Effects of air pollution on moderate and severe asthma exacerbations.

Background: Few studies have evaluated the impact of air pollution levels on the severity of exacerbations. Thus, we compared the relative risks posed by air pollutant levels on moderate and severe exacerbations.Methods: Exacerbation episodes of 618 from 143 adult asthmatics were retrospectively collected between 2005 and 2015 in a tertiary hospital of Korea. Air pollution GPS data for the location closest to each patient's home were obtained from the national ambient monitoring station. The relative impacts of air pollutants on asthma exacerbations were evaluated via a time-trend controlled symmetrical, bidirectional, case-crossover design using conditional logistic regression models on the day of the exacerbation (T-0) and up to 3 days before the exacerbation (T-1-T-3).Results: Overall asthma exacerbation were associated with O3 levels in summer and winter (OR: 1.012[1.003-1.02] and 1.009[1.003-1.016]), SO2 levels in spring and summer (OR: 1.009[1-1.018] and 1.02[1.006-1.035]) and NO2 levels in winter (OR: 1.007[1.003-1.011]). Analyses of the temporal relationship between O3 concentrations and exacerbations demonstrated that 63.2% of episodes in the summer occurred when the O3 concentrations on T-1 were significantly higher than those on control days, while 51% of exacerbation episodes in the winter occurred. Severe and moderate exacerbations were similarly associated with O3 levels in winter (OR: 1.012 [1.003-1.02] vs. 1.01 [0.999-1.021], p > 0.05) and in summer (OR: 1.006 [1.002-1.009] vs. 1.009 [1.003-1.016], p > 0.05).Conclusions: Asthma exacerbations may be associated with the seasonal elevation of O3, SO2 and NO2 levels in summer and winter with the similar relative risk between moderate and severe exacerbations.

Association between TAAR6 polymorphisms and airway responsiveness to inhaled corticosteroids in asthmatic patients.

BACKGROUND: Genetic polymorphisms may be responsible for the wide variation in response to inhaled corticosteroids in asthmatic patients. We had previously reported that one polymorphism rs7772821, located on the 3'-UTR of trace amine-associated receptor 6 (TAAR6), is significantly associated with percentile changes in the forced expiratory volume in 1 s (%ΔFEV1) after inhaled corticosteroid treatment in asthmatics using a genome-wide association study. The aim of the present study was to validate the association between 15 single-nucleotide polymorphisms (SNPs) on the TAAR6 and airway responsiveness to inhaled corticosteroids in the asthmatics. METHODS: The %ΔFEV1 induced by 4 weeks' treatment with inhaled fluticasone propionate (1000 µg daily) was measured in 246 asthmatics. The 15 SNPs of TAAR6 were genotyped using a TaqMan assay. An association analysis between %ΔFEV1 and TAAR6 polymorphisms was carried out using a linear regression model controlling for age, sex, smoking status, presence of atopy, and baseline FEV1 as covariates. RESULTS: Among the 15 SNPs and seven haplotypes of TAAR6, rs7772821 (T>G) on the 3'-UTR showed the strongest correlation with inhaled corticosteroid-induced %ΔFEV1 (Pcorr=0.002 in the codominant model, Pcorr=0.03 in the dominant model, Pcorr=0.01 in the recessive model). The %ΔFEV1 of the rs7772821T>G minor homozygotes (60.77%) was higher than that of patients harboring either the rs7772821 T/G or T/T genotypes (21.32 and 31.60%, respectively). CONCLUSION: The TAAR6 rs7772821 polymorphism may be one of the important genetic factors for predicting the response to treatment with inhaled corticosteroids in asthmatics.

Genome wide identification and expression profile in epithelial cells exposed to TiO2 particles.

Environmental particles are believed to provoke airway inflammation in susceptible individuals by stimulating epithelial cells to release mediators that exacerbate lung diseases. Here, we sought to identify genes expressed throughout the genome by epithelial cells stimulated with TiO2 particles. A human bronchial epithelial cell line, BEAS-2B, was stimulated with or without 40 µg TiO2 for 2 h. RNA was purified from cells and subjected to microarray analysis. Genes exhibiting more than a twofold change in RNA expression were selected. Candidate genes were then analyzed using bioinformatics tools, including pathway, ontology, and network analyses. ITGAV mRNA expression levels were measured in BEAS-2B cells using real-time polymerase chain reaction. Among 37,803 genes, 92 genes displayed more than a twofold change in mRNA levels according to the microarray analysis; 87 genes were upregulated while five genes were downregulated. The 92 genes were classified based on functional annotation using a protein information resource database search for biological processes and a pathway search using the KEGG pathway database. These genes are related to macromolecule biosynthesis, metabolic processes and, in particular, RNA metabolism. When genes with more than a threefold change were analyzed, KIF11, ITGAV, SEMA3C, IBTK, and DEK were selected as candidate genes induced by TiO2 -stimulated BEAS-2B cells. To validate these results, BEAS-2B cells stimulated with 40 µg TiO2 expressed threefold higher ITGAV mRNA levels compared to those without TiO2 particle stimulation. We conclude that KIF11, ITGAV, SEMA3C, IBTK, and DEK are candidate genes expressed by epithelial cells when stimulated with TiO2 particles.

Percutaneous absorption, disposition, and exposure assessment of homosalate, a UV filtering agent, in rats.

Homosalate (HMS) is an ultraviolet (UV) filtering agent used in sunscreens and other cosmetics for skin protection purposes. Despite the widespread use of these products, absorption, disposition, and in vivo endocrine disrupting potential of HMS have not been characterized. Thus, the aim of this study was to examine the percutaneous absorption, disposition, and exposure assessment of HMS in rats. Initially, sunscreen preparations of petrolatum jelly, oily solution, lotion, and gel were prepared and evaluated for in vitro permeation of HMS across excised rat skin. Dermal permeability was greatest for gel, and this preparation was used in subsequent in vivo topical application investigations. After iv injection (0.5, 2, or 5 mg/kg), the pharmacokinetics of HMS was linear and was characterized by a large Vd(ss) (13.2-17 L/kg), high Cl(s) (4.5-6.1 L/h/kg), and long t½ (6.1-8.4 h). After topical application of gel, the bioavailability of HMS was 5.4 ± 1.1 and 4.2 ± 0.6% for high and low doses (10 and 20 mg), respectively. Consistent with the prolonged absorption (Tmax 11.2 ± 1.8 and 12 ± 0 h for low and high doses, respectively), the terminal t½ was longer after topical application (23.6-26.1 h) compared to iv injection. A population pharmacokinetic model was further developed to simultaneously fit the time courses of plasma concentrations and dermal content data after iv injection and topical application. Findings of this study may be useful to further examine the relationship between exposure and endocrine disrupting potential of HMS in risk assessment.

Accelerometer-derived physical activity and sedentary behavior patterns among Korean adults.

PURPOSE: This study aimed to provide an overview of accelerometer-derived physical activity (PA) and sedentary behavior (SB) patterns among Korean adults. We also investigated the association between participant characteristics and the likelihood of adherence to moderate-to-vigorous physical activity (MVPA), SB, and the MVPA-SB guidelines. METHODS: Data from the 2014-2017 Korea National Health and Nutrition Examination Survey were used. The study involved a nationally representative sample of 2,260 Korean adults aged ≥20 years. Accelerometers were used to measure PA and SB for seven days. Multivariate logistic regression models were used to assess the association between the participant characteristics and the likelihood of adhering to the MVPA, SB, and MVPA-SB guidelines. RESULTS: SB (60.61%), light intensity (26.22%), and lifestyle activities (9.4%) accounted for the majority of the participants' days. MVPA and vigorous physical activity (VPA) accounted for 3.72% and 0.06% of the days, respectively. The MVPA guidelines were more likely to be adhered to by men, older adults, participants with higher education, non-smokers, and individuals without multimorbidity. Participants with higher education and household income were less likely to adhere to the SB guidelines. Women (OR=0.51), participants with high education levels (OR=0.54), current smokers (OR=0.47), and patients with multimorbidity (OR=0.46) were less likely to adhere to the MVPA-SB guidelines. CONCLUSION: This study found that participants were predominantly sedentary, with only a small proportion engaging in VPA. There were differences related to demographic factors and health status. Most Korean adults do not adhere to the recommended MVPA-SB guidelines, and that is a serious public health concern. These findings highlight the need to promote PA and reduce SB through public health policies and interventions, particularly for adults facing PA barriers.

Implication of TIPE2 Expression on the Malignant Transformation of Oral Leukoplakia.

BACKGROUND/AIM: Identification of biomarkers involved in the malignant transformation of oral leukoplakia (OL) is required for the early diagnosis and management of patients with OL. This study aimed to evaluate the functions of tumor necrosis factor-alpha-induced protein 8-like 2 (TIPE2) expression in the malignant transformation of OL. MATERIALS AND METHODS: The expression levels of TIPE2 and dormant cell markers phospho-ERK and phospho-p38 in a cohort containing 103 surgical specimens from patients with OL were evaluated using immunohistochemistry. The influence of TIPE2 expression on the biological behavior of the immortalized human oral keratinocyte (IHOK) line was investigated in vitro. RESULTS: Increased TIPE2 expression was detected in 40 (38.8%) patients with OL. In a multivariate analysis using clinicopathological variables and TIPE2 expression as cofactors, the presence of dysplasia (p=0.003) and TIPE2 abundance (p=0.019) were identified as independent risk factors for the malignant transformation of OL. Moreover, the in vitro analysis revealed that TIPE2 knockdown can promote the proliferating ability of IHOK; however, the number of apoptotic cells also increased after TIPE2 knockdown in IHOK. Furthermore, TIPE2 expression was significantly associated with phospho-p38 expression, a dormant cell marker, in our cohort (p=0.047). CONCLUSION: TIPE2 expression may contribute to the malignant transformation of OL, and its function may be related to cellular dormancy in OL pathogenesis.

Robot-assisted radial forearm free flap harvesting: a propensity score-matched case-control study.

Although some surgeons prefer anterolateral thigh and latissimus dorsi flap for soft tissue reconstruction in the head and neck area because it minimizes donor site complications, the radial forearm flap remains the workhorse for soft tissue reconstruction due to its reliability. To reduce donor site morbidity, the authors developed a novel technique for radial forearm flap harvesting using a robotic device. 42 radial forearm free flap reconstruction cases were studied, consisting of 31 conventional and 11 robot-assisted cases. 1:1 propensity score matching was done according to age, sex, previous and postoperative radiation therapy history and method used for vein anastomosis. There was no significant difference in flap outcome, which was 100% vitality in the robot-assisted group and 90.9% vitality in the conventional group. The robot-assisted group showed significantly longer mean harvesting time than did the conventional group, being 107.2 min and 67.0 min, respectively. Robot-assisted radial forearm flap harvesting can reduce donor site complications by minimizing incision. When more surgical experience is gained under appropriate case selection, we expect our robot-assisted method will yield a harvesting time similar to that of the conventional method and thus become more reliable and feasible.

Association between WDR21A polymorphisms and airway responsiveness to inhaled corticosteroids in asthmatic patients.

OBJECTIVE: Genetic polymorphism is partially responsible for the wide variation in the response of moderate-to-severe asthmatic patients to inhaled corticosteroids. The goal of the study was to examine polymorphisms in WDR21A, which encodes a putative glucocorticoid receptor (GR)-interacting protein, for their possible association with corticosteroid responsiveness. METHODS: The change in forced expiratory volume in 1 s [FEV(1) (ΔFEV(1))] induced by 4 weeks of inhaled treatment with fluticasone propionate (1000 µg daily) was measured in 230 asthmatic patients. Fifteen single nucleotide polymorphisms (SNPs) of WDR21A were genotyped using a TaqMan assay, and 11 SNPs were used for further analysis. WDR21A transcripts were analyzed for variant splicing using reverse transcriptase-PCR. The WDR21A protein structure was predicted using a template-based modeling method and docked to a GR using Zdock. RESULTS: Of the 11 SNPs and three haplotypes of WDR21A analyzed, only the intronic SNP -10073G>C appeared to affect ΔFEV(1). The ΔFEV(1) of the -10073C/C homozygous genotype was twice that of the -10073G/G and -10073C/G genotypes (P(corr)=0.04 in recessive model). No splicing variant of WDR21A was observed, regardless of genotype. The predicted WDR21A protein structure was similar to the Gß(1) protein structure (template modeling-score=0.93). CONCLUSION: The minor allele -10073C of WDR21A may induce a good response to inhaled corticosteroids possibly through competition with the Gß(1) proteins for binding to GRs.

Determination and pharmacokinetics of [6]-gingerol in mouse plasma by liquid chromatography-tandem mass spectrometry.

This study describes the development of a rapid and sensitive high-performance liquid chromatography-electrospray ionization tandem mass spectrometry (LC-MS/MS) assay for the quantification of [6]-gingerol in mouse plasma and application to a pharmacokinetic study after dose ranging in mice. The assay involved a protein precipitation step with acetonitrile and an isocratic elution using a mobile phase consisting of acetonitrile and water containing 0.1% formic acid (80:20 v/v). The multiple reaction monitoring was based on the transition of m/z = 277.2 → 177.1 for [6]-gingerol and 294.2 → 137.1 for nonivamide (internal standard). The assay was validated to demonstrate the specificity, linearity, recovery, accuracy, precision and stability. The calibration curves were linear over the wide concentration range of 10-10,000 ng/mL (r ≥ 0.9988). The lower limit of quantification was 10 ng/mL using a small volume of mouse plasma (20 µL). The method was successfully applied to a pharmacokinetic study in mice after intravenous injection of [6]-gingerol at 1.5, 3 and 6 mg/kg doses. The pharmacokinetics of [6]-gingerol were linear over the dose range studied as demonstrated by the linear increase in area under the concentration-time curve (AUC(inf)) with no significant change in the systemic clearance (Cl(s)), volume of distribution (V(ss)) and elimination half-life (t(1/2)) as a function of dose.

Noma disease (cancrum oris, orofacial gangrene) in an acute myeloid leukemia patient: a case report.

BACKGROUND: Noma is a rare disease that occurs mainly in malnourished patients in developing countries. Noma starts as facial swelling and gingival necrosis that eventually necrotizes underlying tissues including the jaw bone, leaving severe disfigurement. It is reported extremely rarely in patients with severe immunosuppression or blood dyscrasia. CASE PRESENTATION: The gingivitis that occurred in a 12-year-old Asian female patient with acute myeloid leukemia was getting increasingly worse. Although the proper treatment was done, the patient's condition did not improve, and eventually, a large full-thickness defect was left in the maxillofacial part. CONCLUSIONS: Early diagnosis and management is the only way to prevent the progression, which leads to facial disfigurement. We present a case of noma in a pediatric acute myeloid leukemia patient, in which oral function was restored through surgical intervention.

Enhanced hypothalamic leptin signaling in mice lacking dopamine D2 receptors.

The dopamine D(2) receptor (D2R) plays a critical role in diverse neurophysiological functions. D2R knock-out mice (D2R(-/-)) show reduced food intake and body weight while displaying an increased basal energy expenditure level, compared with their wild type littermates. Thus, these mice show a lean phenotype. D2R(-/-) mice displayed increased leptin sensitivity, and leptin injection induced increased phosphorylation of the hypothalamic signal transducer and activator of transcription 3 (STAT3) in D2R(-/-) mice relative to wild type littermates. Using double immunofluorescence histochemistry, we have demonstrated that D2Rs are present in leptin-sensitive STAT3-positive cells in the arcuate nucleus of the hypothalamus and that leptin injection induces STAT3 phosphorylation in hypothalamic neurons expressing D2Rs. Stimulation of D2R by the D2R agonist quinpirole suppressed the leptin-induced STAT3 phosphorylation and nuclear trans-localization of phospho-STAT3 in the hypothalamus of wild type mice. However, this regulation was not detected in the D2R(-/-) mice. Treatment of D2R agonist and antagonist could modulate the leptin-induced food intake and body weight changes in wild type mice but not in D2R(-/-) mice. Together, our findings suggest that the interaction between the dopaminergic system and leptin signaling in hypothalamus is important in control of energy homeostasis.

A domain-level DNA strand displacement reaction enumerator allowing arbitrary non-pseudoknotted secondary structures.

Information technologies enable programmers and engineers to design and synthesize systems of startling complexity that nonetheless behave as intended. This mastery of complexity is made possible by a hierarchy of formal abstractions that span from high-level programming languages down to low-level implementation specifications, with rigorous connections between the levels. DNA nanotechnology presents us with a new molecular information technology whose potential has not yet been fully unlocked in this way. Developing an effective hierarchy of abstractions may be critical for increasing the complexity of programmable DNA systems. Here, we build on prior practice to provide a new formalization of 'domain-level' representations of DNA strand displacement systems that has a natural connection to nucleic acid biophysics while still being suitable for formal analysis. Enumeration of unimolecular and bimolecular reactions provides a semantics for programmable molecular interactions, with kinetics given by an approximate biophysical model. Reaction condensation provides a tractable simplification of the detailed reactions that respects overall kinetic properties. The applicability and accuracy of the model is evaluated across a wide range of engineered DNA strand displacement systems. Thus, our work can serve as an interface between lower-level DNA models that operate at the nucleotide sequence level, and high-level chemical reaction network models that operate at the level of interactions between abstract species.

Three-dimensional evaluation of the correlation between lip canting and craniofacial planes.

OBJECTIVE: This study aimed to analyze the correlation of horizontal and sagittal planes used in two-dimensional diagnosis with lip canting by using threedimensional (3D) analysis. METHODS: Fifty-two patients (25 men, 27 women; average age: 24 years) undergoing treatment for dentofacial deformity were enrolled. Computed tomography images were acquired, and digital imaging and communication in medicine files were reconstructed into a 3D virtual model wherein horizontal and sagittal craniofacial planes were measured. Subsequently, the correlations of lip canting with these horizontal and sagittal planes were investigated. RESULTS: The mandibular symmetry plane, the occlusal plane, Camper's plane, the mandibular plane, Broadbent's plane, and the nasal axis plane were correlated with the amount of lip canting (Pearson's correlation coefficients: 0.761, 0.648, 0.556, 0.526, 0.438, and 0.406, respectively). Planes associated with the lower part of the face showed the strongest correlations; the strength of the correlations decreased in the midfacial and cranial regions. None of the planes showed statistically significant differences between patients with clinical lip canting (> 3°) and those without prominent lip canting. CONCLUSIONS: The findings of this study suggest that lip canting is strongly correlated with the mandibular symmetry plane, which includes menton deviation. This finding may have clinical implications with regard to the treatment of patients requiring correction of lip canting. Further studies are necessary for evaluating changes in lip canting after orthognathic surgery.

Global DNA Methylation Pattern of Fibroblasts in Idiopathic Pulmonary Fibrosis.

Our previous transcriptome study of cultured fibroblasts identified 178 genes that were differentially expressed by 8 idiopathic pulmonary fibrosis (IPF) fibroblasts compared with 4 controls. Here, we performed genome-wide DNA methylation analysis to evaluate the relationship of CpG methylation to differential gene expression. Among 485,577 loci, 5850 loci on 2282 genes showed significant differences between the 2 groups (delta-beta >10.21 and p-value <0.05). Among these, beta values of 80 CpGs (30 hypermethylated and 50 hypomethylated) were significantly correlated with mRNA expression of 34 genes (19.1%) of the 178 differentially expressed genes between the 2 groups (13 downregulated and 21 upregulated). Gene ontology enrichment of these genes included cell adhesion, molecule binding, chemical homeostasis, surfactant homeostasis, and receptor binding. One-third of them are involved in the known process of fibrosis; the others are novel genes with respect to pulmonary fibrosis. We identified relationships between the altered DNA methylation levels and about one-fifth of the corresponding changes in gene expression by lung tissue fibroblasts. Findings from this study provide new information on novel genes responsible for the pathogenesis of IPF under the control of CpG methylation changes in IPF lungs.

Association of Genetic Variants of NLRP4 with Exacerbation of Asthma: The Effect of Smoking.

Asthma exacerbation is induced by the interaction of genes and environmental factors such as cigarette smoke. NLRP4 counteracts the activity of the inflammasome, which is responsible for asthma exacerbation. In this study, we analyzed the association of single-nucleotide polymorphisms of NLRP4 with the annual rate of exacerbation and evaluated the additive effect of smoking in 1454 asthmatics. Asthmatics possessing the minor allele of rs1696718G > A had more frequent exacerbation episodes than those homozygous for the common allele (0.59 vs. 0.36/year) and the association was present only in current and ex-smokers. There was a significant interaction between the amount smoked and rs16986718 genotypes (p = 0.014) and a positive correlation between the number of annual exacerbation episodes and amount smoked only in rs16986718G > A AA homozygotes. The prevalence of frequent exacerbators (≥2 exacerbation episodes/year) was 2.5 times higher in rs16986718G > A minor allele homozygotes than in common allele homozygotes (12.0% vs. 5.9%). Furthermore, the prevalence was 6 times higher in rs16986718G > A minor allele homozygotes who were current and ex-smokers than in nonsmokers (25.6% vs. 4.1%). The minor allele of rs16986718G > A in NLRP4 may be a genetic marker that predicts asthma exacerbation in adult asthmatics who smoke.

Role of third intracellular loop of the melanocortin 4 receptor in the regulation of constitutive activity.

The melanocortin 4 receptor (MC4R) has been reported to display constitutive activity, which is probably relevant to the maintenance of a normal energy balance. Among the clinically reported mutants of MC4R in human obesity patients, we investigated the functional characteristics of seven mutants characterized by mutations in the third intracellular (i3) loop of MC4R. Via a CRE (cAMP responsive element)-mediated luciferase reporter gene assay, we show that most of these mutants displayed significantly reduced basal activity with reduced reporter gene activity, whereas the P230L mutant manifested significantly increased basal activity. When the dominant negative G(s) mutant was co-expressed, the majority of the mutants, including the P230L mutant, showed reduced basal activity. These results suggest that the i3 loop of MC4R is essential not only for the functional activity but also for the regulation and maintenance of an optimal constitutive activity of MC4R in association with G protein coupling, in the control of energy homeostasis.

Glucose-regulated protein 78 binds to and regulates the melanocortin-4 receptor.

The melanocortin-4 receptor (MC4R) belongs to the G protein-coupled receptor (GPCR) family and plays an essential role in the control of energy homeostasis. Here, we identified a novel MC4R-interacting protein, glucose-regulated protein 78 (GRP78), from a pulldown assay using hypothalamic protein extracts and the third intracellular loop of MC4R. We found that MC4R interacted with GRP78 in both the cytosol and at the cell surface and that this interaction increased when MC4R was internalized in the presence of the agonist melanotan-II (MTII). Downregulation of GRP78 using a short interfering RNA approach attenuated MTII-mediated receptor internalization. Reduction in GRP78 expression during tunicamycin-induced endoplasmic reticulum stress also suppressed MTII-mediated internalization of MC4R and cAMP-mediated transcriptional activity. Furthermore, lentiviral-mediated short hairpin RNA knockdown of endogenous GRP78 in the paraventricular nucleus (PVN) of the hypothalamus resulted in an increase in body weight in mice fed a high-fat diet. These results suggest that GRP78 in the PVN binds to MC4R and may have a chaperone-like role in the regulation of MC4R trafficking and signaling.

Lung Function Trajectory Types in Never-Smoking Adults With Asthma: Clinical Features and Inflammatory Patterns.

PURPOSE: Asthma is a heterogeneous disease that responds to medications to varying degrees. Cluster analyses have identified several phenotypes and variables related to fixed airway obstruction; however, few longitudinal studies of lung function have been performed on adult asthmatics. We investigated clinical, demographic, and inflammatory factors related to persistent airflow limitation based on lung function trajectories over 1 year. METHODS: Serial post-bronchodilator forced expiratory volume (FEV) 1% values were obtained from 1,679 asthmatics who were followed up every 3 months for 1 year. First, a hierarchical cluster analysis was performed using Ward's method to generate a dendrogram for the optimum number of clusters using the complete post-FEV1 sets from 448 subjects. Then, a trajectory cluster analysis of serial post-FEV1 sets was performed using the k-means clustering for the longitudinal data trajectory method. Next, trajectory clustering for the serial post-FEV1 sets of a total of 1,679 asthmatics was performed after imputation of missing post-FEV1 values using regression methods. RESULTS: Trajectories 1 and 2 were associated with normal lung function during the study period, and trajectory 3 was associated with a reversal to normal of the moderately decreased baseline FEV1 within 3 months. Trajectories 4 and 5 were associated with severe asthma with a marked reduction in baseline FEV1. However, the FEV1 associated with trajectory 4 was increased at 3 months, whereas the FEV1 associated with trajectory 5 was persistently disturbed over 1 year. Compared with trajectory 4, trajectory 5 was associated with older asthmatics with less atopy, a lower immunoglobulin E (IgE) level, sputum neutrophilia and higher dosages of oral steroids. In contrast, trajectory 4 was associated with higher sputum and blood eosinophil counts and more frequent exacerbations. CONCLUSIONS: Trajectory clustering analysis of FEV1 identified 5 distinct types, representing well-preserved to severely decreased FEV1. Persistent airflow obstruction may be related to non-atopy, a low IgE level, and older age accompanied by neutrophilic inflammation and low baseline FEV1 levels.

Dextromethorphan attenuates trimethyltin-induced neurotoxicity via sigma1 receptor activation in rats.

We showed that dextromethorphan (DM) provides neuroprotective/anticonvulsant effects and that DM and its major metabolite, dextrorphan, have a high-affinity for sigma(1) receptors, but a low affinity for sigma(2) receptors. In addition, we found that DM has a higher affinity than DX for sigma(1) sites, whereas DX has a higher affinity than DM for PCP sites. We extend our earlier findings by showing that DM attenuated trimethyltin (TMT)-induced neurotoxicity (convulsions, hippocampal degeneration and spatial memory impairment) in rats. This attenuation was reversed by the sigma(1) receptor antagonist BD 1047, but not by the sigma(2) receptor antagonist ifenprodil. DM attenuates TMT-induced reduction in the sigma(1) receptor-like immunoreactivity of the rat hippocampus, this attenuation was blocked by the treatment with BD 1047, but not by ifenprodil. These results suggest that DM prevents TMT-induced neurotoxicity, at least in part, via sigma(1) receptor stimulation.

Clinical Characteristics of Exacerbation-Prone Adult Asthmatics Identified by Cluster Analysis.

PURPOSE: Asthma is a heterogeneous disease characterized by various types of airway inflammation and obstruction. Therefore, it is classified into several subphenotypes, such as early-onset atopic, obese non-eosinophilic, benign, and eosinophilic asthma, using cluster analysis. A number of asthmatics frequently experience exacerbation over a long-term follow-up period, but the exacerbation-prone subphenotype has rarely been evaluated by cluster analysis. This prompted us to identify clusters reflecting asthma exacerbation. METHODS: A uniform cluster analysis method was applied to 259 adult asthmatics who were regularly followed-up for over 1 year using 12 variables, selected on the basis of their contribution to asthma phenotypes. After clustering, clinical profiles and exacerbation rates during follow-up were compared among the clusters. RESULTS: Four subphenotypes were identified: cluster 1 was comprised of patients with early-onset atopic asthma with preserved lung function, cluster 2 late-onset non-atopic asthma with impaired lung function, cluster 3 early-onset atopic asthma with severely impaired lung function, and cluster 4 late-onset non-atopic asthma with well-preserved lung function. The patients in clusters 2 and 3 were identified as exacerbation-prone asthmatics, showing a higher risk of asthma exacerbation. CONCLUSIONS: Two different phenotypes of exacerbation-prone asthma were identified among Korean asthmatics using cluster analysis; both were characterized by impaired lung function, but the age at asthma onset and atopic status were different between the two.