Eosinophils arise from hematopoietic CD34+ stem cells in the bone marrow. They acquire IL-5Ralpha on their surface at a very early stage during eosinophilopoiesis, and differentiate under the strong influence of interleukin (IL)-5. They then exit to the bloodstream, and enter the lung upon exposure to airway inflammatory signals, including eotaxins. In inflamed tissues, eosinophils act as key mediators of terminal effector functions and innate immunity and in linking to adaptive immune responses. Transcription factors GATA-1, CCAAT/enhancer-binding protein, and PU.1 play instructive roles in eosinophil specification from multipotent stem cells through a network of cooperative and antagonistic interactions. Not surprisingly, the interplay of these transcription factors is instrumental in forming the regulatory circuit of expression of eosinophil-specific genes, encoding eosinophil major basic protein and neurotoxin, CC chemokine receptor 3 eotaxin receptor, and IL-5 receptor alpha. Interestingly, a common feature is that the critical cis-acting elements for these transcription factors are clustered in exon 1 and intron 1 of these genes rather than their promoters. Elucidation of the mechanism of eosinophil development and activation may lead to selective elimination of eosinophils in animals and human subjects. Furthermore, availability of a range of genetically modified mice lacking or overproducing eosinophil-specific genes will facilitate evaluation of the roles of eosinophils in the pathogenesis of asthma. This review summarizes eosinophil biology, focusing on development and regulation of eosinophil-specific genes, with a heavy emphasis on the causative link between eosinophils and pathological development of asthma using genetically modified mice as models of asthma.
Aluminum Hydroxide ; Animals ; Asthma ; Biology ; Bone Marrow ; Carbonates ; Eosinophil Major Basic Protein ; Eosinophils ; Exons ; Humans ; Immunity, Innate ; Interleukin-5 ; Interleukins ; Introns ; Lung ; Mice ; Multipotent Stem Cells ; Receptors, CCR3 ; Stem Cells ; Transcription Factors

Aspirin hypersensitivity is a hallmark of aspirin-exacerbated respiratory disease (AERD), a clinical syndrome characterized by the severe inflammation of the respiratory tract after ingestion of cyclooxygenase-1 inhibitors. We investigated the capacity of aspirin to induce interleukin-4 (IL-4) production in inflammatory cells relevant to AERD pathogenesis and examined the associated biochemical and molecular pathways. We also compared IL-4 production in peripheral blood mononuclear cells (PBMCs) from patients with AERD vs aspirin-tolerant asthma (ATA) upon exposure to aspirin. Aspirin induced IL-4 expression and activated the IL-4 promoter in a report assay. The capacity of aspirin to induce IL-4 expression correlated with its activity to activate mitogen-activated protein kinases, to form DNA-protein complexes on P elements in the IL-4 promoter and to synthesize nuclear factor of activated T cells, critical transcription factors for IL-4 transcription. Of clinical importance, aspirin upregulated IL-4 production twice as much in PBMCs from patients with AERD compared with PBMCs from patients with ATA. Our results suggest that IL-4 is an inflammatory component mediating intolerance reactions to aspirin, and thus is crucial for AERD pathogenesis.
Aspirin* ; Asthma ; Cyclooxygenase 1 ; Eating ; Humans ; Hypersensitivity ; Inflammation ; Interleukin-4* ; Mitogen-Activated Protein Kinases ; Negotiating ; Respiratory System ; T-Lymphocytes ; Transcription Factors

OBJECTIVE: To identify the right and left difference of the facial soft tissue landmarks three-dimensionally from the subjects of normal occlusion individuals. MATERIALS AND METHODS: Cone-beam computed tomography (CT) scans were obtained in 48 normal occlusion adults (24 men, 24 women), and reconstructed into 3-dimensional (3D) models by using a 3D image soft ware. 3D position of 27 soft tissue landmarks, 9 midline and 9 pairs of bilateral landmarks, were identified in 3D coordination system, and their right and left differences were calculated and analyzed. RESULTS: The right and left difference values derived from the study ranged from 0.6 to 4.6 mm indicating a high variability according to the landmarks. In general, the values showed a tendency to increase according to the lower and lateral positioning of the landmarks in the face. Overall differences were determined not only by transverse differences but also by sagittal and vertical differences, indicating that 3D evaluation would be essential in the facial soft tissue analysis. CONCLUSIONS: Means and standard deviations of the right and left difference of facial soft tissue landmarks derived from this study can be used as the diagnostic standard values for the evaluation of facial asymmetry.
Adult ; Cone-Beam Computed Tomography ; Facial Asymmetry ; Humans ; Male

OBJECTIVE: The purpose of this study was to evaluate the effectiveness of the use of Reference Ear Plug (REP) during cone-beam computed tomography (CBCT) scan for the generation of lateral cephalograms from CBCT scan data. METHODS: Two CBCT scans were obtained from 33 adults. One CBCT scan was acquired using conventional methods, and the other scan was acquired with the use of REP. Virtual lateral cephalograms created from each CBCT image were traced and compared with tracings of the real cephalograms obtained from the same subject. RESULTS: CBCT scan with REP resulted in a smaller discrepancy between real and virtual cephalograms. In comparing the real and virtual cephalograms, no measurements significantly differed from real cephalogram values in case of CBCT scan with REP, whereas many measurements significantly differed in the case of CBCT scan without REP. CONCLUSION: Measurements from CBCT-generated cephalograms are more similar to those from real cephalograms when REP are used during CBCT scan. Thus, the use of REP is suggested during CBCT scan to generate accurate virtual cephalograms from CBCT scan data.
Adult ; Cone-Beam Computed Tomography ; Ear ; Humans

OBJECTIVE: The purpose of the present study was to evaluate the effectiveness of the use of Head Posture Aligner (HPA) during cone-beam computed tomography (CBCT) scan in generation of frontal cephalograms using 3D CBCT images. METHODS: CBCT scans and frontal cephalograms were made in 30 adult individuals. While a couple of CBCT scan was made for one subject, one was made with conventional method, without use of HPA, the other was acquired with the use of HPA. After creation of virtual frontal cephalogram from each 3D CBCT image, it was traced and compared with the tracing of real frontal cephalogram. RESULTS: In the comparison of the measurements, the virtual cephalograms with the use of HPA did not show statistically significant differences with the real cephalograms whereas the virtual cephalograms without the use of HPA presented significant differences with real cephalograms in many measurements. In the correlation analysis with the measurements of the real cephalograms, the virtual cephalograms with the use of HPA showed higher correlations in all measurements than the virtual cephalograms without the use of HPA. CONCLUSIONS: Measurements from CBCT-generated cephalograms become similar to those from real cephalograms with the use of HPA during CBCT scan. Thus, the use of HPA is suggested during the CBCT scan in order to construct accurate virtual frontal cephalograms using 3D CBCT images.
Adult ; Cone-Beam Computed Tomography ; Head ; Humans ; Posture

DNA methylation may regulate gene expression by restricting the access of transcription factors. We have previously demonstrated that GATA-1 regulates the transcription of the CCR3 gene by dynamically interacting with both positively and negatively acting GATA elements of high affinity binding in the proximal promoter region including exon 1. Exon 1 has three CpG sites, two of which are positioned at the negatively acting GATA elements. We hypothesized that the methylation of these two CpGs sites might preclude GATA-1 binding to the negatively acting GATA elements and, as a result, increase the availability of GATA-1 to the positively acting GATA element, thereby contributing to an increase in GATA-1-mediated transcription of the gene. To this end, we determined the methylation of the three CpG sites by bisulfate pyrosequencing in peripheral blood eosinophils, cord blood (CB)-derived eosinophils, PBMCs, and cell lines that vary in CCR3 mRNA expression. Our results demonstrated that methylation of CpG sites at the negatively acting GATA elements severely reduced GATA-1 binding and augmented transcription activity in vitro. In agreement, methylation of these CpG sites positively correlated with CCR3 mRNA expression in the primary cells and cell lines examined. Interestingly, methylation patterns of these three CpG sites in CB-derived eosinophils mostly resembled those in peripheral blood eosinophils. These results suggest that methylation of CpG sites at the GATA elements in the regulatory regions fine-tunes CCR3 transcription.
Binding Sites ; Cell Line ; *CpG Islands ; DNA Methylation ; Enhancer Elements, Genetic ; Eosinophils/cytology/*metabolism ; Exons ; Fetal Blood/cytology/metabolism ; GATA1 Transcription Factor/*genetics/metabolism ; Gene Expression Regulation ; Humans ; Promoter Regions, Genetic ; RNA, Messenger/metabolism ; Receptors, CCR3/*genetics/metabolism ; Sequence Analysis, DNA ; *Transcription, Genetic

BACKGROUND AND OBJECTIVES: Despite significant advances in the treatment of acute myocardial infarction (MI), the prevention of sudden cardiac death (SCD), the most common mode of death in patients with MI, remains challenging. Furthermore, previous Korean MI registries did not address the issue of post-MI SCD. Additional risk stratifiers of post-MI SCD are still required to compensate for the limitation of using left ventricular ejection fraction to predict lethal arrhythmic events. SUBJECTS AND METHODS: We designed the first Korean prospective nationwide multicenter registry primarily focused on SCD; the Korean noninvasive Risk Evaluation study for sudden cardiac DEath From INfarction or heart failurE (K-REDEFINE). The registry consists of 2 groups of patients presenting with (1) acute MI or (2) acute heart failure (HF) at 25 tertiary referral cardiovascular centers. The primary endpoint of the MI group study of K-REDEFINE registry is the incidence and risk factors of post-MI SCD. In particular, the association between the risk of SCD and non-invasive Holter-based electrocardiogram (ECG) variables will be evaluated, such as T-wave alternans (marker of repolarization heterogeneity) and heart rate turbulence/variability (a marker of autonomic function). Other secondary study outcomes include atrioventricular arrhythmias, HF-related admission, repeated myocardial ischemic events, stroke, and overall deaths. CONCLUSION AND PERSPECTIVE: The K-REDEFINE registry will provide new prospects for the better management of MI patients with high risk of SCD by clarifying the burden and predictors of SCD and the clinical utility of various non-invasive ambulatory ECG-based variables in risk stratification for SCD in this patient population.
Arrhythmias, Cardiac ; Death, Sudden, Cardiac* ; Electrocardiography ; Heart Failure* ; Heart Rate ; Heart* ; Humans ; Incidence ; Infarction* ; Myocardial Infarction* ; Prospective Studies ; Referral and Consultation ; Registries ; Risk Factors ; Stroke ; Stroke Volume

BACKGROUND AND OBJECTIVES: Sudden cardiac death (SCD) is one of the most common causes of death in patients with heart failure (HF). However, there are no available data on SCD in previous Korean HF registries. Additionally, although widely used, the utility of left ventricular (LV) ejection fraction (EF) in risk stratification for SCD is limited. SUBJECTS AND METHODS: The Korean non-invasive Risk Evaluation study for sudden cardiac DEath From INfarction or heart failurE (KREDEFINE) is the first Korean prospective, nationwide multicenter registry, primarily focused on SCD. The registry consists of 2 groups of patients presenting with (1) acute HF or (2) acute myocardial infarction (MI) at 25 tertiary referral cardiovascular centers. Using the HF-group data of the K-REDEFINE registry, the incidence and risk factors of SCD in patients with HF will be assessed. In particular, the efficacy of Holter-based ECG variables, such as T-wave alternans (marker of repolarization heterogeneity) and heart rate turbulence/ variability (maker of autonomic function), in risk stratification for SCD will be evaluated. Other cardiovascular outcomes will also be analyzed, including atrioventricular arrhythmias, HF-related admission, stroke, and overall deaths. CONCLUSION AND PERSPECTIVE: The K-REDEFINE registry will pave the way for better management of patients with HF at high risk of SCD by elucidating the burden and risk factors of SCD and the clinical utility of various non-invasive ambulatory ECG-based parameters in risk stratification for SCD in this patient population.
Arrhythmias, Cardiac ; Cause of Death ; Death, Sudden, Cardiac* ; Electrocardiography ; Heart Failure* ; Heart Rate ; Heart* ; Humans ; Incidence ; Infarction* ; Myocardial Infarction ; Prospective Studies ; Referral and Consultation ; Registries ; Risk Factors ; Stroke