton mother-infant pairs with nonsmoking mothers were included for main analysis (N = 15 987) from the Taiwan Birth Cohort Study (TBCS), and were further matched with propensity score (n = 5434). We extracted secondhand smoke exposure during pregnancy and infancy, and eight neurodevelopmental milestones from the responses in the baseline visit at 6 months, and 18-month follow-up of TBCS. The associations between secondhand smoke exposure and neurodevelopmental achievement were analyzed with multivariable logistic regression and Cox model. Propensity score weighting and matching were applied for high-versus-low analysis, and relative excess risk due to interaction were used to estimate effect modification. RESULTS: Higher secondhand smoke exposure was associated with increased likelihood of delayed milestone achievement across gross motor, fine motor, language-related, and social-related domains. The associations in fine motor domains remained observable in propensity score-weighted and -matched models. We identified additive interaction with self-reported maternal overweight and obesity status before pregnancy in milestone development for walking with support, scribbling, and waving goodbye. CONCLUSIONS: Secondhand smoke exposure during pregnancy and infancy were associated with delayed neurodevelopmental milestone achievement at 18 months, and the associations were modified by maternal prepregnancy overweight and obesity status. IMPLICATIONS: The study results suggested the association between maternal secondhand smoke exposure during pregnancy and infancy and delayed fine motor and language-related milestone achievement at 18 months in multivariable, propensity score weighting, and matching populations. The results of positive effect modifications for maternal prepregnancy overweight and obesity status suggested the importance of concurrent interventions on smoke-free environment and maternal health during pregnancy.

Prevalence of childhood wheeze and modified DNA methylation at 7 years of age according to maternal folate levels during pregnancy in the Hokkaido Study.

BACKGROUND: A high dose of folic acid during pregnancy may increase the risk of asthma, wheezing, and respiratory disease in childhood. Folate acid can modify inflammation and immune susceptibility of offspring with some epigenetic differentiation, including DNA methylation. This study evaluated associations between maternal folate levels during pregnancy and childhood wheezing; furthermore, the study assessed whether maternal folate-modified DNA methylation is related to asthma. Methods Participants in the current study were 6651 mother-child pairs who had complete data on characteristics and who had completed at least one of the International Study of Asthma and Allergies in Childhood questionnaires when the child was 1, 2, 4, and 7 years of age. Moreover, a case-control study to assess DNA methylation at 7 years of age was conducted among 136 children who experienced wheezing and a control group of 139 children with no history of allergies. Results The median of maternal serum was 16.76 nmol/L, assayed by chemiluminescent immunoassay. We found significantly increased adjusted odds ratios of childhood wheezing at 2 years age according to maternal folate levels, compared with the lowest folate quartile (odds ratio [95% confidence interval] = highest; 1.27 [1.03, 1.56], and second, 1.27 [1.05, 1.55]); however, no changes were observed at 1, 4, and 7 years of age. In a case-control study, no association of maternal folate levels with DNA methylation was observed. Conclusion Our results suggest that maternal folate did not affect persistent wheezing in school-aged children, or DNA methylation of gasdermin B, orosomucoid-like 3, and Ikaros family zinc finger 3 at 7 years of age.

Associations between household incense burning and delayed motor development among preterm infants modified by gestational age and maternal educational status.

BACKGROUND: Household incense burning is a common ritual behavior in the Asia-Pacific region but has been associated with inferior developmental outcomes in term infants. We aimed to examine these associations among preterm infants. METHODS: Information from 1190 mother-infant pairs during 6- and 18-month follow-up to the Taiwan Birth Cohort Study was examined for associations between household incense burning exposure and infant neurodevelopmental milestone achievement using multivariable Cox proportional hazard model with propensity score weighting, along with stratified, sensitivity, and decomposition analysis. RESULTS: Household incense burning exposure was associated with delayed gross motor milestone achievement among all preterm infants according to the Cox model and after propensity score weighting. Meanwhile, associations for delayed development were found in gross motor domain milestones among late preterm infants, while fine motor domain delay was found among other preterm infants. Furthermore, the associations between household incense burning status and gross motor milestone delays were attenuated by the interaction between higher education level and household incense burning exposure status. CONCLUSIONS: Household incense burning exposure was associated with delays, and the motor domains affected differed according to degree of prematurity. These associations were modified by the attenuation upon higher maternal educational status and exposure status interaction.

Intrauterine exposure to per- and polyfluoroalkyl substances may harm children's lung function development.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS), such as perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoic acid (PFNA) and perfluoroundecanoic acid (PFUA), are common persistent environmental organic pollutants. Animal studies have indicated that PFAS influence inflammatory responses and lung development. However, whether prenatal or childhood PFAS exposure affects children's lung function remains unclear. This study aimed to investigate both in utero exposure and childhood exposure to PFAS and the relationships between them and lung function development in childhood. METHODS: In total, 165 children were recruited from the Taiwan Birth Panel Study (TBPS). Cord blood plasma and children's serum were collected when they were eight years old. PFAS levels were analysed by ultra-high-performance liquid chromatography/tandem mass spectrometry. When these children reached eight years of age, we administered detailed questionnaires and lung function examinations. RESULTS: The mean concentrations of PFOA, PFOS, PFNA and PFUA in cord blood among the 165 study children were 2.4, 6.4, 6.0, and 15.4 ng/mL, respectively. The mean concentrations in serum from eight-year-olds were 2.7, 5.9, 0.6, and 0.3 ng/mL, respectively. At eight years of age, the mean FEV1 (forced expiratory volume per sec), FVC (forced vital capacity), PEF (peak expiratory flow) and FEV1/FVC values were 1679 mL, 1835 mL, 3846 mL/s and 92.0%, respectively. PFOA, PFOS, PFNA and PFUA levels in cord blood were inversely associated with FEV1, FVC and PEF values. The PFOS concentration in cord blood was the most consistently correlated with decreasing lung function before and after adjusting for confounding factors. The PFOS concentration was also significantly inversely correlated with lung function in subgroups with lower birth weight and allergic rhinitis. CONCLUSIONS: Our cohort study revealed that the concentrations of PFOA, PFOS, PFNA and PFUA were higher in cord blood than in serum from eight-year-olds. Some trends were also noted between intrauterine PFOS exposure and children's decreasing FEV1, FVC and PEF, especially in subgroups with lower birth weight and allergic rhinitis. Therefore, intrauterine PFAS exposure, especially PFOS, may play a vital role in lung development.

Association between exposure to perfluoroalkyl substances and metabolic syndrome and related outcomes among older residents living near a Science Park in Taiwan.

Perfluoroalkyl substances (PFASs) are an emerging class of artificial environmental chemicals that have multiple potentially harmful effects on health. The largest Science Park in Taiwan discharges wastewater containing PFASs into the Keya River, and a high concentration of PFASs has been found in this river and its aquatic creatures. We conducted a cross-sectional study from 2016 to 2017 of 397 subjects aged 55-75 years living near the river and evaluated the association of PFASs with metabolic syndrome and related outcomes. The results indicated that perfluorooctane sulfonate (PFOS) levels were positively associated with serum low-density lipoprotein (LDL) levels (P for trend = 0.03) and that perfluorononanoic acid (PFNA) and PFOS levels were positively correlated with uric acid levels (P for trend = 0.03 and 0.03). Perfluorodecanoic acid (PFDA) and perfluoroundecanoic acid (PFUnDA) levels were negatively associated with serum triglyceride levels (P for trend = 0.014 and < 0.01). After excluding lipid-lowering drug users, the association between certain PFAS levels and the LDL level was significantly enhanced, but the downward trends of serum triglyceride levels were weakened. When stratified by sex, PFNA (P for trend <0.01), perfluorohexanesulfonate (PFHxS) (P for trend <0.01), and PFOS (P for trend <0.01) showed positive associations with the uric acid level only among males. In conclusion, our results showed that associations were consistently null between PFASs and metabolic syndrome. PFAS levels were associated with serum lipids, and lipid-lowering drugs may interfere with this relationship. Certain PFASs were found to be positively associated with uric acid levels, especially in males. Further studies are warranted to clarify the causal relationships.

A case-control study of perfluoroalkyl substances and the risk of breast cancer in Taiwanese women.

Breast cancer (BC) is a common cancer in women worldwide; however, the incidence of BC is increasing in younger women, possibly associated with the environment. Perfluoroalkyl substances (PFAS) are one of endocrine disruptors that accumulate in environment and impact human health. This study aimed to investigate whether the PFAS and BC are associated. We enrolled 120 BCE patients and 119 controls at National Taiwan University Hospital (NTUH) and also collected bio-specimen and questionnaire from 2013 to 2015. All subjects' plasma PFAS levels were analyzed by ultra-performance liquid chromatography tandem mass spectrometry method with electrospray ionization (UHPLC-ESI-MS/MS). A logistic regression model was used to estimate the association between PFAS and BC. In the ≤50 years age group, the adjusted odds ratio (OR) was 2.34 (95% CI = 1.02, 5.38) for perfluorooctane sulfonate (PFOS) exposure per natural log unit increase. After stratifying the estrogen receptor (ER) status and age group, we obtained a positive association for PFHxS and PFOS concentrations with respect to the risk of ER positive tumors for ≤50 years age group. In conclusion, we found that PFAS were associated with the BC risk of ER positive tumors in young Taiwanese women. Further studies are needed to follow and explore whether these associations are causal.

Children's environmental health based on birth cohort studies of Asia (2) - air pollution, pesticides, and heavy metals.

The life style and child raising environment in Asia are quite different compared with Western countries. Besides, the children's environmental threats and difficulties in conducting studies could be different. To address children's environmental health in Asia area, the Birth Cohort Consortium of Asia (BiCCA) was co-established in 2011. We reviewed the mercury, polychlorinated biphenyls, perfluoroalkyl substances, phthalates, and environmental tobacco smoke in pervious based on birth cohort studies in Asia. The aim of this study was to summarize the traditional environmental pollution and the target subjects were also based on the birth cohort in Asia area. Environmental pollutants included air pollutants, pesticides focusing on organochlorine pesticides, diakylphosphates, and pyrethroid, and heavy metals including lead, arsenic, cadmium, manganese, vanadium, and thallium. Fetal growth and pregnancy outcomes, childhood growth and obesity, neurodevelopment and behavioral problems, and allergic disease and immune function were classified to elucidate the children's health effects. In total, 106 studies were selected in this study. The evidences showed air pollution or pesticides may affect growth during infancy or childhood, and associated with neurodevelopmental or behavioral problems. Prenatal exposure to lead or manganese was associated with neurodevelopmental or behavioral problems, while exposure to arsenic or cadmium may influence fetal growth. In addition to the harmonization and international collaboration of birth cohorts in Asia; however, understand the whole picture of exposure scenario and consider more discipline in the research are necessary.

Childhood exposure to phthalates and pulmonary function.

Phthalate exposure is related to the development of allergic diseases; however, studies regarding its effect on lung function are limited. Our study aims to identify an association between phthalate exposure at different ages and lung function in children at age 9 by conducting a cohort study. The Taiwan Birth Panel Study (TBPS) was established from April 2004 to January 2005. Urine samples were collected from children in the TBPS cohort at ages 2, 5, and 9years. Urinary phthalate metabolite concentrations were measured via ultrahigh-performance liquid chromatography coupled with tandem mass spectrometry. Questionnaires, lung function tests and serum IgE levels were obtained from children at the age of 9. Multiple linear regressions adjusted for confounding factors were applied to investigate the associations between phthalate exposure at different ages and lung function at age 9. Our results demonstrate that in children with allergic diseases, a per log unit increase in the urinary phthalate metabolite mono-ethyl phthalate (MEP) concentration at age 9 was associated with a decreasing forced expiratory volume in 1 sec (FEV1) (ß=-25.22; 95% CI: -47.53 to -2.91 per log ml/ln-µg/g cr) and forced vital capacity (FVC) (ß=-32.3; 95% CI: -63.51 to -1.09 per log ml/ln-µg/g cr). For children with high serum IgE levels (>100kU/L) at age 9, the urinary MEP concentrations at the same age were negatively associated with the FEV1 (ß=-30.4; 95% CI: -56.8 to -4.0 per log ml/ln-µg/g cr), FVC (ß=-47.6; 95% CI: -84.2 to -11.0 per log ml/ln-µg/g cr) and peak expiratory flow (PEF) (ß=-102.4; 95% CI: 180.2 to -24.7 per log ml/ln-µg/g cr). Phthalate exposure at ages 2 and 5 had little effect on lung function at age 9. Our study suggests that concurrent exposure to phthalates, such as MEP, is negatively associated with lung function in children. Further investigation is required to elaborate on this correlation.

Determinants and Temporal Trends of Perfluoroalkyl Substances in Pregnant Women: The Hokkaido Study on Environment and Children's Health.

Perfluoroalkyl substances (PFAS) are persistent bio-accumulative chemicals that impact the health of pregnant women and their children. PFAS derive from environmental and consumer products, which depend on human lifestyle, socioeconomic characteristics, and time variation. Here, we aimed to explore the temporal trends of PFAS in pregnant women and the characteristics related to maternal PFAS concentration. Our study is part of the Hokkaido Study on Environment and Children's Health, the Hokkaido large-scale cohort that recruited pregnant women between 2003 and 2011. Blood samples were acquired from pregnant women during the third trimester to measure PFAS and cotinine concentrations. Maternal basic information was collected with a baseline structured questionnaire. Eleven PFAS were measured from 2123 samples with ultra-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry. Eight PFAS were above 80% detection rate and were included in the final analysis. We used multivariable linear regression to analyze the association of pregnant women characteristics with the levels of eight PFAS. The temporal trend of PFAS was observed in two periods (August 2003 to January 2006 and February 2006 to July 2012). The concentration of perfluorooctane sulfonate (PFOS) significantly decreased from August 2003 to January 2006 and from February 2006 to July 2012. The concentrations of perfluorododecanoic acid (PFDoDA), perfluoroundecanoic acid (PFUnDA), and perfluorotridecanoic acid (PFTrDA) increased significantly between August 2003 and January 2006, whereas they decreased significantly between February 2006 and July 2012. Women with pre-pregnancy body mass index (BMI) >25 kg/m² had lower PFUnDA, PFDoDA, and PFTrDA levels than did those with normal BMI (18.5⁻24.9 kg/m²). Pregnant women, who were active smokers (cotinine > 11.49 ng/mL), had higher PFOS than the non-smokers (cotinine < 0.22 ng/mL). Lower levels of PFHxS, PFOS, PFOA, PFNA, and PFDA were observed in women, who had given birth to more than one child. There were also significant positive associations between PFAS levels and annual income or maternal education. PFAS levels varied in women with higher pre-pregnancy BMI, active smoking status, higher education level and annual income. The causes of the individual PFAS differences should be explored in an independent study.

Nasal methicillin-resistant Staphylococcus aureus colonization among otherwise healthy children aged between 2 months and 5 years in northern Taiwan, 2005-2010.

BACKGROUND: Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections have been increasingly reported worldwide and are associated with nasal colonization. In Taiwan, available data disclosed a similar trend. We conducted a study for the updated childhood nasal MRSA carriage. METHODS: From July 2005 to December 2010, children aged between 2 months and 5 years who presented for a well-child health care visit to a medical center or from kindergarten/daycare center were invited and a nasal swab specimen was obtained for the detection of MRSA. All MRSA isolates were characterized. RESULTS: A total of 3226 children were included and the rate of nasal MRSA carriage was 10.2%. Children aged 2-6 months and >3 years were significantly associated with MRSA carriage, while pneumococcus colonization (p = 0.033) and breastfeeding (p = 0.025) were negatively associated with MRSA carriage. Of the 330 MRSA isolates, a total of 13 pulsotypes with two major patterns (type C, 47.0% and D, 29%) were identified. Most MRSA isolates belonged to two major clones, characterized as sequence type 59 (ST59)/pulsotype C/staphylococcal cassette chromosome (SCCmec) IV/Panton-Valentine leukocidin (PVL)-negative (45.8%) and ST59/pulsotype D/SCCmec VT/PVL-positive (22.7%). Two new clones as ST 508/SCCmec IV (9.7%) and ST573/SCCmec IV (7.3%) emerged and increased markedly since 2007. CONCLUSION: Between 2005 and 2010, 10.2% of healthy children in northern Taiwan carried MRSA in anterior nares, with the highest carriage rate for infants aged 2-6 months. Two emerging clones, ST 508 and ST 573, were identified and the clinical significance needs further surveillance.

Children's environmental health based on birth cohort studies of Asia.

Numerous studies have explored the associations between environmental pollutants and pediatric health. Recent studies have investigated the issue in Asia, but no systematic review has been published to date. This study aims to elucidate the issue by summarizing relevant epidemiologic evidence for cohorts in Asia, using information from the Birth Cohort Consortium of Asia (BiCCA). Environmental pollutants include mercury, environmental tobacco smoke (ETS), polychlorinated biphenyls (PCB), perfluoroalkyl substances (PFAS) and phthalates. This study sought to classify the effects of such compounds on fetal growth and pregnancy outcomes, neurodevelopment and behavioral problems, allergic disease and immune function and the endocrine system and puberty. These evidences showed ETS has been associated with infant birth weight, children's neurodevelopment and allergy disease; mercury and PCB have been shown to affect children's neurodevelopment; phthalate has effects on endocrine function; PFAS alters children's neurodevelopment, the endocrine system, and the allergic response. However, more consistent and coordinated research is necessary to understand the whole picture of single environmental and/or co-exposure and children's health. Therefore, harmonization and international collaboration are also needed in Asia.

Prenatal phenolic compounds exposure and neurobehavioral development at 2 and 7years of age.

BACKGROUND: Phenolic compounds such as bisphenol A (BPA), nonylphenol (NP), and octylphenol (OP) are known as endocrine-disrupting compounds and are commonly used. Their impacts on the neurodevelopment of children are inconclusive. The current study aims to investigate the association between umbilical cord blood levels of BPA, NP, OP and neurodevelopmental outcomes at 2 and 7years of age. METHODS: The study was based on the Taiwan Birth Panel Study, a prospective birth cohort. We collected cord blood plasma to measure phenolic compound levels using ultra-performance liquid chromatography-tandem mass spectrometry. In the follow-up, 208 mother-child pairs with 2-year-old children and 148 mother-child pairs with 7-year-old children were recruited in this study. We used the Comprehensive Developmental Inventory for Infants and Toddlers (CDIIT) and the Wechsler Intelligence Scale for Children (WISC-IV) for neurodevelopmental assessments at 2 and 7years of age, respectively. Multiple linear regressions were used for statistical analysis. RESULTS: The detection rates of BPA, NP, and OP were 55.9%, 77.6%, and 68.3%, respectively. In this study, the median BPA, NP, and OP levels in 2-year-olds were 3.3, 72.6, and 3.3 (ng/ml), respectively. However, the median levels of BPA, NP, and OP were 3.2, 49.3, and 6.6 (ng/ml), respectively. The levels of phenolic compounds were log10-transformed for statistical analysis. Gender stratification was performed. In the WISC-IV neurocognitive assessment, we found both a significant negative association and a trend between cord blood plasma BPA levels and full-scale IQ (p for trend<0.01), the verbal comprehension index (p for trend<0.01), and the perceptual reasoning index (p for trend<0.01) in the study population. After stratification by sex, significant associations were found in full-scale IQ (p for trend=0.03) and the verbal comprehension (p for trend<0.01) index in boys. In girls, prenatal BPA exposure had adverse effects on full-scale IQ (p for trend=0.02), perceptual reasoning index (p for trend<0.01), and working memory index (p for trend=0.02). None of the developmental quotients (DQs) of the CDIIT analysis were significantly associated with phenolic compound levels in cord blood based on continuous or categorical measures. CONCLUSION: Prenatal exposure to BPA affects neurocognitive development, and this effect differs between 7-year-old boys and girls. More studies are needed to elucidate the relationship between phenolic compound exposure in utero and children's neurobehavioral development.

Perfluoroalkyl substances and thyroid hormones in cord blood.

BACKGROUND: Perfluoroalkyl substances (PFASs) are pollutants that tend to accumulate in the environment and organisms. The animal and human studies to date have focused on thyroid function, but the results are inconsistent. METHODS: A sample of 118 mother-infant pairs was obtained from the Taiwan Birth Panel Study (TBPS). Cord blood PFASs levels were evaluated using the Waters ACQUITY UPLC system coupled with a Waters Quattro Premier XE triple quadrupole mass spectrometer, and cord blood thyroid hormones were assessed using a Roche Analytics E170 modular analyser (Roche Diagnostics, Mannheim, Germany). PFASs concentrations were analysed in the final models to examine the associations between cord blood PFASs levels and thyroid hormone concentrations. RESULTS: The cord blood perfluorooctane sulfonate (PFOS) concentration was negatively associated with the cord blood thyroxine (T4) concentration [per ln unit: adjusted ß (95% confidence interval, CI) = -0.458(-0.916, -0.001)]. Moreover, the level of cord blood thyroid stimulating hormone (TSH) was positively associated with the cord blood PFOS concentration [per ln unit: adjusted ß (95% confidence interval, CI) = 0.346(0.101, 0.592)]. The sex stratified effects of PFOS on T4 were suggestive of differential effects in high-exposure groups compared with low-exposure group in boys. CONCLUSIONS: We found that cord blood thyroid hormone levels are affected by PFASs, with a negative association between T4 and PFOS and a positive association between TSH and PFOS. The causal associations of thyroid hormones and PFASs require further exploration.

NbRABG3f, a member of Rab GTPase, is involved in Bamboo mosaic virus infection in Nicotiana benthamiana.

The screening of differentially expressed genes in plants after pathogen infection can uncover the potential host factors required for the pathogens. In this study, an up-regulated gene was identified and cloned from Nicotiana benthamiana plants after Bamboo mosaic virus (BaMV) inoculation. The up-regulated gene was identified as a member of the Rab small guanosine triphosphatase (GTPase) family, and was designated as NbRABG3f according to its in silico translated product with high identity to that of RABG3f of tomato. Knocking down the expression of NbRABG3f using a virus-induced gene silencing technique in a protoplast inoculation assay significantly reduced the accumulation of BaMV. A transiently expressed NbRABG3f protein in N. benthamiana plants followed by BaMV inoculation enhanced the accumulation of BaMV to approximately 150%. Mutants that had the catalytic site mutation (NbRABG3f/T22N) or had lost their membrane-targeting capability (NbRABG3f/ΔC3) failed to facilitate the accumulation of BaMV in plants. Because the Rab GTPase is responsible for vesicle trafficking between organelles, a mutant with a fixed guanosine diphosphate form was used to identify the donor compartment. The use of green fluorescent protein (GFP) fusion revealed that GFP-NbRABG3f/T22N clearly co-localized with the Golgi marker. In conclusion, BaMV may use NbRABG3f to form vesicles derived from the Golgi membrane for intracellular trafficking to deliver unidentified factors to its replication site; thus, both GTPase activity and membrane-targeting ability are crucial for BaMV accumulation at the cell level.

Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope.

The sigma-1 receptor (Sig-1R) chaperone at the endoplasmic reticulum (ER) plays important roles in cellular regulation. Here we found a new function of Sig-1R, in that it translocates from the ER to the nuclear envelope (NE) to recruit chromatin-remodeling molecules and regulate the gene transcription thereof. Sig-1Rs mainly reside at the ER-mitochondrion interface. However, on stimulation by agonists such as cocaine, Sig-1Rs translocate from ER to the NE, where Sig-1Rs bind NE protein emerin and recruit chromatin-remodeling molecules, including lamin A/C, barrier-to-autointegration factor (BAF), and histone deacetylase (HDAC), to form a complex with the gene repressor specific protein 3 (Sp3). Knockdown of Sig-1Rs attenuates the complex formation. Cocaine was found to suppress the gene expression of monoamine oxidase B (MAOB) in the brain of wild-type but not Sig-1R knockout mouse. A single dose of cocaine (20 mg/kg) in rats suppresses the level of MAOB at nuclear accumbens without affecting the level of dopamine transporter. Daily injections of cocaine in rats caused behavioral sensitization. Withdrawal from cocaine in cocaine-sensitized rats induced an apparent time-dependent rebound of the MAOB protein level to about 200% over control on day 14 after withdrawal. Treatment of cocaine-withdrawn rats with the MAOB inhibitor deprenyl completely alleviated the behavioral sensitization to cocaine. Our results demonstrate a role of Sig-1R in transcriptional regulation and suggest cocaine may work through this newly discovered genomic action to achieve its addictive action. Results also suggest the MAOB inhibitor deprenyl as a therapeutic agent to block certain actions of cocaine during withdrawal.