Asthma, a chronic inflammatory disorder of the airway, has features of both heritability as well as environmental influences which can be introduced in utero exposures and modified through aging, and the features may attribute to epigenetic regulation. Epigenetic regulation explains the association between early prenatal maternal smoking and later asthma-related outcomes. Epigenetic marks (DNA methylation, modifications of histone tails or noncoding RNAs) work with other components of the cellular regulatory machinery to control the levels of expressed genes, and several allergy- and asthma-related genes have been found to be susceptible to epigenetic regulation, including genes important to T-effector pathways (IFN-γ, interleukin [IL] 4, IL-13, IL-17) and T-regulatory pathways (FoxP3). Therefore, the mechanism by which epigenetic regulation contributes to allergic diseases is a critical issue. In the past most published experimental work, with few exceptions, has only comprised small observational studies and models in cell systems and animals. However, very recently exciting and elegant experimental studies and novel translational research works were published with new and advanced technologies investigating epigenetic mark on a genomic scale and comprehensive approaches to data analysis. Interestingly, a potential link between exposure to environmental pollutants and the occurrence of allergic diseases is revealed recently, particular in developed and industrialized countries, and endocrine disrupting chemicals (EDCs) as environmental hormone may play a key role. This review addresses the important question of how EDCs (nonylphenol, 4 octylphenol, and phthalates) influences on asthma-related gene expression via epigenetic regulation in immune cells, and how anti-asthmatic agents prohibit expression of inflammatory genes via epigenetic modification. The discovery and validation of epigenetic biomarkers linking exposure to allergic diseases might lead to better epigenotyping of risk, prognosis, treatment prediction, and development of novel therapies.
Acetylation ; Aging ; Animals ; Anti-Asthmatic Agents ; Asthma ; Biomarkers ; Developed Countries ; Endocrine Disruptors ; Environmental Pollutants ; Epigenomics ; Gene Expression ; Histones ; Hypersensitivity ; Interleukin-13 ; Interleukins ; Methylation ; Prognosis ; Smoke ; Smoking ; Statistics as Topic ; Tail ; Translational Medical Research

The prevalence of asthma and allergic disease has increased worldwide over the last few decades. Many common environmental factors are associated with this increase. Several theories have been proposed to account for this trend, especially those concerning the impact of environmental toxicants. The development of the immune system, particularly in the prenatal period, has far-reaching consequences for health during early childhood, and throughout adult life. One underlying mechanism for the increased levels of allergic responses, secondary to exposure, appears to be an imbalance in the T-helper function caused by exposure to the toxicants. Exposure to environmental endocrine-disrupting chemicals can result in dramatic changes in cytokine production, the activity of the immune system, the overall Th1 and Th2 balance, and in mediators of type 1 hypersensitivity mediators, such as IgE. Passive exposure to tobacco smoke is a common risk factor for wheezing and asthma in children. People living in urban areas and close to roads with a high volume of traffic, and high levels of diesel exhaust fumes, have the highest exposure to environmental compounds, and these people are strongly linked with type 1 hypersensitivity disorders and enhanced Th2 responses. These data are consistent with epidemiological research that has consistently detected increased incidences of allergies and asthma in people living in these locations. During recent decades more than 100,000 new chemicals have been used in common consumer products and are released into the everyday environment. Therefore, in this review, we discuss the environmental effects on allergies of indoor and outside exposure.
Adult ; Asthma ; Child ; Humans ; Hypersensitivity ; Immune System ; Immunoglobulin E ; Incidence ; Inflammation* ; Prevalence ; Respiratory Sounds ; Risk Factors ; Smoke ; Smoking ; Tobacco ; Vehicle Emissions

The objectives of this cohort analysis were to explore the relationship between insulin resistance (IR) and the criteria for metabolic syndrome (MetS) and to evaluate the ability to detect IR in subjects fulfilling those criteria. We enrolled 511 healthy subjects (218 men and 283 women) and measured their blood pressure (BP), body mass index, high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), and fasting plasma glucose levels. Insulin suppression testing was done to measure insulin sensitivity as the steady-state plasma glucose (SSPG) value. Subjects with an SSPG value within the top 25% were considered to have IR. The commonest abnormality was a low HDL-C level, followed by high BP. The sensitivity to detect IR in subjects with MetS was about 47%, with a positive predictive value of about 64.8%, which has higher in men than in women. In general, the addition of components to the criteria for MetS increased the predictive value for IR. The most common combination of components in subjects with MetS and IR were obesity, high BP, and low HDL-C levels. All of the components were positive except for HDL-C, which was negatively correlated with SSPG. The correlation was strongest for obesity, followed by high TG values. In subjects with MetS, sensitivity for IR was low. However, body mass index and TG values were associated with IR and may be important markers for IR in subjects with MetS.
Adult ; Aged ; *Biological Markers ; Blood Glucose/metabolism ; Blood Pressure ; Body Mass Index ; Cholesterol, HDL/blood ; Female ; Humans ; *Insulin Resistance ; Male ; Metabolic Syndrome X/*diagnosis/*epidemiology ; Middle Aged ; Obesity, Morbid/diagnosis/epidemiology ; Predictive Value of Tests ; Prevalence ; Risk Factors ; Sensitivity and Specificity ; Triglycerides/blood

INTRODUCTIONCardiopulmonary resuscitation (CPR) guidelines were revised in 2005 based on new evidence and expert consensus. However, the benefits of the new guidelines remain undetermined and their influence has not been published in Asia. This study aimed to evaluate the impact of implementing the new resuscitation guidelines and identify factors that influence the discharge survival of out-of-hospital cardiac arrest (OHCA) patients in an Asian metropolitan city.

MATERIALS AND METHODSThis was an observational cohort study of all OHCA patients seen by the emergency medical service during the period before (Nov 2003 to Oct 2005) and after (May 2006 to Oct 2008) implementing the new resuscitation guidelines. Detailed clinical information was recorded using the Ustein style template. Statistical analysis was done using X2 test or t-test for univariate analysis and the logistic regression model for multivariate analysis.

RESULTSThere were 463 patients before and 430 patients after the new guidelines who received resuscitation. The rate of recovery of spontaneous circulation (ROSC), survival-to-intensive care unit (ICU) admission, and survival-to-hospital discharge all showed no benefits regarding the new resuscitation guidelines (ROSC: 42% vs 39%, P = 0.32; Survival-to-ICU admission: 33% vs 30%, P = 0.27; survival-to-hospital discharge: 10% vs 7%, P = 0.09). The rate of ventricular fibrillation/pulseless ventricular tachycardia (VF/pulseless VT), rate of witnessed arrest, and rate of bystander CPR were much lower than in Western studies. After multivariate logistic regression, factors related to discharge survival were witnessed arrest and initial rhythm with VF/pulseless VT. The new resuscitation guidelines did not significantly influence the discharge survival.

CONCLUSIONSWe did not observe any improvement in survival after implementing the new guidelines. Independent factors of survival-to-hospital discharge are witnessed arrest and initial rhythm with VF/pulseless VT. Because the rates of VF/pulseless VT and bystander CPR in Asia are low, popularising CPR training programmes and increasing the rate of bystander CPR may be more important for improving OHCA survival rates than frequent guideline changes.

Aged ; Aged, 80 and over ; Cardiopulmonary Resuscitation ; methods ; standards ; Emergency Service, Hospital ; statistics & numerical data ; Female ; Hospitals, University ; statistics & numerical data ; Humans ; Male ; Middle Aged ; Out-of-Hospital Cardiac Arrest ; mortality ; therapy ; Patient Discharge ; statistics & numerical data ; Practice Guidelines as Topic ; Survival Analysis ; Taiwan ; epidemiology

Objective: The impact of serotonergic system on obsessive-compulsive disorder (OCD) is well studied. However, the correlation between OC presentations and autonomic nervous system (ANS) is still unclear. Furthermore, whether the correlation might be modulated by serotonin is also uncertain. Methods: We recruited eighty-nine healthy subjects. Serotonin transporter (SERT) availability by [ 123 I]ADAM and heart rate variability (HRV) tests were measured. Symptoms checklist-90 was measured for the OC presentations. The interaction between HRV and SERT availability were calculated and the correlation between HRV and OC symptoms were analyzed after stratified SERT level into two groups, split at medium. Results: The interactions were significant in the factors of low frequency (LF), high frequency (HF), and root mean square of successive differences (RMSSD). Furthermore, the significantly negative correlations between OC symptoms and the above HRV indexes existed only in subjects with higher SERT availability. Conclusion OC symptoms might be correlated with ANS regulations in subjects with higher SERT availability.

Objective: The characteristics of patients with metachronous breast and ovarian malignancies and the pathogenic role of BRCA1/2 mutations remain poorly understood. We investigated these issues through a review of hospital records and nationwide Taiwanese registry data, followed by BRCA1/2 mutation analysis in hospital-based cases. Methods: We retrospectively retrieved consecutive clinical records of Taiwanese patients who presented with these malignancies to our hospital between 2001 and 2017. We also collected information from the Data Science Center of the Taiwan Cancer Registry (TCR) between 2007 and 2015. Next-generation sequencing and multiplex ligation-dependent probe amplification were used to identify BRCA1/2 mutations and large genomic rearrangements, respectively. When BRCA1/2 mutations were identified in index cases, pedigrees were reconstructed and genetic testing was offered to family members. Results: A total of 12,769 patients with breast cancer and 1,537 with ovarian cancer were retrieved from our hospital records. Of them, 28 had metachronous breast and ovarian malignancies. We also identified 113 cases from the TCR dataset. Eighteen hospital-based cases underwent BRCA1/2 sequencing and germline pathogenic mutations were detected in 7 patients (38.9%, 5 in BRCA1 and 2 in BRCA2). All BRCA1/2 mutation carriers had ovarian high-grade serous carcinomas. Of the 12 patients who were alive at the time of analysis, 5 were BRCA1/2 mutation carriers. All of them had family members with BRCA1/2-associated malignancies. Conclusions Our results provide pilot evidence that BRCA1/2 mutations are common in Taiwanese patients with metachronous breast and ovarian malignancies, supporting the clinical utility of genetic counseling.

The impact the metabolic syndrome (MetS) components on the severity of insulin resistance (IR) has not been reported. We enrolled 564 subjects with MetS and they were divided into quartiles according to the level of each component; and an insulin suppression test was performed to measure IR. In males, steady state plasma glucose (SSPG) levels in the highest quartiles, corresponding to body mass index (BMI) and fasting plasma glucose (FPG), were higher than the other three quartiles and the highest quartiles, corresponding to the diastolic blood pressure and triglycerides, were higher than in the lowest two quartiles. In females, SSPG levels in the highest quartiles, corresponding to the BMI and triglycerides, were higher than in all other quartiles. No significant differences existed between genders, other than the mean SSPG levels in males were greater in the highest quartile corresponding to BMI than that in the highest quartile corresponding to HDL-cholesterol levels. The factor analysis identified two underlying factors (IR and blood pressure factors) among the MetS variables. The clustering of the SSPG, BMI, triglyceride and HDLcholesterol was noted. Our data suggest that adiposity, higher FPG and triglyceride levels have stronger correlation with IR and subjects with the highest BMI have the highest IR.
Waist-Hip Ratio ; Triglycerides/blood ; Middle Aged ; Metabolic Syndrome X/*metabolism ; Male ; *Insulin Resistance ; Humans ; Female ; Fasting/blood ; Cholesterol, HDL/blood ; Body Mass Index ; Blood Glucose/analysis ; Aged ; Adult

Objective: To quantitatively assess the pulmonary vasculature using non-contrast computed tomography (CT) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) pre- and post-treatment and correlate CT-based parameters with right heart catheterization (RHC) hemodynamic and clinical parameters. Materials and Methods: A total of 30 patients with CTEPH (mean age, 57.9 years; 53% female) who received multimodal treatment, including riociguat for ≥ 16 weeks with or without balloon pulmonary angioplasty and underwent both noncontrast CT for pulmonary vasculature analysis and RHC pre- and post-treatment were included. The radiographic analysis included subpleural perfusion parameters, including blood volume in small vessels with a cross-sectional area ≤ 5 mm 2 (BV5) and total blood vessel volume (TBV) in the lungs. The RHC parameters included mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR), and cardiac index (CI). Clinical parameters included the World Health Organization (WHO) functional class and 6-minute walking distance (6MWD). Results: The number, area, and density of the subpleural small vessels increased after treatment by 35.7% (P < 0.001), 13.3% (P = 0.028), and 39.3% (P < 0.001), respectively. The blood volume shifted from larger to smaller vessels, as indicated by an 11.3% increase in the BV5/TBV ratio (P = 0.042). The BV5/TBV ratio was negatively correlated with PVR (r = -0.26; P = 0.035) and positively correlated with CI (r = 0.33; P = 0.009). The percent change across treatment in the BV5/TBV ratio correlated with the percent change in mPAP (r = -0.56; P = 0.001), PVR (r = -0.64; P < 0.001), and CI (r = 0.28; P = 0.049).Furthermore, the BV5/TBV ratio was inversely associated with the WHO functional classes I–IV (P = 0.004) and positively associated with 6MWD (P = 0.013). Conclusion Non-contrast CT measures could quantitatively assess changes in the pulmonary vasculature in response to treatment and were correlated with hemodynamic and clinical parameters.

PURPOSE: The main objective of this study was to investigate the relationship among the clinical characteristics and the frequency of T790M mutation in advanced epidermal growth factor receptor (EGFR)–mutant lung adenocarcinoma patients with acquired resistance after firstline EGFR–tyrosine kinase inhibitor (TKI) treatment. MATERIALS AND METHODS: We enrolled EGFR-mutant stage IIIB-IV lung adenocarcinoma patients, who had progressed to prior EGFR-TKI therapy, and evaluated their rebiopsy EGFR mutation status. RESULTS: A total of 205 patients were enrolled for analysis. The overall T790M mutation rate of rebiopsy was 46.3%. The T790M mutation rates among patients with exon 19 deletion mutation, exon 21 L858R point mutation, and other mutations were 55.0%, 37.3%, and 27.3%, respectively. Baseline exon 19 deletion was associated with a significantly higher frequency of T790M mutation (adjusted odds ratio, 2.14; 95% confidence interval [CI], 1.20 to 3.83; p=0.010). In the exon 19 deletion subgroup, there was a greater prevalence of T790M mutation than other exon 19 deletion subtypes in patients with the Del E746-A750 mutation (61.6% vs. 40.6%; odds ratio, 2.35; 95% CI, 1.01 to 5.49; p=0.049). The progression-free survival (PFS) of first-line TKI treatment > 11 months was also associated with a higher T790M mutation rate (54.1% vs. 39.3%; adjusted odds ratio, 1.82; 95% CI, 1.02 to 3.25; p=0.044). Patients who underwent rebiopsy at metastatic sites had more chance to harbor T790M mutation (52.6% vs. 33.8%; adjusted odds ratio, 1.97; 95% CI, 1.06 to 3.67; p=0.032). CONCLUSION: PFS of first-line EGFR-TKI, rebiopsy site, EGFR exon 19 deletion and its subtype Del E746-A750 mutation are associated with the frequency of T790M mutation.
Adenocarcinoma* ; Disease-Free Survival ; Epidermal Growth Factor* ; Exons ; Humans ; Lung Neoplasms ; Lung* ; Mutation Rate ; Odds Ratio ; Phosphotransferases ; Point Mutation ; Prevalence ; Receptor, Epidermal Growth Factor* ; Sequence Deletion

Background/Aims: Despite the high efficacy of direct-acting antivirals (DAAs), approximately 1–3% of hepatitis C virus (HCV) patients fail to achieve a sustained virological response. We conducted a nationwide study to investigate risk factors associated with DAA treatment failure. Machine-learning algorithms have been applied to discriminate subjects who may fail to respond to DAA therapy. Methods: We analyzed the Taiwan HCV Registry Program database to explore predictors of DAA failure in HCV patients. Fifty-five host and virological features were assessed using multivariate logistic regression, decision tree, random forest, eXtreme Gradient Boosting (XGBoost), and artificial neural network. The primary outcome was undetectable HCV RNA at 12 weeks after the end of treatment. Results: The training (n=23,955) and validation (n=10,346) datasets had similar baseline demographics, with an overall DAA failure rate of 1.6% (n=538). Multivariate logistic regression analysis revealed that liver cirrhosis, hepatocellular carcinoma, poor DAA adherence, and higher hemoglobin A1c were significantly associated with virological failure. XGBoost outperformed the other algorithms and logistic regression models, with an area under the receiver operating characteristic curve of 1.000 in the training dataset and 0.803 in the validation dataset. The top five predictors of treatment failure were HCV RNA, body mass index, α-fetoprotein, platelets, and FIB-4 index. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the XGBoost model (cutoff value=0.5) were 99.5%, 69.7%, 99.9%, 97.4%, and 99.5%, respectively, for the entire dataset. Conclusions Machine learning algorithms effectively provide risk stratification for DAA failure and additional information on the factors associated with DAA failure.