Skeletal and upper airway stability following modified maxillomandibular advancement for treatment of obstructive sleep apnea in skeletal class I or II deformity.

OBJECTIVES: Maxillomandibular advancement (MMA) is an effective short-term treatment for obstructive sleep apnea (OSA). This study aimed to evaluate the long-term stability of the facial skeleton, upper airway, and its surrounding structures, as well as improvement in OSA following MMA. MATERIALS AND METHODS: Thirty-one adults with moderate-to-severe OSA underwent surgery-first modified MMA as primary surgery. Polysomnography and cone-beam computed tomography were obtained pre-surgery, early post-surgery, and at follow-up (i.e., ≥ 2 years post-surgery). Image analysis software assessed the facial skeleton, upper airway, and its surrounding structures. RESULTS: Early post-surgery, apnea-hypopnea index (AHI) had decreased significantly (p < 0.001) and the minimum oxygen saturation (MSAT) increased (p = 0.001), indicating significant improvement in OSA. At follow-up, the AHI and MSAT remained stable. However, the anterior maxilla, soft palate, and tongue moved backward while the hyoid moved downward. There was also a significant decrease in the minimal cross-sectional area of the oropharynx. The reduction in AHI was significantly related to the anterior movement of the anterior maxilla and tongue, inferior movement of the posterior maxilla, and superior movement of the soft palate tip. CONCLUSIONS: The improvement of OSA after modified MMA remained stable for at least 2 years following treatment, despite the relapse of the facial skeleton, upper airway, and its surrounding structures. The reduction of AHI was not related to changes in the caliber of the upper airway but to the movement of the maxilla, soft palate, and tongue. Clinical relevance Modified MMA is clinically effective for long-term treatment of patients with moderate-to-severe OSA.

Clinical outcomes and prognostic factors for prolonged mechanical ventilation in patients with acute stroke and brain trauma.

BACKGROUND/PURPOSE: Neurological dysfunction is a common condition necessitating prolonged mechanical ventilation (PMV). We investigated the clinical features and outcomes of patients with acute neurological diseases requiring PMV. METHODS: This retrospective observational study was conducted at the Respiratory Care Center (RCC) of Chang Gung Memorial Hospital, Taiwan, between January 2011 and January 2014. The main outcome was weaning success, defined as successful withdrawal from mechanical ventilator support for more than 5 days. RESULTS: The study included 103 patients with acute stroke and brain trauma receiving PMV. Weaning success was reported in 63 (61%) patients and weaning failure was reported in 40 (39%) patients. Patients in the weaning failure group were older and had a lower RCC Glasgow Coma Scale (GCS) score (6.0 vs 7.9, p = 0.005), lower albumin level (2.8 vs 3.1, p = 0.015), longer RCC stay (28.7 vs 21.3 days, p = 0.017), and higher in-hospital mortality rate (47% vs 9%, p < 0.01). Multivariate analysis revealed that reduced RCC GCS score is an independent prognostic factor for weaning failure (odds ratio [OR] = 1.22, 95% confidence interval [CI] = 1.05-1.46, p = 0.016) and that per unit increase of RCC GCS score is associated with a lower risk of in-hospital mortality (OR = 0.83, 95% CI = 0.70-0.96, p = 0.019). CONCLUSION: Reduced RCC GCS score is an independent prognostic factor for weaning failure, and is associated with increased in-hospital mortality rates in patients with acute stroke and brain trauma requiring PMV.

Elevated Monocytic Interleukin-8 Expression under Intermittent Hypoxia Condition and in Obstructive Sleep Apnea Patients.

Obstructive sleep apnea (OSA) is a disease with great cardiovascular risk. Interleukin-8 (IL-8), an important chemokine for monocyte chemotactic migration, was studied under intermittent hypoxia condition and in OSA patients. Monocytic THP-1 cells were used to investigate the effect of intermittent hypoxia on the regulation of IL-8 by an intermittent hypoxic culture system. The secreted protein and mRNA levels were studied by means of enzyme-linked immunosorbent assay and RT/real-time PCR. The chemotactic migration of monocytes toward a conditioned medium containing IL-8 was performed by means of the transwell filter migration assay. Peripheral venous blood was collected from 31 adult OSA patients and RNA was extracted from the monocytes for the analysis of IL-8 expression. The result revealed that intermittent hypoxia enhanced the monocytic THP-1 cells to actively express IL-8 at both the secreted protein and mRNA levels, which subsequently increased the migration ability of monocytes toward IL-8. The ERK, PI3K and PKC pathways were demonstrated to contribute to the activation of IL-8 expression by intermittent hypoxia. In addition, increased monocytic IL-8 expression was found in OSA patients, with disease severity dependence and diurnal changes. This study concluded the monocytic IL-8 gene expression can be activated by intermittent hypoxia and increased in OSA patients.

Effects of Pressure Control Device (SensAwake™) on Obstructive Sleep Apnea (OSA) Patients Who Remove the Mask for Unknown Reasons during Automatic Continuous Positive Airway Pressure (Auto-CPAP) Therapy: A Prospective Randomized Crossover Trial.

Backgroundand Objectives: Obstructive sleep apnea (OSA) patients may remove their mask unconsciously during automatic continuous positive airway pressure (Auto-CPAP) therapy and therefore cannot receive good treatment. The discomfort from the airflow of Auto-CPAP may be one reason for interrupted sleep. Sens Awake (SA) can detect the arousal and lower the pressure to prevent patients from fully awakening from sleep. Materials and Methods: To evaluate the effect of SA, we designed a prospective, randomized, crossover trial comparing Auto-CPAP with and without SA on Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), Nasal Obstruction Symptom Evaluation (NOSE) Scale and recorded data from the auto-CPAP machine. Results: In the 25 patients who completed the study, the gender, age, body mass index, neck circumference, polysomnography data, and previous CPAP use were not significantly different between the two arms. The average and 90th percentile pressures were significantly lower during SA on (SA on vs. off: 6.9 ± 2.7 vs. 7.3 ± 2.6 [p = 0.032] and 8.6 ± 3.0 vs. 9.2 ± 2.9 [p = 0.002], respectively). The time used, days used, compliance, average and 90th percentile leaks, and the residual Apnea-Hypopnea Index (AHI) were not significantly changed between the SA on-and-off. Based on the subjective evaluation, PSQI, ESS, and NOSE were not significantly different between the SA on-and-off; however, based on additional analyses which were compared with baseline data, the ESS was significantly lower when the SA was on (SA on vs. baseline: 11.1 ± 6.1 vs. 13.2 ± 6.0 [p = 0.023]). Conclusions: CPAP therapy with or without two weeks of the SA had a similar effect on CPAP use, sleep quality, daytime sleepiness, and nasal obstruction. The SA may have a tendency to improve daytime sleepiness, but needs further study with a longer duration of treatment.

Low-Molecular-Weight Heparin Reduces Ventilation-Induced Lung Injury through Hypoxia Inducible Factor-1α in a Murine Endotoxemia Model.

Patients with sepsis frequently require mechanical ventilation (MV) to survive. However, MV has been shown to induce the production of proinflammatory cytokines, causing ventilator-induced lung injury (VILI). It has been demonstrated that hypoxia-inducible factor (HIF)-1α plays a crucial role in inducing both apoptotic and inflammatory processes. Low-molecular-weight heparin (LMWH) has been shown to have anti-inflammatory activities. However, the effects of HIF-1α and LMWH on sepsis-related acute lung injury (ALI) have not been fully delineated. We hypothesized that LMWH would reduce lung injury, production of free radicals and epithelial apoptosis through the HIF-1α pathway. Male C57BL/6 mice were exposed to 6-mL/kg or 30-mL/kg MV for 5 h. Enoxaparin, 4 mg/kg, was administered subcutaneously 30 min before MV. We observed that MV with endotoxemia induced microvascular permeability; interleukin-6, tumor necrosis factor-α, macrophage inflammatory protein-2 and vascular endothelial growth factor protein production; neutrophil infiltration; oxidative loads; HIF-1α mRNA activation; HIF-1α expression; bronchial epithelial apoptosis; and decreased respiratory function in mice (p < 0.05). Endotoxin-induced augmentation of VILI and epithelial apoptosis were reduced in the HIF-1α-deficient mice and in the wild-type mice following enoxaparin administration (p < 0.05). Our data suggest that enoxaparin reduces endotoxin-augmented MV-induced ALI, partially by inhibiting the HIF-1α pathway.

Ethyl pyruvate attenuates ventilation-induced diaphragm dysfunction through high-mobility group box-1 in a murine endotoxaemia model.

Mechanical ventilation (MV) can save the lives of patients with sepsis. However, MV in both animal and human studies has resulted in ventilator-induced diaphragm dysfunction (VIDD). Sepsis may promote skeletal muscle atrophy in critically ill patients. Elevated high-mobility group box-1 (HMGB1) levels are associated with patients requiring long-term MV. Ethyl pyruvate (EP) has been demonstrated to lengthen survival in patients with severe sepsis. We hypothesized that the administration of HMGB1 inhibitor EP or anti-HMGB1 antibody could attenuate sepsis-exacerbated VIDD by repressing HMGB1 signalling. Male C57BL/6 mice with or without endotoxaemia were exposed to MV (10 mL/kg) for 8 hours after administrating either 100 mg/kg of EP or 100 mg/kg of anti-HMGB1 antibody. Mice exposed to MV with endotoxaemia experienced augmented VIDD, as indicated by elevated proteolytic, apoptotic and autophagic parameters. Additionally, disarrayed myofibrils and disrupted mitochondrial ultrastructures, as well as increased HMGB1 mRNA and protein expression, and plasminogen activator inhibitor-1 protein, oxidative stress, autophagosomes and myonuclear apoptosis were also observed. However, MV suppressed mitochondrial cytochrome C and diaphragm contractility in mice with endotoxaemia (P < 0.05). These deleterious effects were alleviated by pharmacologic inhibition with EP or anti-HMGB1 antibody (P < 0.05). Our data suggest that EP attenuates endotoxin-enhanced VIDD by inhibiting HMGB1 signalling pathway.

Pharyngeal distensibility during expiration is an independent predictor of the severity of obstructive sleep apnoea.

BACKGROUND AND OBJECTIVE: Pharyngeal distensibility and collapsibility reflect the passive properties of tissue in the airway, are an indicator of the ease with which an airway can be deformed and are related to the severity of obstructive sleep apnoea (OSA). During normal tidal respiration, the collapsibility of the pharynx during expiration is passive without confounding by neuromuscular activation that occurs during inspiration. We evaluated the distensibility and collapsibility of the upper airway in subjects with OSA during wakefulness using sophisticated dynamic computed tomography (CT) imaging. We hypothesized that the dynamic changes of the upper airway during expiration would be related to the severity of OSA. METHODS: Twenty-three patients with OSA and eight normal subjects underwent simultaneous measurement of respiratory flow and airway calibre using ultrafast CT. The change in pharyngeal cross-sectional area divided by the change in concomitant flow (as distensibility or collapsibility) was measured and compared across different severities of OSA. RESULTS: The slope of this relationship between delta area and delta flow during expiration was significantly higher in severe OSA when compared with normal controls and mild-moderate OSA. Differences in airway distensibility or collapsibility between severity groups were significant in expiration but not in inspiration. Distensibility or collapsibility contributed most to the apnoea-hypopnoea index in regression modelling. Age, gender, and body mass index (BMI) were not significant independent predictors. CONCLUSION: Our study demonstrates that airway distensibility during the expiratory phase of awake respiration is correlated with the severity of OSA.

Monocytic C-C chemokine receptor 5 expression increases in in vitro intermittent hypoxia condition and in severe obstructive sleep apnea patients.

PURPOSE: Obstructive sleep apnea (OSA) patients have higher risk of cardiovascular disease. C-C chemokine receptor 5 (CCR5), as an important receptor for monocyte recruitment and the initiation of atherosclerosis, was studied under intermittent hypoxia and in OSA patients. METHODS: The expression and function of CCR5 regulated by intermittent hypoxia in monocytic THP-1 cells were investigated in an in vitro intermittent hypoxia culture system. The expression levels of protein and mRNA were analyzed by western blot and RT/real-time PCR analysis. Cell adhesion assay and transwell filter migration assay were carried out to investigate the adhesion and chemotaxis of monocytes. In addition, the mRNA expression of CCR5 in monocytes isolated from peripheral blood of 72 adults was analyzed. RESULTS: Intermittent hypoxia upregulated the expression of CCR5 in THP-1 cells and enhanced the adhesion and chemotaxis of monocytes to vascular endothelial cells mediated by RANTES. The CCR5 expression induced by intermittent hypoxia was inhibited by inhibitor for p42/44 MAPK. Besides, the expression of CCR5 in monocytes increased along the AHI value especially in severe OSA patients that was statistically significant compared with mild and moderate OSA groups. CONCLUSIONS: This study demonstrated the increased monocytic CCR5 gene expression in patients with severe OSA. Intermittent hypoxia, the characteristic of OSA, induced monocytic CCR5 gene expression and the enhanced RANTES-mediated chemotaxis and adhesion through p42/44 MAPK signal pathways.

Home sleep apnea testing: comparison of manual and automated scoring across international sleep centers.

PURPOSE: To determine the agreement between the manual scoring of home sleep apnea tests (HSATs) by international sleep technologists and automated scoring systems. METHODS: Fifteen HSATs, previously recorded using a type 3 monitor, were saved in European Data Format. The studies were scored by nine experienced technologists from the sleep centers of the Sleep Apnea Global Interdisciplinary Consortium (SAGIC) using the locally available software. Each study was scored separately by human scorers using the nasal pressure (NP), flow derived from the NP signal (transformed NP), or respiratory inductive plethysmography (RIP) flow. The same procedure was followed using two automated scoring systems: Remlogic (RLG) and Noxturnal (NOX). RESULTS: The intra-class correlation coefficients (ICCs) of the apnea-hypopnea index (AHI) scoring using the NP, transformed NP, and RIP flow were 0.96 [95% CI 0.93-0.99], 0.98 [0.96-0.99], and 0.97 [0.95-0.99], respectively. Using the NP signal, the mean differences in AHI between the average of the manual scoring and the automated systems were - 0.9 ± 3.1/h (AHIRLG vs AHIMANUAL) and - 1.3 ± 2.6/h (AHINOX vs AHIMANUAL). Using the transformed NP, the mean differences in AHI were - 1.9 ± 3.3/h (AHIRLG vs AHIMANUAL) and 1.6 ± 3.0/h (AHINOX vs AHIMANUAL). Using the RIP flow, the mean differences in AHI were - 2.7 ± 4.5/h (AHIRLG vs AHIMANUAL) and 2.3 ± 3.4/h (AHINOX vs AHIMANUAL). CONCLUSIONS: There is very strong agreement in the scoring of the AHI for HSATs between the automated systems and experienced international technologists. Automated scoring of HSATs using commercially available software may be useful to standardize scoring in future endeavors involving international sleep centers.

Snoring sound energy as a potential biomarker for disease severity and surgical response in childhood obstructive sleep apnoea: A pilot study.

OBJECTIVE: To investigate the relationship between baseline snoring sound energy (SSE) and disease severity, changes in SSE after adenotonsillectomy, and the predictors of surgical success in children with obstructive sleep apnoea (OSA). DESIGN: Prospective cohort study. SETTING: Tertiary referral medical centre. PARTICIPANTS: Thirty-two children with OSA whose apnoea-hypopnoea index ≥5 or apnoea-hypopnoea index ≥1.5 with OSA comorbidities were recruited. Patients with complicated OSA were excluded. All participants underwent snoring sound analysis, polysomnography, and adenotonsillectomy. MAIN OUTCOME MEASURES: Snoring sound energy and apnoea-hypopnoea index were assessed at baseline and 6 months after adenotonsillectomy. Surgical success was defined as a postoperative apnoea-hypopnoea index <1.5. RESULTS: The median age, body mass index, and apnoea-hypopnoea index was 9 years, 19.0 kg/m2 , and 13.2 events/h, respectively. Multivariate logistic regression showed that a baseline tonsil size of IV (odds ratio 15.7 [95% CI: 1.5-166.3]) and SSE of 801-1000 Hz > 21.9 dB (odds ratio 32.3 [95% CI: 2.6-396.6]) were significantly related to severe OSA. Following adenotonsillectomy, apnoea-hypopnoea index decreased significantly (P < 0.001). SSE of 41-200 Hz, 201-400 Hz and 801-1000 Hz also decreased significantly (P = 0.04, 0.01 and 0.006, respectively). Baseline SSE of 801-1000 Hz < 8.5 dB significantly predicted surgical success (odds ratio 11.0 [95% CI: 1.4-85.2]). CONCLUSIONS: Our findings suggest the potential utility of SSE of 801-1000 Hz to screen for severe OSA, predict surgical success and assess therapeutic outcomes. Specific baseline SSE may represent a potential biomarker for childhood OSA.

Attenuation of ventilation-induced diaphragm dysfunction through toll-like receptor 4 and nuclear factor-κB in a murine endotoxemia model.

Mechanical ventilation (MV) is often used to maintain life in patients with sepsis and sepsis-related acute lung injury. However, controlled MV may cause diaphragm weakness due to muscle injury and atrophy, an effect termed ventilator-induced diaphragm dysfunction (VIDD). Toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) signaling pathways may elicit sepsis-related acute inflammatory responses and muscle protein degradation and mediate the pathogenic mechanisms of VIDD. However, the mechanisms regulating the interactions between VIDD and endotoxemia are unclear. We hypothesized that mechanical stretch with or without endotoxin treatment would augment diaphragmatic structural damage, the production of free radicals, muscle proteolysis, mitochondrial dysfunction, and autophagy of the diaphragm via the TLR4/NF-κB pathway. Male C57BL/6 mice, either wild-type or TLR4-deficient, aged between 6 and 8 weeks were exposed to MV (6 mL/kg or 10 mL/kg) with or without endotoxemia for 8 h. Nonventilated mice were used as controls. MV with endotoxemia aggravated VIDD, as demonstrated by the increases in the expression levels of TLR4, caspase-3, atrogin-1, muscle ring finger-1, and microtubule-associated protein light chain 3-II. In addition, increased NF-κB phosphorylation and oxidative loads, disorganized myofibrils, disrupted mitochondria, autophagy, and myonuclear apoptosis were also observed. Furthermore, MV with endotoxemia reduced P62 levels and diaphragm muscle fiber size (P < 0.05). Endotoxin-exacerbated VIDD was attenuated by pharmacologic inhibition with a NF-κB inhibitor or in TLR4-deficient mice (P < 0.05). Our data indicate that endotoxin-augmented MV-induced diaphragmatic injury occurs through the activation of the TLR4/NF-κB signaling pathway.

Three-dimensional photography for the evaluation of facial profiles in obstructive sleep apnoea.

BACKGROUND AND OBJECTIVE: Craniofacial structure is an important determinant of obstructive sleep apnoea (OSA) syndrome risk. Three-dimensional stereo-photogrammetry (3dMD) is a novel technique which allows quantification of the craniofacial profile. This study compares the facial images of OSA patients captured by 3dMD to three-dimensional computed tomography (3-D CT) and two-dimensional (2-D) digital photogrammetry. Measurements were correlated with indices of OSA severity. METHODS: Thirty-eight patients diagnosed with OSA were included, and digital photogrammetry, 3dMD and 3-D CT were performed. Distances, areas, angles and volumes from the images captured by three methods were analysed. RESULTS: Almost all measurements captured by 3dMD showed strong agreement with 3-D CT measurements. Results from 2-D digital photogrammetry showed poor agreement with 3-D CT. Mandibular width, neck perimeter size and maxillary volume measurements correlated well with the severity of OSA using all three imaging methods. Mandibular length, facial width, binocular width, neck width, cranial base triangle area, cranial base area 1 and middle cranial fossa volume correlated well with OSA severity using 3dMD and 3-D CT, but not with 2-D digital photogrammetry. CONCLUSION: 3dMD provided accurate craniofacial measurements of OSA patients, which were highly concordant with those obtained by CT, while avoiding the radiation associated with CT.

Factors associated with undiagnosed obstructive sleep apnoea among hypertensive patients: A multisite cross-sectional survey study in Taiwan.

AIMS AND OBJECTIVES: To investigate the distribution and risk factors associated with undiagnosed obstructive sleep apnoea among hypertensive patients. BACKGROUND: Obstructive sleep Apnoea has been deemed a cardinal risk factor affecting cardiovascular event, and the condition is still frequently overlooked clinically. The lack of advanced diagnosis often causes hypertensive patients with obstructive sleep apnoea to miss opportunities for preventing chronic diseases. DESIGN: A cross-sectional design. METHODS: A total of 215 hypertensive participants were recruited from the cardiovascular outpatients of medical centre in northern and middle Taiwan. The Chinese version of Pittsburgh Sleep Quality Index, the Chinese version of the Epworth Sleep Scale and a portable sleep monitoring device were used for data collection. Logistic regression analysis was conducted to identify the factors affecting hypertensive patients with obstructive sleep apnoea, and a multinomial logistic regression analysis was used to examine the major influence factors for each obstructive sleep apnoea severity level. RESULTS: 81.9% of the hypertensive participants were found having obstructive sleep apnoea. Concerning to the obstructive sleep apnoea severity, 50.0% of participants had mild obstructive sleep apnoea. After controlling the confounding variables, the supine position (odds ratio, 1.04; 95% CI, 1.01-1.07), SO2 (odds ratio, 0.58; 95% CI, 0.38-0.89) and oxygen desaturation index (odds ratio, 2.70; 95% CI, 1.18-6.18) were significantly associated with obstructive sleep apnoea. Furthermore, severe obstructive sleep apnoea was significantly correlated with gender (odds ratio, 0.04; 95% CI, 0.00-0.66), excessive daytime sleepiness (odds ratio, 20.27; 95% CI, 1.58-26.97) and oxygen desaturation index (odds ratio, 4.05; 95% CI, 1.86-8.81). CONCLUSIONS: Nearly 82% of the hypertensive participants were found having undiagnosed obstructive sleep apnoea, and 80% of them were mild or moderate severity. Oxygen desaturation index, SO2 and the supine position were found to be major predictors for obstructive sleep apnoea. Remarkably, oxygen desaturation index was the most significant predictor for mild, moderate and severe obstructive sleep apnoea. RELEVANCE TO CLINICAL PRACTICE: Healthcare providers should enhance their sensitivities to hypertensive patients at a high risk for obstructive sleep apnoea by actively assessing common obstructive sleep apnoea symptoms and providing strategies to alleviate obstructive sleep apnoea symptoms.

Nintedanib reduces ventilation-augmented bleomycin-induced epithelial-mesenchymal transition and lung fibrosis through suppression of the Src pathway.

Mechanical ventilation (MV) used in patients with acute respiratory distress syndrome (ARDS) can increase lung inflammation and pulmonary fibrogenesis. Src is crucial in mediating the transforming growth factor (TGF)-ß1-induced epithelial-mesenchymal transition (EMT) during the fibroproliferative phase of ARDS. Nintedanib, a multitargeted tyrosine kinase inhibitor that directly blocks Src, has been approved for the treatment of idiopathic pulmonary fibrosis. The mechanisms regulating interactions among MV, EMT and Src remain unclear. In this study, we suggested hypothesized that nintedanib can suppress MV-augmented bleomycin-induced EMT and pulmonary fibrosis by inhibiting the Src pathway. Five days after administrating bleomycin to mimic acute lung injury (ALI), C57BL/6 mice, either wild-type or Src-deficient were exposed to low tidal volume (VT ) (6 ml/kg) or high VT (30 ml/kg) MV with room air for 5 hrs. Oral nintedanib was administered once daily in doses of 30, 60 and 100 mg/kg for 5 days before MV. Non-ventilated mice were used as control groups. Following bleomycin exposure in wild-type mice, high VT MV induced substantial increases in microvascular permeability, TGF-ß1, malondialdehyde, Masson's trichrome staining, collagen 1a1 gene expression, EMT (identified by colocalization of increased staining of α-smooth muscle actin and decreased staining of E-cadherin) and alveolar epithelial apoptosis (P < 0.05). Oral nintedanib, which simulated genetic downregulation of Src signalling using Src-deficient mice, dampened the MV-augmented profibrotic mediators, EMT profile, epithelial apoptotic cell death and pathologic fibrotic scores (P < 0.05). Our data indicate that nintedanib reduces high VT MV-augmented EMT and pulmonary fibrosis after bleomycin-induced ALI, partly by inhibiting the Src pathway.

Simple obstructive sleep apnea patients without hypertension or diabetes accelerate kidney dysfunction: a population follow-up cohort study from Taiwan.

BACKGROUNDS: Obstructive sleep apnea (OSA) is common in patients on hemodialysis, but its correlation with chronic kidney disease (CKD) is not clear. We aimed to clarify the relationship between OSA without hypertension or diabetes and incidence of CKD in Taiwan. METHODS: This population-based cohort study consisted of patients with newly diagnosed OSA between 2000 and 2009. The comparison cohort was matched for age, sex, diabetes mellitus, and hypertension. All subjects previously diagnosed with acute or chronic kidney disease were excluded. The primary end point was newly diagnosed CKD. RESULTS: We identified 6866 subjects with OSA during the 10-year study period. The median duration until development of CKD in the OSA cohort was 3.2 years, 2.5 months earlier than that in the non-OSA cohort. After exclusion of hypertension and diabetes, 4319 OSA patients was identified and the hazard ratio (HR) of CKD with OSA was 1.37 (95 % confidence interval [CI], 1.05-1.77; p = 0.019). In the subgroup analysis, an increased incidence of CKD in OSA was observed in women (HR, 1.41; 95 % CI, 1.12-1.78; p = 0.0036). CONCLUSIONS: This longitudinal population-based cohort study provides evidence that patients with OSA even without diabetes or hypertension are at higher risk of developing CKD over the next 3 years and nearly 2.5 months earlier than the non-OSA cohort, particularly women.

The gender difference of snore distribution and increased tendency to snore in women with menopausal syndrome: a general population study.

PURPOSE: Sleep-disordered breathing (SDB) is a prevalent disorder with a major impact in women, especially postmenopausal women. However, few studies have investigated the prevalence of a specific SDB, snoring, among women especially those with menopausal syndrome. METHODS: Computer-assisted telephone interviews were conducted in Taiwan. Adults over 20 years of age were interviewed. The number of successful interviews was calculated based on the population prior to the study. Demographic data and information about snoring, menopausal syndrome, and medical conditions were obtained. RESULTS: In total, 3624 adults, 1473 males and 2151 females, completed the interviews. Both men and women shows an increase in snoring until age 50 to 59 years, followed by a decline in snoring that is less steep among women. The prevalence of snoring increased significantly in females after age 50 years, which is the mean menopausal age in our country (p < 0.05). After adjusting for age, body mass index, and other major diseases, the percentage of women with snoring was significantly higher among those with menopausal syndrome than those without menopausal syndrome (p = 0.021, odds ratio = 1.629). CONCLUSIONS: This population-based study revealed different snoring percentages among men and women and diminishing differences in the older population. Additionally, the percentage of women with snoring was increased among those women who were older than 50 years and those with menopausal syndrome.

Increased MCP-1 gene expression in monocytes of severe OSA patients and under intermittent hypoxia.

PURPOSE: Obstructive sleep apnea (OSA) is known to be a risk factor of coronary artery disease. Monocyte chemoattractant protein-1 (MCP-1), as a critical factor for monocyte infiltration, is known to play a role in the development of atherosclerosis. This study aimed to investigate the effect of intermittent hypoxia, the hallmark of OSA, on the MCP-1 expression of monocytes. METHODS: Peripheral blood was sampled from 61 adults enrolled for suspected OSA. RNA was prepared from the isolated monocytes for the analysis of MCP-1. The effect of in vitro intermittent hypoxia on the regulation and function of MCP-1 was investigated on THP-1 monocytic cells and human monocytes. The mRNA and secreted protein levels were investigated by RT/real-time PCR and enzyme-linked immunosorbent assay, respectively. RESULTS: Monocytic MCP-1 gene expression was found to be increased significantly in severe OSA patients. In vitro intermittent hypoxia was demonstrated to increase the mRNA and protein expression levels of MCP-1 dose- and time-dependently in THP-1 monocytic cells. The MCP-1 mRNA expression in monocytes isolated from OSA patient was induced to a much higher level compared to that from normal control. Pre-treatment with inhibitor for p42/44 MAPK or p38 MAPK suppressed the activation of MCP-1 expression by intermittent hypoxia. CONCLUSIONS: This is the first study to demonstrate the increase of MCP-1 gene expression in monocytes of severe OSA patients. In addition, monocytic MCP-1 gene expression can be induced under intermittent hypoxia.

Factors responsible for poor sleep quality in patients with chronic obstructive pulmonary disease.

BACKGROUND: Sleep disturbance is a common complaint in patients with chronic obstructive lung disease (COPD). However, the factors resulting in sleep disturbance remain unclear. This retrospective, observational, multicenter study aimed to identify the factors associated with sleep disturbance in patients with COPD. METHODS: The study was a retrospective, observational, and multicenter research. Data including age, sex, body mass index, smoking status, COPD inhaler prescribed, clinical symptoms, pulmonary function tests, medical history of comorbidities, and questionnaires were collected. Parameters including demographics, symptoms, medication, severity, functional classification, and comorbidities were correlated with sleep quality scores. RESULTS: Among 377 patients with COPD, 200 (53 %) patients experienced poor sleep quality (Pittsburg Sleep Quality Index scores > 5). A significant difference in sleep quality, as measured by PSQI scores, was noted between groups based on the 2011 Global Initiatives for Chronic Obstructive Lung Disease (GOLD) classification system. The most common sleep disturbances included "getting up to use the bathroom" (70.3 %), "wake up at night or early morning" (40.3 %), and "cough and snore loudly at night" (15.9 %). The use of inhaled corticosteroids, the presence of wheezing, COPD Assessment Test (CAT) scores, and Modified Medical Research Council (mMRC) dyspnea scale scores positively correlated with poor sleep quality (odds ratio: 1.51, 1.66, 1.09, and 1.30, respectively). Upon multivariate analysis, the CAT score was an independent factor for poor sleep quality in these patients. With the exception of sleep problem items, based on the CAT questionnaire, phlegm was significantly higher in COPD patients with poor sleep quality. CONCLUSIONS: Poor sleep quality is common among patients with COPD and symptoms including wheeze, phlegm, and inhaled corticosteroid use may contribute to poor sleep quality. The CAT score is a good indicator of poor sleep quality in patients with COPD.

Activation of Src-dependent Smad3 signaling mediates the neutrophilic inflammation and oxidative stress in hyperoxia-augmented ventilator-induced lung injury.

BACKGROUND: Mechanical ventilation and concomitant administration of hyperoxia in patients with acute respiratory distress syndrome can damage the alveolar epithelial and capillary endothelial barrier by producing inflammatory cytokines and reactive oxygen species. The Src tyrosine kinase and Smad3 are crucial inflammatory regulators used for ventilator-induced lung injury (VILI). The mechanisms regulating interactions between high-tidal-volume mechanical ventilation, hyperoxia, and acute lung injury (ALI) are unclear. We hypothesized that high-tidal-volume mechanical stretches and hyperoxia augment lung inflammation through upregulation of the Src and Smad3 pathways. METHODS: Wild-type or Src-deficient C57BL/6 mice, aged between 6 and 8 weeks, were exposed to high-tidal-volume (30 mL/kg) ventilation with room air or hyperoxia for 1-4 h after 2-mg/kg Smad3 inhibitor (SIS3) administration. Nonventilated mice were used as control subjects. RESULTS: We observed that the addition of hyperoxia to high-tidal-volume mechanical ventilation further induced microvascular permeability, neutrophil infiltration, macrophage inflammatory protein-2 and matrix metalloproteinase-9 (MMP-9) production, malondialdehyde, nicotinamide adenine dinucleotide phosphate oxidase activity, MMP-9 mRNA expression, hypoxemia, and Src and Smad3 activation (P < 0.05). Hyperoxia-induced augmentation of VILI was attenuated in Src-deficient mice and mice with pharmacological inhibition of Smad3 activity by SIS3 (P < 0.05). Mechanical ventilation of Src-deficient mice with hyperoxia further reduced the activation of Smad3. CONCLUSIONS: Our data suggest that hyperoxia-increased high-tidal-volume ventilation-induced ALI partially depends on the Src and Smad3 pathways.

Clinical outcomes and molecular typing of heterogenous vancomycin-intermediate Staphylococcus aureus bacteremia in patients in intensive care units.

BACKGROUND: Staphylococcus aureus is one of most common pathogens in humans. Methicillin-resistant S. aureus (MRSA) accounts for 64 % of S. aureus bacteremia isolated in intensive care units (ICUs), and heteroresistant vancomycin-intermediates S. aureus (hVISA) is a phenotype of MRSA. However, studies focusing on the hVISA impact on critically ill patients are scarce. METHODS: This was a retrospective study conducted in a tertiary medical center from January 2009 to December 2010. All adult patients in ICUs with MRSA bloodstream infection were eligible. A modified population analysis profile and area under the curve method was applied to all isolates to confirm hVISA phenotype. Multilocus sequence typing (MLST), staphylococcal cassette chromosome mec (SCCmec) and the accessory gene regulator (agr) typing were performed individually. Clinical outcomes including in-hospital mortality, length of stay in intensive care unit and hospital after MRSA bacteremia of the patients were also analyzed. RESULTS: A total of 48 patients were enrolled and 14 patients were confirmed to have the hVISA phenotype. The prevalence of hVISA was 29.2 %. There was no difference in the age, sex, comorbidity, Charlson's comorbidity score and previous vancomycin therapy between the hVISA and VSSA groups. The hVISA group had a significantly higher in-hospital mortality than the VSSA group (13/14 versus 22/34; p = 0.046). All of the 14 hVISA patients had an MIC = 2 mg/L by E-test and this represented a significant association between high MIC and the development of hVISA (p < 0.001). MLST analysis showed all the isolates in the hVISA group were ST239, while ST239 (14/34; 41.2 %) and ST5 (12/34; 35.3 %) were predominant in the VSSA group (p = 0.007). A comparison of the survivor and non-survivor group showed that the hVISA phenotype (OR 11.8; 95 % CI 1.1-126.99; p = 0.042) and sequential organ failure assessment (SOFA) score (OR 1.39; 95 % CI 1.07-1.81; p = 0.014) were independent factors significantly associated with in-hospital mortality. CONCLUSIONS: Patients in ICUs with MRSA bacteremia may have a higher in-hospital mortality if they have the hVISA phenotype. SOFA score is also predictor of mortality.