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.

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.

Leptin and the control of pharyngeal patency during sleep in severe obesity.

RATIONALE: Obesity imposes mechanical loads on the upper airway, resulting in flow limitation and obstructive sleep apnea (OSA). In previous animal models, leptin has been considered to serve as a stimulant of ventilation and may prevent respiratory depression during sleep. We hypothesized that variations in leptin concentration among similarly obese individuals will predict differences in compensatory responses to upper airway obstruction during sleep. METHODS: An observational study was conducted in 23 obese women [body mass index (BMI): 46 ± 3 kg/m(2), age: 41 ± 12 yr] and 3 obese men (BMI: 46 ± 3 kg/m(2), age: 43 ± 4 yr). Subjects who were candidates for bariatric surgery were recruited to determine upper airway collapsibility under hypotonic conditions [pharyngeal critical pressure (passive PCRIT)], active neuromuscular responses to upper airway obstruction during sleep, and overnight fasting serum leptin levels. Compensatory responses were defined as the differences in peak inspiratory airflow (ΔVImax), inspired minute ventilation (ΔVI), and pharyngeal critical pressure (ΔPCRIT) between the active and passive conditions. RESULTS: Leptin concentration was not associated with sleep disordered breathing severity, passive PCRIT, or baseline ventilation. In the women, increases in serum leptin concentrations were significantly associated with increases in ΔVImax (r(2) = 0.44, P < 0.001), ΔVI (r(2) = 0.40, P < 0.001), and ΔPCRIT (r(2) = 0.19, P < 0.04). These responses were independent of BMI, waist-to-hip ratio, neck circumference, or sagittal girth. CONCLUSION: Leptin may augment neural compensatory mechanisms in response to upper airway obstruction, minimizing upper airway collapse, and/or mitigating potential OSA severity. Variability in leptin concentration among similarly obese individuals may contribute to differences in OSA susceptibility.

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.

High value of combined serum C-reactive protein and BODE score for mortality prediction in patients with stable COPD.

INTRODUCTION: Both BODE score (body mass index, degree of airflow obstruction, functional dyspnea, and exercise capacity) and serum C-reactive protein (CRP) are validated predictors of mortality in patients with chronic obstructive pulmonary disease (COPD). The aim of this study is to investigate the predictive value of combined serum CRP and BODE score for mortality in COPD patients. PATIENTS AND METHODS: A cohort of 114 clinically stable COPD patients was assessed for predictors of longitudinal mortality. Variables included age, gender, current smoking status, pack-years, maximal inspiratory/expiratory pressure, BODE score (body mass index, degree of airflow obstruction, functional dyspnea, and exercise capacity), serum CRP, and fibrinogen. Predictors were assessed by Cox proportional hazards regression model. Survival was estimated by Kaplan-Meier method and log-rank test. RESULTS: Serum CRP (P=0.005; HR=1.042; 95% CI=1.019-1.066) and BODE score (P=0.032; HR=1.333; 95% CI=1.025-1.734) were independent predictors of survival in the multivariate analysis. The cumulative survival rates of COPD patients were sorted from the worst to the best as following: serum CRP >3mg/L & quartile 3-4; serum CRP >3mg/L & quartile 1-2; serum CRP ≤3mg/L & quartile 3-4; serum CRP ≤3mg/L & quartile 1-2 (P<0.001). CONCLUSIONS: Serum CRP and BODE score are independent predictors of survival in stable COPD patients. Combination of serum CRP and BODE score has higher predictive value in clinical practice.

Down-regulation of insulin-like growth factor I (IGF-I) in the mouse diaphragm during sepsis.

BACKGROUND: Diaphragmatic muscle impairment is an important cause of respiratory failure during sepsis. Insulin-like growth factor I (IGF-I) is an anabolic growth factor which prevents muscle degradation and wasting during sepsis, but its role in the diaphragmatic muscle during sepsis is unknown. The aim of this study was to investigate the expression of IGF-I in the diaphragmatic muscle in a murine model of sepsis induced by lipopolysaccharide (LPS). METHODS: Male B57 mice were peritoneally injected with LPS, and were killed and studied at different time-points, 24 h, 48 h, 72 h, and 96 h after injection. Diaphragm sarcolemmal damage was visualized by orange tracer dye infusion, and the expression of IGF-I, interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) in diaphragm tissue extracts were measured using ELISA. RESULTS: LPS induced sarcolemmal damage in diaphragm myofibers from 24 h to 96 h, which was accompanied by a significant increase in IL-1ß expression in the tissues while IGF-I levels were down-regulated. No change in TNF-α was observed. Body weights of animals were also reduced, especially at 96 h. CONCLUSIONS: The expression of IGF-I in diaphragm tissues was down-regulated during sepsis- induced diaphragm myofiber damage, suggesting that IGF-I may be an important factor in the regulation of diaphragm myofiber repair. Further studies are needed to examine the mechanisms involved.

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.

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.

Prognostic factors of tracheobronchial mucoepidermoid carcinoma--15 years experience.

BACKGROUND AND OBJECTIVES: Mucoepidermoid carcinoma of the tracheobronchial tree is a rare tumour which displays a variable degree of clinical aggressiveness and malignancy. The relationship between the patient's prognosis and the tumour's histological features and clinical behaviour is uncertain. The aim of this study was to identify the clinicopathological features and analyse the outcomes of patients with this type of cancer. METHODS: A retrospective analysis of the medical records of patients diagnosed with mucoepidermoid carcinoma of the lung between 1991 and 2006 was conducted. RESULTS: The study comprised 15 patients. Higher histological grade tumours had a higher proportion of squamoid cells (P = 0.019); the tumours of patients with lymph node metastases also had a higher proportion of squamoid cells than did the tumours of patients without lymph node metastases (P = 0.015). Patients with early stage tumours (stage IA, IB, IIB) had better outcomes (10-year survival rate = 87.5%), than did patients with late-stage tumours (stage IIIB, IV) (1-year survival rate = 28.6%; 2-year survival rate = 0%, P = 0.001). Patients with lower-grade tumours (grade 1 and grade 2) had better outcomes (1-year survival rate = 80%; 5-year survival rate = 57.1%) than did patients with higher-grade tumours (grade 3) (1-year survival rate = 20%, P = 0.035). Tumour staging was a significant independent predictor of survival on Cox proportional hazards analysis. CONCLUSIONS: The proportion of squamoid cells on tumour histology may be an indicator of the level of tumour malignancy. Tumour, node, metastasis staging is a significant determinant of prognosis in patients with tracheobronchial mucoepidermoid carcinoma.

Sarcoidosis in southern Taiwan.

PURPOSE: To investigate the disease characteristics of sarcoidosis in southern Taiwan, and to investigate diagnostic methods. METHODS: We retrospectively reviewed the medical records of all patients diagnosed with sarcoidosis at Chang Gung Memorial Hospital, Kaohsiung, from March 1988 to February 2002. RESULTS: A total of 12 patients (3 men, 9 women), with a mean age of 44.5 years, and a diagnosis of sarcoidosis by positive histology and either a typical chest roentgenogram or clinical presentation were included. All 12 patients had intrathoracic involvement (hilar or mediastinal lymph nodes, 12; lungs, 5), eight had skin involvement, and two had extrathoracic lymph node involvement. The most frequent biopsy specimens were from the skin (n = 10), followed by the intrathoracic lymph nodes (n = 4), lungs (n = 2), and extrathoracic lymph nodes (n = 2). Four patients had positive biopsies from two organs. Our data showed an older age distribution and a greater female predominance of the disease compared with Western countries. A higher rate of intrathoracic and skin involvement was also found, but the reason for this was not clear. CONCLUSIONS: Greater awareness of possible skin involvement may enable chest physicians and clinical practitioners to suspect this condition earlier. A histologic diagnosis from skin biopsy should then be made, rather than using more invasive procedures.