Aspirin Challenge-Induced Genome-Wide DNA Methylation Profile of Peripheral Blood Lymphocytes in Aspirin-Exacerbated Respiratory Disease.

Genetic variation and epigenetic factors are thought to contribute to the development of hypersensitivity to aspirin. DNA methylation fluctuates dynamically throughout the day. To discover new CpG methylation in lymphocytes associated with aspirin-exacerbated respiratory disease (AERD), we evaluated changes in global CpG methylation profiles from before to after an oral aspirin challenge in patients with AERD and aspirin-tolerant asthma (ATA). Whole-genome CpG methylation levels of peripheral blood mononuclear cells were quantified with an Illumina 860K Infinium Methylation EPIC BeadChip array and then adjusted for inferred lymphocyte fraction (ILF) with GLINT and Tensor Composition Analysis. Among the 866,091 CpGs in the array, differentially methylated CpGs (DMCs) were found in 6 CpGs in samples from all 12 patients with asthma included in the study (AERD, n = 6; ATA, n = 6). DMCs were found in 3 CpGs in the 6 ATA samples and in 615 CpGs in the 6 AERD samples. A total of 663 DMCs in 415 genes and 214 intergenic regions differed significantly in the AERD compared with the ATA. In promoters, 126 CpG loci were predicted to bind to 38 transcription factors (TFs), many of which were factors already known to be involved in the pathogenesis of asthma and immune responses. In conclusion, we identified 615 new CpGs methylated in peripheral blood lymphocytes by oral aspirin challenge in AERD but not in ATA. These findings indicate that oral aspirin challenge induces epigenetic changes in ILFs, specifically in AERD patients, possibly via changes in TF binding, which may have epigenetic effects on the development of AERD.

S100 Calcium-Binding Protein A9, a Potential Novel Diagnostic Biomarker for Idiopathic Pulmonary Fibrosis.

BACKGROUND: Neutrophilic inflammation is a characteristic feature of idiopathic pulmonary fibrosis (IPF). S100 calcium-binding protein A9 (S100A9) is a neutrophil-derived protein involved in the development of neutrophil-related chronic inflammatory disorders. However, the role of S100A9 in IPF remains unclear. METHODS: We used enzyme-linked immunosorbent assays to measure S100A9 levels in bronchoalveolar lavage fluid (BALF) and serum obtained from healthy controls (HCs) and patients with IPF, non-specific interstitial pneumonia, hypersensitivity pneumonitis, and sarcoidosis. RESULTS: Compared with HCs, BALF S100A9 levels were significantly higher in IPF patients (P < 0.001), patients with hypersensitivity pneumonitis (P = 0.043), and patients with nonspecific interstitial pneumonia (P < 0.001). The S100A9 level in BALF of 0.093 ng/mL could distinguish IPF patients from HCs, with a specificity of 78.8% and a sensitivity of 81.6%. Similarly, the S100A9 level in BALF of 0.239 ng/mL had a specificity of 64.7% and a sensitivity of 66.7% for distinguishing IPF patients from patients with other interstitial lung diseases. Additionally, BALF S100A9 levels were significantly correlated with neutrophil counts (r = 0.356, P < 0.001) in BALF. IPF patients with S100A9 levels in BALF > 0.533 ng/mL had lower survival rates, compared with patients who had levels ≤ 0.553 ng/mL (n = 49; hazard ratio [HR], 3.62; P = 0.021). Combination analysis revealed that IPF patients with S100A9 levels in BALF> 0.553 ng/mL or neutrophil percentages > 49.1% (n = 43) had significantly lower survival rates than patients with S100A9 levels in BALF ≤ 0.553 ng/mL and neutrophil percentages ≤ 49.1% (n = 41) (HR, 3.91; P = 0.014). Additionally, patients with serum S100A9 levels > 0.077 ng/mL (n = 29) had significantly lower survival rates than patients with levels ≤ 0.077 ng/mL (n = 53, HR, 2.52; P = 0.013). S100A9 was expressed on neutrophils and macrophages in BALF from IPF patients as well as α-smooth muscle actin positive cells in the lung tissues. CONCLUSION: S100A9 is involved in the development and progression of IPF. Moreover, S100A9 levels in BALF and serum may be surrogate markers for IPF diagnosis and survival prediction, particularly when analyzed in combination with neutrophil percentages.

Relationships Between High-Resolution Computed Tomographic Features and Lung Function Trajectory in Patients With Asthma.

PURPOSE: A subset of asthmatics suffers from persistent airflow limitation, known as remodeled asthma, despite optimal treatment. Typical quantitative scoring methods to evaluate structural changes of airway remodeling on high-resolution computed tomography (HRCT) are time-consuming and laborious. Thus, easier and simpler methods are required in clinical practice. We evaluated the clinical usefulness of a simple, semi-quantitative method based on 8 HRCT parameters by comparing asthmatics with a persistent decline of post-bronchodilator (BD)-FEV1 to those with a BD-FEV1 that normalized over time and evaluated the relationships of the parameters with BD-FEV1. METHODS: Asthmatics (n = 59) were grouped into 5 trajectories (Trs) according to the changes of BD-FEV1 over 1 year. After 9-12 months of guideline-based treatment, HRCT parameters including emphysema, bronchiectasis, anthracofibrosis, bronchial wall thickening (BWT), fibrotic bands, mosaic attenuation on inspiration, air-trapping on expiration, and centrilobular nodules were classified as present (1) or absent (0) in 6 zones. RESULTS: The Tr5 group (n = 11) was older and exhibited a persistent decline in BD-FEV1. The Tr5 and Tr4 groups (n = 12), who had a lower baseline BD-FEV1 that normalized over time, had longer durations of asthma, frequent exacerbations, and higher doses of steroid use compared to the Tr1-3 groups (n = 36), who had a normal baseline BD-FEV1. The Tr5 group had higher emphysema and BWT scores than the Tr4 (P = 8.25E-04 and P = 0.044, respectively). Scores for the other 6 parameters were not significantly different among the Tr groups. BD-FEV1 was inversely correlated with the emphysema and BWT scores in multivariate analysis (P = 1.70E-04, P = 0.006, respectively). CONCLUSIONS: Emphysema and BWT are associated with airway remodeling in asthmatics. Our simple, semi-quantitative scoring system based on HRCT may be an easy-to-use method for estimating airflow limitation.

Association of ATP8B3 gene polymorphisms with aspirin-exacerbated respiratory disease in asthmatics.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD), an asthma phenotype, often presents with severe manifestations and it remains widely underdiagnosed because of insufficient awareness of the relationship between the ingestion of nonsteroidal anti-inflammatory drugs, including acetylsalicylic acid (ASA), and asthma exacerbation. Our previous genome-wide association study demonstrated an association between a single nucleotide polymorphism (SNP) of the ATP8B3 gene and the risk of AERD. This study examined AERD-related SNPs of the ATP8B3 gene in a large population. METHODS: Twenty-five SNPs of ATP8B3 were genotyped with the GoldenGate assay using VeraCode microbeads in 141 asthmatics with AERD and 995 Aspirin-tolerant asthma (ATA). The genotype distribution was analyzed using logistic regression models. The declines in forced expiratory volume in 1 second (FEV1)following an ASA challenge were compared among the genotypes and haplotypes using a type III generalized linear model. RESULTS: The minor allele frequencies (MAFs) of rs10421558 A>G in the 5'UTR and rs10403288 G>A in the intron were significantly lower in the AERD than the ATA [34.0% vs. 43.8%, OR = 0.66 (0.62-0.92), Pcorr = 0.03 and 28.4% vs. 35.4%, OR = 0.62 (0.59-0.89), Pcorr = 0.016, respectively]. BL1ht5 was significantly higher in the AERD [7.6% vs. 1.6%, OR = 12.23 (0.2-0.51), P = 4.7 × 10 -4 , Pcorr = 0.001]. Among them, rs10421558 A>G and BL1ht5 were associated with the percent decline in FEV1 on the oral ASA challenge test. CONCLUSION: The minor allele of rs10421558 A>G in the 5'UTR may protect against the development of AERD via the increased production of ATP8B3.

Genome-wide DNA methylation profile of peripheral blood lymphocytes from subjects with nonsteroidal anti-inflammatory drug-induced respiratory diseases.

BACKGROUND: Significant changes in CpG methylation have been identified in nasal polyps, which are the main targets of nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (NERD); however, these polyps are composed of various cellular components. In the present study, whole-genome CpG methylation in peripheral blood lymphocytes (PBLs) was analyzed to define the epigenetic changes in lymphocytes, which are the primary immune cells involved in NERD. MATERIALS AND METHODS: Genomic DNA from peripheral blood mononuclear cells from 27 NERD and 24 aspirin-tolerant asthma (ATA) was subjected to bisulfate conversion and a methylation array. Quantitative CpG methylation, the ß-values as a quantitative measure of DNA methylation, in lymphocytes were calculated after adjustments for cellular composition. RESULTS: Fifty-six hypermethylated and three hypomethylated differentially methylated CpGs (DMCs) in PBLs in the NERD compared with ATA. The top 10 CpG loci predicted the methylation risk score, with a positive predictive value of 91.3%, a negative predictive value of 81.5% and an accuracy of 84.3%. As demonstrated in the nasal polyps, 30 DMCs were predicted to bind to the following 10 transcription factors, ranked in descending order: AP-2alphaA, TFII-1, STAT4, FOXP3, GR, c-Est-1, E2F-1, XBP1, ENKTF-1 and NF-1. Gene ontology analysis identified 13 categories such as regulation of T-helper 17 cell differentiation, including SMAD7 and NFKBIZ. PBLs in NERD contained no DMCs in genes associated with the prostaglandin and leukotriene pathways, which were found in ATA. CONCLUSION: PBLs in NERD form a unique pattern of DNA CpG methylation, and the combined analysis may provide predictive values for NERD.

Magnetic resonance findings of acute severe lower back pain.

OBJECTIVE: To determine abnormal MRI findings in adults hospitalized with acute severe axial LBP. METHOD: Sixty patients with back pain were divided into 3 groups consisting of 1) 23 adults with acute axial severe LBP who could not sit up or stand up for several days, but had not experienced previous back-related diseases or trauma (group A), 2) 19 adults who had been involved in a minor traffic accident, and had mild symptoms but not limited mobility (group B), and 3) 18 adults with LBP with radicular pain (group C)., Various MRI findings were assessed among the above 3 groups and compared as follows: disc herniation (protrusion, extrusion), lumbar disc degeneration (LDD), annular tear, high intensity zone (HIZ), and endplate changes. RESULTS: THE MRI FINDINGS OF A GROUP WERE AS FOLLOWS: disc herniation (87%), LDD (100%), annular tear (100%), HIZ (61%), and end plate changes (4.4%). The findings of disc herniation, annular tear, HIZ, and LDD were more prevalent in A group than in B group (p<0.01). HIZ findings were more prevalent in A group than in group B or group C (p<0.05). CONCLUSION: Patients with acute severe axial LBP were more likely to have disc herniation, LDD, annular tear, HIZ. Among LBP groups, there was a significant association of HIZ on MRI with acute severe axial LBP.

Cefepime neurotoxicity in patients with renal insufficiency.

Cefepime is a fourth-generation cephalosporin that is active against both gram-positive and gram-negative organisms. It is administered parenterally for the treatment of severe infections. Approximately 85% of the drug is excreted unchanged by the kidneys. Neurotoxicity in patients with renal failure who are treated with cefepime has been reported sporadically. We report on two senile patients with renal impairment who developed neurotoxicity including lethal outcome after treatment with cefepime.