Paternal Tobacco Smoke Correlated to Offspring Asthma and Prenatal Epigenetic Programming.

Rationale: Little is known about effects of paternal tobacco smoke (PTS) on the offspring's asthma and its prenatal epigenetic programming. Objective: To investigate whether PTS exposure was associated with the offspring's asthma and correlated to epigenetic CG methylation of potential tobacco-related immune genes: LMO2, GSTM1 or/and IL-10 genes. Measurements and Main Results: In a birth cohort of 1,629 newborns, we measured exposure rates of PTS (23%) and maternal tobacco smoke (MTS, 0.2%), cord blood DNA methylation, infant respiratory tract infection, childhood DNA methylation, and childhood allergic diseases. Infants with prenatal PTS exposure had a significantly higher risk of asthma by the age of 6 than those without (p = 0.026). The PTS exposure doses at 0, <20, and ≧20 cigarettes per day were significantly associated with the trend of childhood asthma and the increase of LMO2-E148 (p = 0.006), and IL10_P325 (p = 0.008) CG methylation. The combination of higher CG methylation levels of LMO2_E148, IL10_P325, and GSTM1_P266 corresponded to the highest risk of asthma by 43.48%, compared to other combinations (16.67-23.08%) in the 3-way multi-factor dimensionality reduction (MDR) analysis. The LMO2_P794 and GSTM1_P266 CG methylation levels at age 0 were significantly correlated to those at age of 6. Conclusions: Prenatal PTS exposure increases CG methylation contents of immune genes, such as LMO2 and IL-10, which significantly retained from newborn stage to 6 years of age and correlated to development of childhood asthma. Modulation of the LMO2 and IL-10 CG methylation and/or their gene expression may provide a regimen for early prevention of PTS-associated childhood asthma. Descriptor number: 1.10 Asthma Mediators. Scientific Knowledge on the Subject: It has been better known that maternal tobacco smoke (MTS) has an impact on the offspring's asthma via epigenetic modification. Little is known about effects of paternal tobacco smoke (PTS) on the offspring's asthma and its prenatal epigenetic programming. What This Study Adds to the Field: Prenatal tobacco smoke (PTS) can program epigenetic modifications in certain genes, such as LMO2 and IL-10, and that these modifications are correlated to childhood asthma development. The higher the PTS exposure dose the higher the CG methylation levels are found. The combination of higher CG methylation levels of LMO2_E148, IL10_P325 and GSTM1_P266 corresponded to the highest risk of asthma. Measuring the DNA methylation levels of certain genes might help to predict high-risk populations for childhood asthma and provide a potential target to prevent the development of childhood asthma.

Prevalence of infant sneezing without colds and prediction of childhood allergy diseases in a prospective cohort study.

BACKGROUND: Allergy sensitization may begin during the perinatal period, but predicting allergic diseases in infancy remains difficult. This study attempted to identify early predictors of childhood allergy diseases in a prospective cohort study. MATERIALS AND METHODS: In a prospective birth cohort study at southern Taiwan locating in a subtropical region, questionnaire surveys of sneezing or cough without colds at 6 and 18 months of age were recorded, and the correlation with allergy diseases was assessed at 3 and 6 years of age. RESULTS: A total of 1812 pregnant women and 1848 newborn infants were prenatally enrolled, and 1543, 1344, 1236, and 756 children completed the follow-up at ages 6 months, 18 months, 3 years and 6 years, respectively. The prevalence of infant sneezing without colds at 6 and 18 months of age was 30.3% and 19.2%, respectively. The prevalence of infant cough without colds at 6 and 18 months of age was 10.6% and 5.7%, respectively. Infant sneezing without colds at 18 months of age was significantly correlated with atopic dermatitis, allergic rhinitis and asthma at 6 years of age. Infant cough without colds at 18 months of age significantly predicted asthma but not atopic dermatitis or allergic rhinitis at 6 years of age. CONCLUSIONS: Infant sneezing without colds predicted all allergy diseases at 6 years of age in a subtropical country. This highlights a potential non-invasive clue in a subtropical region for the early prediction, treatment and prevention of childhood allergy diseases in infancy.

Aging-dependent DNA hypermethylation and gene expression of GSTM1 involved in T cell differentiation.

This study investigated whether aging was associated with epigenetic changes of DNA hypermethylation on immune gene expression and lymphocyte differentiation. We screened CG sites of methylation in blood leukocytes from different age populations, picked up genes with age-related increase of CG methylation content more than 15%, and validated immune related genes with CG hypermethylation involved in lymphocyte differentiation in the aged population. We found that 12 genes (EXHX1、 IL-10、 TSP50、 GSTM1、SLC5A5、SPI1、F2R、LMO2、PTPN6、FGFR2、MMP9、MET) were associated with promoter or exon one DNA hypermethylation in the aged group. Two immune related genes, GSTM1 and LMO2, were chosen to validate its aging-related CG hypermethylation in different leukocytes. We are the first to validate that GSTM1_P266 and LMO2_E128 CG methylation contents in T lymphocytes but not polymorphonuclear cells (PMNs) or mononuclear cells (MNCs) were significantly increased in the aged population. The GSTM1 mRNA expression in T lymphocytes but not PMNs or MNCs was inversely associated with the GSTM1 CG hypermethylation levels in the aged population studied. Further studies showed that lower GSTM1 CG methylation content led to the higher GSTM1 mRNA expression in T cells and knockdown of GSTM1 mRNA expression decreased type 1 T helper cell (Th1) differentiation in Jurkat T cells and normal adult CD4 T cells. The GSTM1_P266 hypermethylation in the aged population associated with lower GSTM1 mRNA expression was involved in Th1 differentiation, highlighting that modulation of aging-associated GSTM1 methylation may be able to enhance T helper cell immunity in the elders.

A prospective birth cohort study of different risk factors for development of allergic diseases in offspring of non-atopic parents.

BACKGROUND: Allergic diseases are thought to be inherited. Prevalence of allergic diseases has, however, increased dramatically in last decades, suggesting environmental causes for the development of allergic diseases. OBJECTIVE: We studied risk factors associated with the development of atopic dermatitis (AD), allergic rhinitis (AR) and asthma (AS) in children of non-atopic parents in a subtropical country. METHODS: In a birth cohort of 1,497 newborns, parents were prenatally enrolled and validated for allergic diseases by questionnaire, physician-verified and total or specific Immunoglobulin E (IgE) levels; 1,236 and 756 children, respectively, completed their 3-year and 6-year follow-up. Clinical examination, questionnaire, and blood samples for total and specific IgE of the children were collected at each follow-up visit. RESULTS: Prevalence of AD, AR and AS was, respectively, 8.2%, 30.8% and 12.4% in children of non-atopic parents. Prevalence of AR (p<.001) and AS (p=.018) was significantly higher in children of parents who were both atopic. A combination of Cesarean section (C/S) and breastfeeding for more than 1 month showed the highest risk for AD (OR=3.111, p=.006). Infants living in homes with curtains and no air filters had the highest risk for AR (OR=2.647, p<.001), and male infants of non-atopic parents living in homes without air filters had the highest risk for AS (OR=1.930, p=.039). CONCLUSIONS: Breastfeeding and C/S affect development of AD. Gender, use of curtains and/or air filters affect AR and AS, suggesting that control of the perinatal environment is necessary for the prevention of atopic diseases in children of non-atopic parents.

Seroprevalence of Helicobacter pylori and Hepatitis A Virus among Children in Rural Central Taiwan.

Helicobacter pylori and hepatitis A virus (HAV) are thought to have similar routes of transmission and epidemiology. This study investigated the seroprevalence of these 2 pathogens among children in rural, central Taiwan. Serum samples were collected from 856 children between 2010 and 2012 and levels of anti-HAV and anti-H. pylori antibodies were measured by ELISA. Questionnaires were used to investigate possible risk factors. The overall H. pylori and HAV infection rates were 6% and 0.8%, respectively. There was a significant difference in H. pylori infection rates (P value=0.008), but not HAV infection rates, between different age groups. H. pylori infection rates were significantly higher in children whose mothers had lower education levels. In contrast, HAV infection rates were significantly higher in children whose fathers had lower education levels. The risk of HAV infection was also 14.20-fold higher in children whose family members had traveled to China or Southeast Asia. No significant correlation was found between H. pylori and HAV seropositivity. The seroprevalences of H. pylori and HAV were low in rural central Taiwan. Universal HAV vaccination is highly recommended to prevent outbreak due to low seroprevalence.

Gender-dependent effect of GSTM1 genotype on childhood asthma associated with prenatal tobacco smoke exposure.

It remains unclear whether the GSTM1 genotype interacts with tobacco smoke exposure (TSE) in asthma development. This study aimed to investigate the interactions among GSTM1 genotype, gender, and prenatal TSE with regard to childhood asthma development. In a longitudinal birth cohort in Taiwan, 756 newborns completed a 6-year follow-up, and 591 children with DNA samples available for GSTM1 genotyping were included in the study, and the interactive influences of gender-GSTM1 genotyping-prenatal TSE on childhood asthma development were analyzed. Among these 591 children, 138 (23.4%) had physician-diagnosed asthma at 6 years of age, and 347 (58.7%) were null-GSTM1. Prenatal TSE significantly increased the prevalence of childhood asthma in null-GSTM1 children relative to those with positive GSTM1. Further analysis showed that prenatal TSE significantly increased the risk of childhood asthma in girls with null-GSTM1. Furthermore, among the children without prenatal TSE, girls with null-GSTM1 had a significantly lower risk of developing childhood asthma and a lower total IgE level at 6 years of age than those with positive GSTM1. This study demonstrates that the GSTM1 null genotype presents a protective effect against asthma development in girls, but the risk of asthma development increases significantly under prenatal TSE.

Influence and mechanisms of maternal and infant diets on the development of childhood asthma.

Perinatal nutrition has been implicated in the programming of diseases in children and adults. The prevalence of asthma has dramatically increased in the past few decades, particularly in children. This suggests that the perinatal environment, including maternal and infant diets, may be involved in the increase in the prevalence of asthma. Recent studies have demonstrated that certain maternal and infant diets have a protective or augmentative effect on the development of asthma. Maternal diets with higher vitamin D, vitamin E, or/and probiotics are related to asthma prevention. Infants with breast feeding for at least 4 months and/or complementary diets between 4 and 6 months may have regulatory effects on the prevention of asthma. In summary, diets may have epigenetic or immune regulatory effects on the promotion or prevention of asthma. This article analyzes recent reports on the potential mechanism and mechanism-driven early prevention of childhood asthma by modification of maternal and infant diets.

Different profiles of allergen sensitization in different ages and geographic areas in Changhua, Taiwan.

BACKGROUND/PURPOSE: Environmental factors, different ages, and detection methods might affect the profiles of allergy sensitization and confound the diagnosis of allergic diseases. The purpose of this study was to investigate the different profiles of allergen sensitization in different ages, geographic areas, and detection methods. METHODS: We analyzed the patients who received allergen sensitization tests by the automated microfluidic-based immunoassay system (BioIC) method at Show Chwan Memorial Hospital in Changhua City and at Chang Bing Show Chwan Hospital in Lu-gang from January 2011 to December 2011. Results were compared in different ages (3-6, 7-18, and ≥19), different geographic areas, and different detection methods and analyzed by Chi-square or Fisher exact test depending on sample size. RESULTS: A total of 1145 patients were analyzed. The younger the age, the higher the food allergy sensitization rate is found (26.6% vs. 14.7% vs.11.1% p < 0.001). The older the age, the higher the sensitization of Blomia tropicalis occurs (33.4% vs.15.1% p < 0.001). The food allergen specific IgE directed against egg white was higher in coast area than city (15.4% vs. 3%, p = 0.015). A higher rate of pollen sensitization was found in the detection by BioIC method (Bermuda grass, 17.2%; Timothy, 12.3%; ragweed, 5.7%). The sensitization rates of cockroach and cat dander were lower in both city and coast areas. CONCLUSION: Children have higher food allergy sensitization and adults have higher Blomia tropicalis sensitization. Children living in Changhua area no matter in city or coast area had a higher pollen sensitization rate but lower cat or dog dander sensitization rate. Apparently, age, environmental factors, and different methods significantly affect the allergen sensitization in the different areas of Taiwan.

Higher levels of soluble Fas ligand and transforming growth factor-ß after omalizumab treatment: a case report.

A skewed T-helper (T(h))1/T(h)2 immune response is considered to be the major cause of allergic disorders. Overproduction of T(h)2 cytokines, which promote recruitment and activation of mast cells and eosinophils, plays a key part in the pathogenesis of allergic asthma. The mechanisms by which omalizumab is effective in asthma treatment are not yet fully understood. A 16-year-old girl who was experiencing frequent asthma attacks in spite of daily administration of budesonide (640 µg) and montelukast (10mg) was given omalizumab (375 mg) at intervals of 2 weeks, to prevent a visit to the emergency room. Plasma levels of T(h)1 cytokines [interferon (IFN)-γ and interleukin (IL)-12p70], T(h)2 cytokines (IL-4 and IL-13), other proinflammatory and regulatory cytokines [IL-6, IL-10, IL-17, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-ß], chemokines [monocyte chemotactic protein (MCP)-1, chemokine ligand (CCL)7, and CCL17], and soluble Fas ligand (sFasL) were measured before treatment and after treatment for 8 weeks. She showed a good clinical response to omalizumab: her lung function parameters improved and the use of ß2-agonist decreased. No emergency room visits were required after omalizumab treatment for 8 weeks. Plasma levels of sFasL and TGF-ß showed obvious increases after omalizumab therapy. IL-12p70 levels were decreased as compared to the corresponding baseline levels. These findings suggest that the effects of omalizumab in asthma treatment are not restricted to the regulation of the skewed T(h)1/T(h)2 cytokine immune response, and sFasL-mediated apoptosis and regulatory T-cell (Treg)-mediated TGF-ß seem to have important roles in the therapeutic effects of omalizumab.

Different implications of paternal and maternal atopy for perinatal IgE production and asthma development.

Asthma is a hereditary disease associated with IgE-mediated reaction. Whether maternal atopy and paternal atopy have different impacts on perinatal IgE production and asthma development remains unclear. This paper reviews and summarizes the effects of maternal and paternal atopy on the developmental aspects of IgE production and asthma. Maternal atopy affects both pre- and postnatal IgE production, whereas paternal atopy mainly affects the latter. Maternally transmitted genes GSTP1 and FceRI-beta are associated with lung function and allergic sensitization, respectively. In IgE production and asthma development, the maternal influence on gene-environment interaction is greater than paternal influence. Maternal, paternal, and/or postnatal environmental modulation of allergic responses have been linked to epigenetic mechanisms, which may be good targets for early prevention of asthma.

Deep and alignment free patterned etching of GaN surface using an atomic force microscope.

Successful deep and alignment-free patterned etching on GaN using atomic force microscope (AFM) local oxidation followed by in-situ chemical etching is demonstrated. Oxide ridges are grown on GaN on an AFM by applying positive sample bias at 80% humidity, with the oxidation reaction expedited by UV light. The oxide ridges are then etched by HCl solution, leaving troughs in the GaN surface. A dripping strategy for the in-situ chemical etching is recommended that allows deep, alignment-free multiple AFM oxidation/etching works on the GaN surface without any need of substrate removal from the AFM platform. Repeated etching followed by AFM oxidation on a spot on a GaN surface resulting in a hole as deep as 800 nm was also demonstrated. Further, a preliminary evaluation of the porosity of the AFM-grown oxide indicates that the oxide ridges grown on GaN at an AFM cantilever moving speed of 300 nm/s are porous in structure, with an estimated porosity of 86%, which porosity could be reduced if longer resident time of the AFM cantilever on the target oxidation region was used.

Etanercept treatment for children with refractory juvenile idiopathic arthritis.

BACKGROUND: Etanercept has been shown to be an effective treatment for juvenile idiopathic arthritis (JIA). In this study, we evaluated the effectiveness of etanercept therapy in the treatment of refractory JIA. METHODS: This was a retrospective analysis of 11 patients with refractory JIA (polyarticular type n=7; pauciarticular type, n=2; systemic type, n=2) who received treatment with etanercept during the period 2005-2009 in a medical center. The indications for etanercept treatment included persistent fever, arthritis/arthralgia, or elevated levels of inflammatory mediators after treatment with methotrexate and/or prednisolone for more than 6 months. The patients were treated with etanercept (0.4 mg/kg, with maximal 25mg, subcutaneously, twice a week) for a total of 12 months. RESULTS: The degree of arthritis/arthralgia improved (range of motion and painful sensation of involved joints), and the levels of inflammatory markers (C-reactive protein and erythrocyte sedimentation rate) decreased progressively in 10 of the 11 patients (p<0.05) at 1-, 3-, 5-, and 12-month follow-up after treatment with etanercept. Mean hemoglobin levels significantly increased, whereas mean platelet counts decreased after etanercept treatment (p<0.05). Only one patient with systemic type of JIA failed to respond to the treatment after 6 weeks of etanercept therapy. Methotrexate, prednisolone, and other immunosuppressive drugs were successfully discontinued after a mean of 2.5 months (range, 1-5 months) of etanercept therapy in the 10 patients who responded to etanercept treatment. CONCLUSION: Etanercept is beneficial for patients with polyarticular and pauciarticular type of JIA that is refractory to conventional treatment but less beneficial for systemic type of JIA.

Comparison of the Global Initiative for Asthma guideline-based Asthma Control Measure and the Childhood Asthma Control Test in evaluating asthma control in children.

BACKGROUND: Reliable assessment of asthma control is essential for effective treatment. While several validated tools for assessing asthma control in children are currently available, few studies have evaluated the correlations between different asthma control measures in children. This study aimed to determine the correlations between the Childhood Asthma Control Test (C-ACT) and the Global Initiative for Asthma (GINA) guideline-based asthma control measure (ACM) with lung function parameters in children with asthma. METHODS: Sixty-three children aged 6-11 years with mild-intermittent to severe-persistent asthma were evaluated. They completed the C-ACT, the GINA guideline-based assessment and lung function tests with the help of their caregivers. RESULTS: C-ACT scores and GINA guideline-based ACM were positively correlated. The average C-ACT scores for children with controlled, partly controlled and uncontrolled asthma according to the GINA guidelines were 24.4±0.3, 22.8±0.6 and 21.3±1.0 (mean±SE), respectively. High C-ACT scores were also noted in children with uncontrolled asthma based on the GINA guidelines. The GINA guideline-based ACM was correlated with spot spirometry parameters (forced vital capacity, forced expiratory volume in 1 second, and maximal mid-expiratory flow). Conversely, the C-ACT score was not correlated with these spirometry parameters. CONCLUSIONS: The C-ACT may overestimate asthma control in certain circumstances. For children with poorly controlled asthma or poor symptom perception, more frequent visits and serial pulmonary function tests are recommended.

Association of acute urticaria with Mycoplasma pneumoniae infection in hospitalized children.

BACKGROUND: Acute urticaria is a common and disturbing disorder in children and has a versatile etiology. OBJECTIVE: To investigate the association of acute urticaria with Mycoplasma pneumoniae infection in hospitalized children. METHODS: Hospitalized children with acute urticaria from Taiwan who did not respond to antihistamine treatment and avoidance of food allergens were studied from February 1, 2006, to July 31, 2007. These patients with urticaria were compared with those who had other respiratory tract diseases and were classified into 2 groups: urticaria patients with and without M pneumoniae infection. The presence of M pneumoniae infection was determined by positive serologic findings. RESULTS: Sixty-five patients with acute urticaria and 49 patients with other respiratory tract diseases were enrolled in this study. Patients with urticaria had significantly less febrile duration but significantly higher platelet and lymphocyte counts than those with other respiratory tract diseases. Of the 65 patients with urticaria, 21 (32%) showed serologic evidence of M pneumoniae infection. Patients with M pneumoniae-associated urticaria received azithromycin treatment and needed a shorter time for improvement (P = .01) and complete resolution (P = .04). The total IgE levels and the results of specific IgE tests were not significantly different between urticaria patients with and without M pneumoniae infection. CONCLUSION: This study found that in Taiwan one-third of acute childhood urticaria leading to patient hospitalization was related to M pneumoniae infection. Therefore, children with urticaria who are not responding to antihistamine treatment and abstinence from food allergens should be encouraged to undergo serologic examinations for M pneumoniae to diagnose this antibiotic-responsive disorder.

Prolonged acquired neutropenia in children.

BACKGROUND: Acquired neutropenia is not uncommon in childhood. This study investigated the risk factors associated with developing prolonged acquired neutropenia. PROCEDURE: We reviewed 66,062 hospital admission medical records from the 5-year period January 1, 2002 to December 31, 2006 to identify neutropenic patients, with and without follow-up of their neutropenic course until December 31, 2007. After excluding patients with malignancy, collagen disease, bone marrow failure, prematurity, hereditary disease, congenital neutropenia, immunodeficiency, or status post-liver transplantation, 735 admissions with acquired neutropenia were included in our study. RESULTS: A total of 474 patients with 735 admissions had moderate or severe neutropenia during the 5-year period. Among the 252 acquired neutropenia patients who had follow-up for at least 1 month, 226 patients recovered within 3 months, while 26 patients remained neutropenic after 3 months. Of these 26 patients, 14 recovered after 1 year. An absolute neutrophil count of <500/mm(3) (odds ratio [OR]: 13.66, 95% confidence interval [CI]: 2.90-64.41), thrombocytosis (OR: 5.76, 95% CI: 1.78-18.58), and age <1 year (OR: 4.93, 95% CI: 1.03-23.54) were associated with prolonged acquired neutropenia, as shown by multivariate logistic regression. Kaplan-Meier analysis showed that neutropenia associated with cytomegalovirus (CMV) was more prolonged than neutropenia associated with influenza or Epstein-Barr virus infection. CONCLUSIONS: Prolonged acquired neutropenia was associated with younger age, thrombocytosis, and CMV infection. Neutropenic infants with CMV infection may require antiviral therapy to prevent prolonged acquired neutropenia.

Non-Langerhans cell histiocytosis in a child with Kawasaki disease.

Polymorphous skin rashes are one of the major presentations in children with Kawasaki disease. This report describes an unusual presentation of a skin rash (non-Langerhans cell histiocytosis) in a 4-month-old baby with resistance to intravenous immunoglobulin (IVIG) treatment and coronary artery dilatation. Though refractory to repeat dosages of IVIG treatment, the patient had a favourable response to methylprednisolone pulse therapy.