Long non-coding RNA FKSG29 regulates oxidative stress and endothelial dysfunction in obstructive sleep apnea.

Altered expressions of pro-/anti-oxidant genes are known to regulate the pathophysiology of obstructive sleep apnea (OSA).We aim to explore the role of a novel long non-coding (lnc) RNA FKSG29 in the development of intermittent hypoxia with re-oxygenation (IHR)-induced endothelial dysfunction in OSA. Gene expression levels of key pro-/anti-oxidant genes, vasoactive genes, and the FKSG29 were measured in peripheral blood mononuclear cells from 12 subjects with primary snoring (PS) and 36 OSA patients. Human monocytic THP-1 cells and human umbilical vein endothelial cells (HUVEC) were used for gene knockout and double luciferase under IHR exposure. Gene expression levels of the FKSG29 lncRNA, NOX2, NOX5, and VEGFA genes were increased in OSA patients versus PS subjects, while SOD2 and VEGFB gene expressions were decreased. Subgroup analysis showed that gene expression of the miR-23a-3p, an endogenous competitive microRNA of the FKSG29, was decreased in sleep-disordered breathing patients with hypertension versus those without hypertension. In vitro IHR experiments showed that knock-down of the FKSG29 reversed IHR-induced ROS overt production, early apoptosis, up-regulations of the HIF1A/HIF2A/NOX2/NOX4/NOX5/VEGFA/VEGFB genes, and down-regulations of the VEGFB/SOD2 genes, while the protective effects of FKSG29 knock-down were abolished by miR-23a-3p knock-down. Dual-luciferase reporter assays confirmed that FKSG29 was a sponge of miR-23a-3p, which regulated IL6R directly. Immunofluorescence stain further demonstrated that FKSGH29 knock-down decreased IHR-induced uptake of oxidized low density lipoprotein and reversed IHR-induced IL6R/STAT3/GATA6/ICAM1/VCAM1 up-regulations. The findings indicate that the combined RNA interference may be a novel therapy for OSA-related endothelial dysfunction via regulating pro-/anti-oxidant imbalance or targeting miR-23a-IL6R-ICAM1/VCAM1 signaling.

Exertional Desaturation Has Higher Mortality Than Non-Desaturation in COPD.

Background and objectives: Exertional desaturation (ED) is often overlooked in chronic obstructive pulmonary disease (COPD). We aim to investigate the impact of ED on mortality and the predictors of ED in COPD. Materials andmethods: A cohort of COPD patients with clinically stable, widely ranging severities were enrolled. ED is defined as oxyhemoglobin saturation by pulse oximetry (SpO2) < 90% or a drop of ΔSpO2 ≥ 4% during a six-minute walk test (6MWT). Cox regression analysis is used to estimate the hazard ratio (HR) for three-year mortality. Results: A total of 113 patients were studied, including ED (N = 34) and non-ED (N = 79) groups. FVC (% of predicted value), FEV1/FVC (%), FEV1 (% of predicted value), DLCO (%), maximal inspiratory pressure, SpO2 during the 6MWT, GOLD stage, and COPD severity were significantly different between the ED and non-ED groups in univariate analysis. Low minimal SpO2 (p < 0.001) and high maximal heart rate (p = 0.04) during the 6MWT were significantly related to ED in multivariate analysis. After adjusting for age, gender, body mass index, 6MWD, FEV1, mMRC, GOLD staging, exacerbation, hs-CRP, and fibrinogen, the mortality rate of the ED group was higher than that of the non-ED group (p = 0.012; HR = 4.12; 95% CI 1.37-12.39). For deaths, the average survival time of ED was shorter than that of the non-ED group (856.4 days vs. 933.8 days, p = 0.033). Conclusions: ED has higher mortality than non-ED in COPD. COPD should be assessed for ED, especially in patients with low minimal SpO2 and high maximal HR during the 6MWT.

miR-21-5p Under-Expression in Patients with Obstructive Sleep Apnea Modulates Intermittent Hypoxia with Re-Oxygenation-Induced-Cell Apoptosis and Cytotoxicity by Targeting Pro-Inflammatory TNF-α-TLR4 Signaling.

The purpose of this study is to explore the anti-inflammatory role of microRNAs (miR)-21 and miR-23 targeting the TLR/TNF-α pathway in response to chronic intermittent hypoxia with re-oxygenation (IHR) injury in patients with obstructive sleep apnea (OSA). Gene expression levels of the miR-21/23a, and their predicted target genes were assessed in peripheral blood mononuclear cells from 40 treatment-naive severe OSA patients, and 20 matched subjects with primary snoring (PS). Human monocytic THP-1 cell lines were induced to undergo apoptosis under IHR exposures, and transfected with miR-21-5p mimic. Both miR-21-5p and miR-23-3p gene expressions were decreased in OSA patients as compared with that in PS subjects, while TNF-α gene expression was increased. Both miR-21-5p and miR-23-3p gene expressions were negatively correlated with apnea hypopnea index and oxygen desaturation index, while TNF-α gene expression positively correlated with apnea hypopnea index. In vitro IHR treatment resulted in decreased miR-21-5p and miR-23-3p expressions. Apoptosis, cytotoxicity, and gene expressions of their predicted target genes-including TNF-α, ELF2, NFAT5, HIF-2α, IL6, IL6R, EDNRB, and TLR4-were all increased in response to IHR, while all were reversed with miR-21-5p mimic transfection under IHR condition. The findings provide biological insight into mechanisms by which IHR-suppressed miRs protect cell apoptosis via inhibit inflammation, and indicate that over-expression of the miR-21-5p may be a new therapy for OSA.

Co-upregulation of Toll-like receptors 2 and 6 on peripheral blood cells in patients with obstructive sleep apnea.

PURPOSE: Toll-like receptor (TLR) 2 can heterodimerise with TLR6 to detect diacylated lipoproteins. Hypoxia inducible factor-1 α co-ordinates selective induction of TLR2 and TLR6 during persistent hypoxia. We hypothesized that TLR 2/6 co-expression may be upregulated by chronic intermittent hypoxia with re-oxygenation (IHR) in obstructive sleep apnea (OSA). METHODS: TLR2/6 expressions on blood immune cells were measured in 144 patients with sleep-disordered breathing (SDB), including primary snoring (PS, n = 24), moderate to severe OSA (MSO, n = 60), very severe OSA (VSO, n = 36), and very severe OSA on continuous positive airway pressure (CPAP) treatment (VSOC, n = 24). An in vitro IHR experiment was also undertaken. RESULTS: Patients in both the MSO and VSO groups had increased TLR2/6 co-expression on CD16(+) neutrophil than those in the PS group. Patients in the VSOC group had reduced TLR2/6 co-expression on neutrophil than those in either the MSO or VSO group. Blood absolute neutrophil count was positively but weakly correlated with TLR2/6 co-expression on neutrophil. TLR2/6 co-expressions on both CD14(+) monocyte and CD3(+)CD4(+)T helper cell, and TLR2 expressions on both monocyte and T helper cell in SDB patients with low Minimum SaO2 (≦70%) were all higher than those with high Minimum SaO2. In vitro IHR for 1-4 days resulted in TLR2/6 co-upregulation on both neutrophil and monocyte. CONCLUSIONS: OSA patients had increased TLR2/6 co-expressions on blood immune cells, which were related to their immune cell counts and could be reversed with CPAP treatment. In vitro IHR could induce TLR2/6 co-upregulation.

The influence of obesity on different genders in patients with obstructive sleep apnea.

Obesity is considered to be a major contributing factor to obstructive sleep apnea (OSA); however, there is limited evidence with regard to gender predominance. We analyzed 2345 patients (339 females) in correlation with body mass index (BMI) and OSA severity. Male AHIs were significantly higher than female AHIs in each BMI group. As the BMI increased, the AHI increased in both males and females, and this trend was more obvious in males. For BMI-matched male and female patients with OSA, the severity of OSA was higher in males. As BMI increased, the severity of OSA increased more obviously in males. Our findings suggest that increased body fat contributes to the pathogenesis of OSA more in males than in females and that obesity plays a more significant role in contributing to OSA in male patients.

Effects of Pillar implants for sleep-related breathing disorders on middle ear function.

Pillar implants provide a reasonable outcome with minimal post-operative morbidity and complications in treating patients with sleep-disordered breathing (SDB) who had obvious palatal obstruction. The palatal structure is responsible for a normal functioning Eustachian tube; however, little is known if there is any potential otologic implication of minimally invasive palatal stiffening surgery for SDB. The aim of this study is to evaluate the effects of Pillar implantation on middle ear function. We performed a prospective study in a tertiary referral center. Thirty SDB patients (25 men, 5 women; mean age, 44.3 years) who underwent Pillar implants for treating palatal obstruction were enrolled. The subjects had normal otologic exam and no previous history of chronic ear disease. Pure-tone audiometry and tympanometry were performed pre-operatively, and post-operative days 1 and 7, and months 1 and 3. Baseline and post-operative middle ear pressures (MEPs) in decipascals were compared. Statistical analysis was performed by repeated measures of ANOVA. Eight patients (8/30, 26.7%) reported otologic complaints such as ear pressure and/or otalgia within 1 week post-operatively. No permanent otologic discomfort occurred. A trend toward reduced MEP was noted in this study. The decrease in MEP became apparent on post-operative day 1 after surgery. However, mean pressure changes were no longer significantly different from pre-operative values by 1 week after surgery. Pillar implantation for SDB induces changes in middle ear function. However, the changes were temporary and not significant 1 week after surgery.

Autophagy impairment in patients with obstructive sleep apnea modulates intermittent hypoxia-induced oxidative stress and cell apoptosis via hypermethylation of the ATG5 gene promoter region.

BACKGROUND: Autophagy is a catabolic process that recycles damaged organelles and acts as a pro-survival mechanism, but little is known about autophagy dysfunction and epigenetic regulation in patients with obstructive sleep apnea (OSA). METHODS: Protein/gene expressions and DNA methylation levels of the autophagy-related genes (ATG) were examined in blood leukocytes from 64 patients with treatment-naïve OSA and 24 subjects with primary snoring (PS). RESULTS: LC3B protein expression of blood monocytes, and ATG5 protein expression of blood neutrophils were decreased in OSA patients versus PS subjects, while p62 protein expression of cytotoxic T cell was increased, particularly in those with nocturia. ATG5, ULK1, and BECN1 gene expressions of peripheral blood mononuclear cells were decreased in OSA patients versus PS subjects. LC3B gene promoter regions were hypermethylated in OSA patients, particularly in those with excessive daytime sleepiness, while ATG5 gene promoter regions were hypermethylated in those with morning headache or memory impairment. LC3B protein expression of blood monocytes and DNA methylation levels of the LC3B gene promoter region were negatively and positively correlated with apnea hyponea index, respectively. In vitro intermittent hypoxia with re-oxygenation exposure to human THP-1/HUVEC cell lines resulted in LC3B/ATG5/ULK1/BECN1 down-regulations and p62 up-regulation along with increased apoptosis and oxidative stress, while rapamycin and umbilical cord-mesenchymal stem cell treatment reversed these abnormalities through de-methylation of the ATG5 gene promoter. CONCLUSIONS: Impaired autophagy activity in OSA patients was regulated by aberrant DNA methylation, correlated with clinical phenotypes, and contributed to increased cell apoptosis and oxidative stress. Autophagy enhancers may be novel therapeutics for OSA-related neurocognitive dysfunction.

The clinical COPD questionnaire correlated with BODE index-A cross-sectional study.

The Global initiative for Chronic Obstructive Lung Disease (GOLD) staging has widely used in the stratification of the severity of COPD, while BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index was proven superior to FEV1 in predicting mortality, exacerbation and disease severity in patients with COPD. Clinical COPD Questionnaire (CCQ), a questionnaire with ten items categorized into three domains (symptoms, functional state and mental state) was developed to measure health status of COPD patients. However, little is known about the relationship between CCQ score and BODE index. We performed a prospective study with the inclusion of 89 patients who were clinically stable after a 6-week-therapy for COPD symptoms comparing their health status assessed by CCQ, BODE index and GOLD staging. We found that the total CCQ score was correlated with BODE score (P < 0.001) and GOLD staging (P < 0.001); of three CCQ domains, the functional status correlated the most with BODE index (rS = 0.670) and GOLD staging (rS = 0.531), followed by symptoms (rS = 0.482; rS = 0.346, respectively), and mental status (rS = 0.340; rS = 0.236, respectively). Our data suggest that CCQ is a reliable and convenient alternative tool to evaluate the severity of COPD.

Decreased retinal nerve fiber layer thickness in patients with obstructive sleep apnea/hypopnea syndrome.

BACKGROUND: To compare parameters for retinal nerve fiber layer (RNFL) thickness, optic nerve head (ONH) measurements, and macular thickness in patients with different severities of obstructive sleep apnea/hypopnea syndrome (OSAHS) versus normal controls. METHODS: Patients presenting with snoring and daytime sleepiness who underwent overnight polysomnography to determine OSAHS severity were recruited, and subsequently referred for ophthalmologic evaluation. Optical coherence tomography was used to evaluate the retinal nerve fiber layer (RNFL), optic nerve head topography, and macular thickness for early detection of glaucoma. Patients determined not to have OSAHS were included as controls. RESULTS: A total of 127 subjects were recruited, including 105 patients with OSAHS and 22 normal control subjects. RNFL thickness was significantly lower for the severe OSAHS group than for the control and mild OSAHS groups in the average (p < 0.0001) and in the superior quadrant (p = 0.0007). When subjects without OSAHS or with mild disease (AHI < 15) were grouped together and compared with patients with moderate/severe OSAHS (AHI ≧ 15), RNFL thickness measurements for the latter group were significantly lower in the average (p < 0.0001), and in the superior (p = 0.001), inferior (p = 0.029), and temporal (p = 0.007) quadrants. Positive correlations were identified between lowest oxygenation saturation on PSG and RNFL thickness in the average (r = 0.260), superior (r = 0.200) and nasal (r = 0.156) quadrants. CONCLUSIONS: Compared to patients without OSAHS or those with mild disease, RNFL thickness was lower in patients with moderate/severe OSAHS. Lowest saturation of oxygen in the moderate/severe OSAHS group correlated with decreased RNFL thickness. Patients with moderate and severe OSAHS are at increased risk for glaucoma.

H3K23/H3K36 hypoacetylation and HDAC1 up-regulation are associated with adverse consequences in obstructive sleep apnea patients.

The aim of this study is to determine the roles of global histone acetylation (Ac)/methylation (me), their modifying enzymes, and gene-specific histone enrichment in obstructive sleep apnea (OSA). Global histone modifications, and their modifying enzyme expressions were assessed in peripheral blood mononuclear cells from 56 patients with OSA and 16 matched subjects with primary snoring (PS). HIF-1α gene promoter-specific H3K36Ac enrichment was assessed in another cohort (28 OSA, 8 PS). Both global histone H3K23Ac and H3K36Ac expressions were decreased in OSA patients versus PS subjects. H3K23Ac expressions were further decreased in OSA patients with prevalent hypertension. HDAC1 expressions were higher in OSA patients, especially in those with excessive daytime sleepiness, and reduced after more than 6 months of continuous positive airway pressure treatment. H3K79me3 expression was increased in those with high C-reactive protein levels. Decreased KDM6B protein expressions were noted in those with a high hypoxic load, and associated with a higher risk for incident cardiovascular events or hypertension. HIF-1α gene promoter-specific H3K36Ac enrichment was decreased in OSA patients versus PS subjects. In vitro intermittent hypoxia with re-oxygenation stimuli resulted in HDAC1 over-expression and HIF-1α gene promoter-specific H3K36Ac under-expression, while HDAC1 inhibitor, SAHA, reversed oxidative stress through inhibiting NOX1. In conclusions, H3K23/H3K36 hypoacetylation is associated with the development of hypertension and disease severity in sleep-disordered breathing patients, probably through up-regulation of HDAC1, while H3K79 hypermethylation is associated with higher risk of cardiovascular diseases, probably through down-regulation of KDM6B.

MicroRNA Sequencing Analysis in Obstructive Sleep Apnea and Depression: Anti-Oxidant and MAOA-Inhibiting Effects of miR-15b-5p and miR-92b-3p through Targeting PTGS1-NF-κB-SP1 Signaling.

The aim of this study was to identify novel microRNAs related to obstructive sleep apnea (OSA) characterized by intermittent hypoxia with re-oxygenation (IHR) injury. Illumina MiSeq was used to identify OSA-associated microRNAs, which were validated in an independent cohort. The interaction between candidate microRNA and target genes was detected in the human THP-1, HUVEC, and SH-SY5Y cell lines. Next-generation sequencing analysis identified 22 differentially expressed miRs (12 up-regulated and 10 down-regulated) in OSA patients. Enriched predicted target pathways included senescence, adherens junction, and AGE-RAGE/TNF-α/HIF-1α signaling. In the validation cohort, miR-92b-3p and miR-15b-5p gene expressions were decreased in OSA patients, and negatively correlated with an apnea hypopnea index. PTGS1 (COX1) gene expression was increased in OSA patients, especially in those with depression. Transfection with miR-15b-5p/miR-92b-3p mimic in vitro reversed IHR-induced early apoptosis, reactive oxygen species production, MAOA hyperactivity, and up-regulations of their predicted target genes, including PTGS1, ADRB1, GABRB2, GARG1, LEP, TNFSF13B, VEGFA, and CXCL5. The luciferase assay revealed the suppressed PTGS1 expression by miR-92b-3p. Down-regulated miR-15b-5p/miR-92b-3p in OSA patients could contribute to IHR-induced oxidative stress and MAOA hyperactivity through the eicosanoid inflammatory pathway via directly targeting PTGS1-NF-κB-SP1 signaling. Over-expression of the miR-15b-5p/miR-92b-3p may be a new therapeutic strategy for OSA-related depression.

Toll-like receptor 2 gene polymorphisms, pulmonary tuberculosis, and natural killer cell counts.

BACKGROUND: To investigate whether the toll-like receptor 2 polymorphisms could influence susceptibility to pulmonary TB, its phenotypes, and blood lymphocyte subsets. METHODS: A total of 368 subjects, including 184 patients with pulmonary TB and 184 healthy controls, were examined for TLR2 polymorphisms over locus -100 (microsatellite guanine-thymine repeats), -16934 (T>A), -15607 (A>G), -196 to -174 (insertion>deletion), and 1350 (T>C). Eighty-six TB patients were examined to determine the peripheral blood lymphocyte subpopulations. RESULTS: We newly identified an association between the haplotype [A-G-(insertion)-T] and susceptibility to pulmonary TB (p = 0.006, false discovery rate q = 0.072). TB patients with systemic symptoms had a lower -196 to -174 deletion/deletion genotype frequency than those without systemic symptoms (5.7% vs. 17.7%; p = 0.01). TB patients with the deletion/deletion genotype had higher blood NK cell counts than those carrying the insertion allele (526 vs. 243.5 cells/microl, p = 0.009). TB patients with pleuritis had a higher 1350 CC genotype frequency than those without pleuritis (12.5% vs. 2.1%; p = 0.004). TB patients with the 1350 CC genotype had higher blood NK cell counts than those carrying the T allele (641 vs. 250 cells/microl, p = 0.004). TB patients carrying homozygous short alleles for GT repeats had higher blood NK cell counts than those carrying one or no short allele (641 vs. 250 cells/microl, p = 0.004). CONCLUSIONS: TLR2 genetic polymorphisms influence susceptibility to pulmonary TB. TLR2 variants play a role in the development of TB phenotypes, probably by controlling the expansion of NK cells.

Association of tumor necrosis factor-alpha-863C/A gene polymorphism with chronic obstructive pulmonary disease.

The aim of this study was to investigate genetic effects on the pathogenesis of chronic obstructive pulmonary disease (COPD). The study was conducted as a prospective case-control study in a medical center in southern Taiwan. The patient group consisted of 145 male patients with smoking-related COPD and a control group of 139 resistant smokers from July 2004 to September 2009. We compared allele and genotype frequencies of three tag single nucleotide polymorphisms (SNP) of the TNF-alpha gene promoter region at -308, -863, and -1031 in all subjects. We also analyzed the influence of each genetic variant on pulmonary function parameters, body mass index (BMI), serum TNF-alpha levels, and outcomes among heavy smokers with or without COPD. COPD patients had a significantly lower A allele frequency (9.7 vs. 15.1%, OR = 0.6, p = 0.048, false discovery rate q = 0.144) and a significantly lower A carrier genotype frequency (19.3 vs. 30.2%, OR = 0.52, p = 0.042, q = 0.135) than resistant smokers. The -863 CA genotype was associated with a better FEV(1)/FVC ratio (79 vs. 71.5%, p = 0.034), and higher BMI (24.9 vs. 23.6 kg/m(2), p = 0.048). In addition, COPD patients with the -1031 C carrier genotype had higher serum TNF-alpha levels (20.9 vs. 16.2 pg/ml, p = 0.01). BMI (hazard ratio = 0.84, 95% CI = 0.74-0.96, p = 0.008) was the only independent predictor for mortality. The TNF-alpha -863 A allele may confer a degree of resistance to the susceptibility to and muscle wasting of COPD among heavy smokers.

Aberrant DNA methylation levels of the formyl peptide receptor 1/2/3 genes are associated with obstructive sleep apnea and its clinical phenotypes.

BACKGROUND: FPR1 over-expression and insufficiency of FPR2 and FPR3 are associated with disease severity of obstructive sleep apnea (OSA). We hypothesized that epigenetic modification of the FPR1/2/3 genes may underlie intermittent hypoxia with re-oxygenation (IHR) injury in OSA. METHODS: DNA methylation levels over 17 CpG sites of the FPR1/2/3 genes and their gene expression levels in the peripheral blood mononuclear cells were determined in 40 treatment-naïve OSA patients, 12 severe OSA patients under long-term continuous positive airway pressure treatment, 16 primary snoring (PS) subjects, and 10 healthy non-snorers (HS). RESULTS: Both -524 and -264 CpG sites of the FPR1 gene were hypomethylated in treatment-naïve OSA versus HS, while -264 CpG site methylation level was negatively correlated with FPR1/FPR3 gene expression ratio and associated with prevalent diabetes mellitus. Both +8802 and +8845 CpG sites of the FPR2 gene were hypermethylated in treatment-naive OSA versus HS, while hypermethylated +9132 and +9150 CpG sites were both associated with prevalent hypertension. FPR3 gene expression and DNA methylation levels over -842/-516 CpG sites of the FPR3 gene were both decreased in treatment-naive OSA versus HS, while hypermethylated -429 CpG site was associated with elevated serum C-reactive protein level. In vitro IHR stimuli in human monocytic THP-1 cells resulted in gene promoter hypomethylation-mediated FPR1 over-expression, increased production of reactive oxygen species, and increased cell apoptosis, which could be reversed with re-methylation agent, folic acid, treatment. CONCLUSIONS: Aberrant DNA methylation patterns of the FPR1/2/3 gene promoters contribute to disease severity and diabetes mellitus or cardiovascular disease in OSA patients, probably through regulating FPR1/2/3 gene expressions.

Aberrant DNA methylation of the toll-like receptors 2 and 6 genes in patients with obstructive sleep apnea.

Obstructive sleep apnea (OSA) is a syndrome leading to chronic intermittent hypoxia, and the up-regulation of toll-like receptors (TLR) 2 and 6 on peripheral blood cells has been reported. We hypothesized that DNA methylation in TLR2 and TLR6 genes may play a role in the development of OSA and its excessive daytime sleepiness (EDS) phenotype. DNA methylation over 28 cytosine-phosphate-guanine (CpG) sites of the TLR2 promoter region and 3 CpG sites of the TLR6 gene body, and their protein expressions were measured by using pyrosequencing and ELISA methods in 18 heathy subjects (HS) and 58 patients with severe OSA (divided into 18 non-EDS and 40 EDS group). Patients with severe OSA had higher DNA methylation levels over five CpG sites (#1, #2, #3, #25 and #28) and lower DNA methylation levels over CpG site #18 of the TLR2 promoter region, higher DNA methylation levels over two CpG sites (#1 and #3) of the TLR6 gene body, and higher protein expressions of TLR6 than HS. The CpG site #2 of the TLR6 gene body was hypermethylated in severe OSA patients with EDS. Both DNA methylation levels over CpG site #1 of the TLR6 gene body and protein expressions of TLR6 were reduced after more than 6 months of nasal CPAP treatment in seven selected patients. Aberrant DNA methylation of the TLR2 promoter region and TLR6 gene body are associated with the consequence of severe OSA and its EDS phenotype.

Il13 promoter (-1055) polymorphisms associated with chronic obstructive pulmonary disease in Taiwanese.

Interleukin-13 (IL13) -1055 polymorphism has been implicated in the development of chronic obstructive pulmonary disease (COPD) in various studies with conflicting results. The aims of this study are to investigate whether IL13 -1055 polymorphism is associated with the development of COPD in Taiwanese smokers; and to determine if IL13 -1055 polymorphism is associated with the severity of COPD. A case-control study was conducted on COPD patients (n = 85) and healthy smoker (n = 72). Genomic DNA was extracted for genotyping of IL13 sequencing and serum IL-13 was measured using by enzyme-linked immunosorbent assay (ELISA). After adjusting smoking index and age confounding, the T-allelic frequencies of the IL13 -1055 gene polymorphisms in COPD group are significantly higher than those in control group (18.8% versus 1.4%; P < .001; odds ratio [OR] = 29.3; 95% confidence interval [CI]: 5.9-145.3); and the frequencies of CT/TT genotypes in COPD group are significantly higher than those in control group (27.1% versus 2.8%; P < .001; OR = 20.0; 95% CI: 3.9-100.8). In COPD patients, stepwise linear regression shows IL13 -1055 T allele is the independent factor associated with forced expiratory volume in 1 second (P = .007), but not associated with serum IL-13. In conclusion, IL13 -1055 T allele is associated with the development and severity of COPD in Taiwanese smokers.

Correlation between serum biomarkers and BODE index in patients with stable COPD.

BACKGROUND AND OBJECTIVE: The BODE index, based on BMI, obstructive ventilatory impairment, dyspnoea scale and exercise capacity, has been used to evaluate the severity of patients with COPD. However, the correlations between serum biomarkers and the BODE index in patients with stable COPD are not widely studied. This study evaluated potential serum biomarkers for their ability to identify smokers with COPD and reflect disease severity. METHODS: A comparative study was conducted of 100 clinically stable COPD patients and 50 matched healthy smokers and the difference in levels of biomarkers between the COPD patients and healthy smokers was measured. Serum inflammatory mediators measured were growth-related oncogene-alpha (GRO-alpha), IL-8, tumour necrosis factor-alpha (TNF-alpha), matrix metalloproteinase-9 (MMP-9) and monocyte chemoattractant protein-1 (MCP-1). Variables included age, pack-years, current or ex-smoker status, inhaler or oral steroid use and BODE index components, including airflow obstruction, the distance walked in 6MWD, modified Medical Research Council (MMRC) dyspnoea scale and BMI. The association between serum biomarkers and the components of the BODE index was assessed in the COPD patients. RESULTS: The level of serum MCP-1 was significantly different between the COPD group and the healthy smoker group (P = 0.003). Significant results in univariate and multivariate analysis of the association between biomarkers and BODE components were: serum MCP-1 correlated with FEV(1)% and 6MWD; serum IL-8 and GRO-alpha correlated with steroid use; serum TNF-alpha correlated with steroid use and FEV(1)%; and serum MMP-9 correlated with MMRC dyspnoea scale. CONCLUSIONS: No single specific serum inflammatory mediator was completely correlated with BODE variable parameters in patients with stable COPD. Serum MCP-1 may be an important biomarker for identifying COPD subjects from healthy smokers and classifying COPD severity.

Effects of OSA Surgery on Leptin and Metabolic Profiles.

OBJECTIVES: This study is designed to investigate the effects of obstructive sleep apnea/hypopnea syndrome (OSA) surgery on serum leptin levels and metabolic disturbances, both of which contribute to the risk of cardiovascular diseases. STUDY DESIGN: Case series with planned data collection. SETTING: Tertiary referral medical center. SUBJECTS AND METHODS: A retrospective chart review of 101 consecutive patients with OSA who refused or failed conservative therapy and who then underwent upper airway surgery for OSA treatment was conducted. The personal medical history, anthropometric measurements, subjective symptoms, and objective polysomnographic parameters and fasting morning blood samples for leptin and metabolic biomarkers measurements were collected preoperatively and at a minimum of 3 months postoperatively. RESULTS: Eighty patients with OSA (69 men and 11 women; mean [SD] age of 42.2 [10.2] years) with complete data were included in the final analysis. At least 3 months after surgery, serum leptin, low-density lipoprotein cholesterol (LDL-C), and triglyceride levels and the mean systolic blood pressure (SBP) (night and morning) significantly decreased. According to the classical definition of surgical success, 40 subjects had successful surgery and were categorized as surgical responders, and the other 40 patients who failed surgery were categorized as surgical nonresponders. Significant reductions in serum leptin, total cholesterol, LDL-C, and triglyceride levels and improvement of mean SBP (morning) occurred in surgical responders but not in nonresponders. CONCLUSIONS: Effective OSA surgery improves serum leptin, lipid profiles, and SBP. Further studies are needed to investigate the role of serial measurements of these biomarkers in monitoring surgical outcome of OSA treatment.

Effects of OSA Surgery on Ophthalmological Microstructures.

OBJECTIVE: Obstructive sleep apnea/hypopnea syndrome (OSA) could compromise oxygenation of the optic nerve and cause glaucomatous optic neuropathy; however, there were no studies to investigate the changes of visual function and retinal microstructures in OSA patients after upper airway surgery. We aim to assess the changes in the visual sensitivity and retinal fiber layer thickness in OSA patients before and after surgery. METHODS: This prospective single-blind study enrolled patients with OSA from a tertiary academic medical center who had unsuccessful conservative therapy and then underwent surgery. The patients were referred for comprehensive ophthalmologic evaluation at baseline and 6 months after OSA surgery. The polysomnographic findings were collected pre- and postoperatively. Visual sensitivities on standard automated perimetry (SAP) were assessed. Peripapillary retinal nerve fiber layer (RNFL) thickness and macular layer (ML) thickness parameters were measured by spectral-domain optical coherence tomography (OCT). RESULTS: A total of 108 OSA patients were enrolled. Six months after surgery, the major parameters of polysomnography (PSG), mean deviation, and pattern standard deviation of SAP significantly improved in these OSA patients. Regarding the OCT parameters, thickness of ML in the nasal-outer, superior-inner, temporal-inner, inferior-inner, nasal-inner sectors, and total ML thickness significantly increased 6 months after upper airway surgery in the severe OSA group (apnea/hypopnea index ⩾30 per hour). CONCLUSION: The visual sensitivities on SAP, ML thickness on OCT, and oxygenation status on PSG significantly improved 6 months after upper airway surgery in patients with severe OSA. Upper airway surgery may ameliorate the microstructures of the retina in patients with severe OSA.

Clinical Prediction Model for Obstructive Sleep Apnea among Adult Patients with Habitual Snoring.

OBJECTIVE: To identify standard clinical parameters that may predict the presence and severity of obstructive sleep apnea/hypopnea syndrome (OSA). DESIGN: Case series with chart review. SETTING: Tertiary academic medical center. SUBJECTS AND METHODS: A total of 325 adult patients (274 men and 51 women; mean age, 44.2 years) with habitual snoring completed comprehensive polysomnography and anthropometric measurements, including modified Mallampati grade (also known as updated Friedman's tongue position [uFTP]), tonsil size grading, uvular length, neck circumference, waist circumference, hip circumference, and body mass index (BMI). RESULTS: When the aforementioned physical parameters were correlated singly with the apnea/hypopnea index (AHI), we found that sex, uFTP, tonsil size grading, neck circumference, waist circumference, hip circumference, thyroid-mental distance, and BMI grade were reliable predictors of OSA. When all important factors were considered in a multiple stepwise regression analysis, an estimated AHI can be formulated by factoring sex, uFTP, tonsil size grading, and BMI grade as follows: -43.0 + 14.1 × sex + 12.8 × uFTP + 5.0 × tonsil size + 8.9 × BMI grade. Severity of OSA can be predicted with a receiver operating characteristic curve. Predictors of OSA can be further obtained by the "OSA score." CONCLUSION: This study has distinguished the correlations between sex, uFTP, tonsil size, and BMI grade and the presence and severity of OSA. An OSA score might be beneficial in identifying patients who should have a full sleep evaluation.