Increased Production of Interleukin-10 and Tumor Necrosis Factor-Alpha in Stimulated Peripheral Blood Mononuclear Cells after Inhibition of S100A12.

Sepsis may induce immunosuppression and result in death. S100A12 can bind to the receptor for advanced glycation end-products (RAGE) and Toll-like receptor (TLR)4 following induction of various inflammatory responses. It is unclear whether S100A12 significantly influences the immune system, which may be associated with sepsis-related mortality. We measured plasma S100A12 levels and cytokine responses (mean ± standard error mean) of lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs) after S100A12 inhibition in healthy controls and patients with sepsis on days one and seven. Day one plasma soluble RAGE (sRAGE) and S100A12 levels in patients with sepsis were significantly higher than those in controls (2481.3 ± 295.0 vs. 1273.0 ± 108.2 pg/mL, p < 0.001; 530.3 ± 18.2 vs. 310.1 ± 28.1 pg/mL, p < 0.001, respectively). Day seven plasma S100A12 levels in non-survivors were significantly higher than those in survivors (593.1 ± 12.7 vs. 499.3 ± 23.8 pg/mL, p = 0.002, respectively). In survivors, plasma sRAGE levels were significantly decreased after 6 days (2297.3 ± 320.3 vs. 1530.1 ± 219.1 pg/mL, p = 0.009, respectively), but not in non-survivors. Inhibiting S100A12 increased the production of tumor necrosis factor (TNF)-α and interleukin (IL)-10 in stimulated PBMCs for both controls and patients. Therefore, S100A12 plays an important role in sepsis pathogenesis. S100A12 may competitively bind to TLR4 and RAGE, resulting in decreased IL-10 and TNF-α production.

Decreased Monocyte HLA-DR Expression in Patients with Sepsis and Acute Kidney Injury.

Background and objectives: Acute kidney injury (AKI) is common in critically ill patients, especially those with sepsis. Persistently low human leukocyte antigen (HLA)-DR expression in monocytes reflects the decreased function of antigen-presenting cells, contributing to poor outcomes in sepsis. This study aimed to establish an association between AKI and HLA-DR expression in monocytes of patients with sepsis. Materials and Methods: We detected HLA-DR expression in monocytes and measured plasma levels of S100A12, high-mobility group box 1 (HMGB1), advanced glycation end products (AGE), and soluble receptor for AGE (sRAGE) from septic patients and healthy controls. Results: HLA-DR expression in monocytes was decreased in patients with AKI than in those without AKI (29.8 ± 5.0% vs. 53.1 ± 5.8%, p = 0.005). Compared with AKI patients, the mean monocyte HLA-DR expression in patients with end-stage renal disease was increased without statistical significance. There were no differences in the AGE/sRAGE ratio and plasma levels of S100A12, HMGB1, AGE, and sRAGE between patients with and without AKI. Conclusions: Compared with septic patients without AKI, patients with AKI had significantly lower HLA-DR expression in monocytes. The role of hemodialysis in monocyte HLA-DR expression needs further studies to explore.

Mechanical power during extracorporeal membrane oxygenation and hospital mortality in patients with acute respiratory distress syndrome.

BACKGROUND: Mechanical power (MP) refers to the energy delivered by a ventilator to the respiratory system per unit of time. MP referenced to predicted body weight (PBW) or respiratory system compliance have better predictive value for mortality than MP alone in acute respiratory distress syndrome (ARDS). Our objective was to assess the potential impact of consecutive changes of MP on hospital mortality among ARDS patients receiving extracorporeal membrane oxygenation (ECMO). METHODS: We performed a retrospective analysis of patients with severe ARDS receiving ECMO in a tertiary care referral center in Taiwan between May 2006 and October 2015. Serial changes of MP during ECMO were recorded. RESULTS: A total of 152 patients with severe ARDS rescued with ECMO were analyzed. Overall hospital mortality was 53.3%. There were no significant differences between survivors and nonsurvivors in terms of baseline values of MP or other ventilator settings. Cox regression models demonstrated that mean MP alone, MP referenced to PBW, and MP referenced to compliance during the first 3 days of ECMO were all independently associated with hospital mortality. Higher MP referenced to compliance (HR 2.289 [95% CI 1.214-4.314], p = 0.010) was associated with a higher risk of death than MP itself (HR 1.060 [95% CI 1.018-1.104], p = 0.005) or MP referenced to PBW (HR 1.004 [95% CI 1.002-1.007], p < 0.001). The 90-day hospital mortality of patients with high MP (> 14.4 J/min) during the first 3 days of ECMO was significantly higher than that of patients with low MP (≦ 14.4 J/min) (70.7% vs. 46.8%, p = 0.004), and the 90-day hospital mortality of patients with high MP referenced to compliance (> 0.53 J/min/ml/cm H2O) during the first 3 days of ECMO was significantly higher than that of patients with low MP referenced to compliance (≦ 0.53 J/min/ml/cm H2O) (63.6% vs. 29.7%, p < 0.001). CONCLUSIONS: MP during the first 3 days of ECMO was the only ventilatory variable independently associated with 90-day hospital mortality, and MP referenced to compliance during ECMO was more predictive for mortality than was MP alone.

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.

A five-year longitudinal study of the relation between end-stage kidney disease as the outcomes.

BACKGROUND: Patients with end-stage kidney disease (ESKD) are required to undergo consecutive time-based blood and biochemical tests to determine the progression of the disease according to changes in their blood and biochemical data. This study employed a random intercept model to investigate whether time-based blood and biochemical data present any notable clinical meaning that can be used to track disease progression. METHODS: This study conducted a retrospective analysis on the dialytic data of 148 patients with ESKD, who received hemodialysis between January 2005 and December 2015. The patients were all at least 20 years old, and the data used included patient demographic information and results for at least 60 blood and biochemical tests. A random intercept model was used to analyze the relationships among blood and biochemical test results, explanatory variables of patient comorbidities, and time. RESULTS: The age range of patients was between 33 and 98 years, with an average of 66.1 years and those over 65 years old comprising 51.3% (n = 76) of the total. Furthermore, hypertension was found to be the most common comorbidity among patients (87.2%, n = 129), followed by anemia (48.6%, n = 72), diabetes (47.3%, n = 70), dyslipidemia (19.6%, n = 29), and peptic ulcer (19.6%, n = 29). Coronary atherosclerotic heart disease is a comorbidity that can serve as a strong and independent marker for prognosis in patients with ESKD. Serum creatinine level can serve as an alternative indicator because patients with ESKD and comorbid diabetes may exhibit increased creatinine levels. CONCLUSIONS: The results of a parameter estimation for longitudinal data analysis suggested that comorbidity and time were critical variables influencing blood and biochemical test results. Furthermore, WBC and HBC, HCT, albumin, protein, and creatinine levels were recognized as variables of critical significance. The results obtained in this study indicate that multimorbidity increases the treatment burden on patients, leading to polypharmacy. For this reason, comprehensive care and treatment of ESKD cannot rely solely on data from one single time point; instead, longitudinal analysis and other data that can affect patient prognosis must also be considered.

Outcomes of severe H1N1 pneumoniae: A retrospective study at intensive care units.

BACKGROUND: The incidence of acute respiratory distress syndrome (ARDS) and the mortality rate of H1N1 influenza pneumonia are unclear. The aim of this study is to investigate the clinical features and outcomes of adult patients admitted to intensive care units (ICUs) with H1N1 pneumonia related ARDS. METHODS: This retrospective study included patients with confirmed H1N1 influenza pneumonia admitted to the ICUs of a medical center between July 2009 and May 2014. We investigated the patients' characteristics, clinical presentations, illness severities, and outcomes. RESULTS: Sixty-six patients were confirmed to have H1N1 influenza pneumonia requiring mechanical ventilation. Fifty-four of those patients (82%) developed ARDS, while their hospital mortality rate was 33% (22/66). There were no significant differences in the ICU and hospital mortality rates of the ARDS and non-ARDS patients. Among the ARDS patients, there were higher rates of solid malignant disease (22.8% vs. 2.8%, p = 0.038) and sepsis (66.7% vs. 33.3%, p = 0.020) and a higher mean tidal volume (8.9 ± 1.8 vs. 7.8 ± 1.9 ml/kg, p = 0.032) in the non-survivors than the survivors. Logistic regression analysis revealed that a high tidal volume (odds ratio = 1.448, 95 % CI = 1.033-2.030; p = 0.032) and sequential organ failure assessment (SOFA) score (odds ratio = 1.233, 95% CI = 1.029-1.478; p = 0.023) were the risk factors of hospital mortality. CONCLUSION: For H1N1 influenza pneumonia patients admitted to ICUs with mechanical ventilation, there is a high probability of developing ARDS with a modest mortality rate. For patients with ARDS due to H1N1 influenza pneumonia, the tidal volume and SOFA score are the predictors of hospital mortality.

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.

Antiobesity and Uric Acid-Lowering Effect of Lactobacillus plantarum GKM3 in High-Fat-Diet-Induced Obese Rats.

Objective: Obesity has become one of the world's biggest issues. This condition has a great impact on several metabolic and chronic diseases. For example, obesity is often accompanied by hyperuricemia or gout. However, few drugs are available for the treatment of obesity. The present study is to evaluate the antiobesity effect of Lactobacillus plantarum GKM3 in high-fat-diet-induced obese rats and whether taking L plantarum GKM3 can effectively reduce uric acid accumulation caused by obesity and ameliorate other harmful factors. Method: Sixty male Wistar rats were divided into five groups as follows: ( 1 ) ND group, fed normal diet; ( 2 ) HFC group, fed AIN93G-based high-fat diet containing 65% solids, 7% soybean oil, and 25% lard; ( 3 ) HFL group, fed AIN93G-based high-fat diet supplemented with 102.7 mg/kg/d L plantarum GKM3; ( 4 ) HFM group, fed AIN93G-based high-fat diet supplemented with 205.4 mg/kg/d L plantarum GKM3; and ( 5 ) HFH group, fed AIN93G-based high-fat diet supplemented with 513.5 mg/kg/d L plantarum GKM3. After 6 weeks, the body, organ, and fat weights; food intake; blood serum levels; and adipocyte size were measured. Results: Results showed that rats fed on the high-fat diet showed more body weight, increased feed efficiency, higher fat deposition, higher total liver weight, elevated serum lipid levels, and increased adipocyte size compared with those on the normal diet. All these effects were reversed by supplementation of L plantarum GKM3. Conclusions: In conclusion, we suggest that the L plantarum GKM3 supplement may have beneficial antiobesity and uric acid-lowering effects.

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.

Using Nursing Information and Data Mining to Explore the Factors That Predict Pressure Injuries for Patients at the End of Life.

This study investigated the association between patient characteristics and the occurrence of pressure injuries for patients at the end of life. A retrospective study was conducted using data collected from 2062 patients at the end of life between January 2007 and October 2015. In addition to demographic data and pressure injury risk assessment scale scores, injury history, disease type, and length of hospitalization were revealed as the major independent variables for predicting the occurrence of pressure injuries. Both χ tests and t tests were employed for binary variable analysis, and logistic regression was used to conduct multivariate analysis. Classification models were formulated through decision tree analysis, backpropagation neural network, and support vector machine algorithms. The rules obtained using the decision tree algorithm were analyzed and interpreted. The accuracy rate, sensitivity, and specificity of the decision tree, backpropagation neural network, and support vector machine algorithms were 77.15%, 79.54%, and 74.76%; 78.12%, 81.37%, and 74.85%; and 79.32%, 81.03%, and 78.75%, respectively. The predictive factors, ranked in order of importance, were history of pressure injuries, without cancer, excretion, activity/mobility, and skin condition/circulation. These were the primary shared risk factors among the four models used in this study.

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.

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.

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.

Non-invasive Assessment of Swallowing and Respiration Coordination for the OSA Patient.

The objectives of this study are to investigate swallowing and its coordination with respiration in patients with obstructive sleep apnea (OSA). This is a prospective cohort study conducted in a tertiary referred Medical Center. A non-invasive method of assessing swallowing was used to detect the oropharyngeal swallowing parameters and the coordination with respiration during swallowing. The system used to assess swallowing detected: (1) movement of the larynx using a force-sensing resistor; (2) submental muscle activity using surface electromyography; and (3) coordination with respiration by measuring nasal airflow. Five sizes of water boluses (maximum 20 mL) were swallowed three times, and the data recorded and analyzed for each participant. Thirty-nine normal controls and 35 patients with OSA who fulfilled the inclusion criteria were recruited. The oropharyngeal swallowing parameters of the patients differed from the controls, including longer total excursion duration and shorter duration of submental muscles contraction. A longer swallowing respiratory pause (SRP), temporary coordination with respiration during swallowing, was demonstrated in the patients compared with the controls. The frequency of non-expiratory/expiratory pre- and postswallowing respiratory phase patterns of the patients was similar with the controls. There was significantly more piecemeal deglutition in OSA patients when clumping 10- and 20-mL water boluses swallowing together (p = 0.048). Oropharyngeal swallowing and coordination with respiration affected patients with OSA, and it could be detected using a non-invasive method. The results of this study may serve as a baseline for further research and help advance research methods in obstructive sleep apnea swallowing studies.

α-Melanocyte-stimulating hormone inhibits angiogenesis through attenuation of VEGF/VEGFR2 signaling pathway.

BACKGROUND: Gene therapy of proopiomelanocortin, the precursor of α-melanocyte-stimulating hormone (α-MSH), suppresses the neovascularization in tumors. However, the roles of α-MSH in angiogenesis remain unclear. METHODS: The influence of α-MSH on angiogenesis was evaluated by ex vivo rat aorta and in vivo, including transgenic zebrafish and chicken chorioallantoic membrane (CAM) assays. The effect of α-MSH on proliferation, matrix metalloproteinase (MMP) secretion, migration and tube formation was examined using human umbilical vein endothelial cells (HUVECs). The expression of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) was investigated by quantitative RT-PCR, immunoblot and immunofluorescent analysis. Antibodies' neutralization was employed to dissect the receptor(s) transmitting α-MSH signaling. RESULTS: Application of α-MSH potently suppressed the microvessels sprouting in organotypic aortic rings. Besides, α-MSH perturbed the vessels development in zebrafish and chicken embryos. α-MSH (0.01-10nM) inhibited the MMP-2 secretion, migration and tube formation of HUVECs without affecting proliferation. Mechanistic studies unveiled α-MSH decreased the VEGF expression and release in HUVECs. Besides, α-MSH downregulated the VEGFR2 expression at transcriptional and translational levels. Importantly, α-MSH attenuated the Akt phosphorylation, but enhanced the expression of PTEN, endogenous antagonist of PI3K/Akt signaling. Expression analysis and antibody neutralization revealed that MC1-R and MC2-R participated in α-MSH-induced blockage of migration and VEGF/VEGFR2/Akt signaling. However, VEGF supply failed to reverse the anti-angiogenic function of α-MSH. CONCLUSIONS: α-MSH inhibits the physiological angiogenesis by attenuating VEGF/VEGFR2/Akt signaling in endothelial cells. GENERAL SIGNIFICANCE: α-MSH is a potent angiogenesis inhibitor targeting at endothelial VEGF/VEGFR2 signaling, which may have potential for therapeutic application.

Diffuse alveolar damage associated mortality in selected acute respiratory distress syndrome patients with open lung biopsy.

INTRODUCTION: Diffuse alveolar damage (DAD) is the pathological hallmark of acute respiratory distress syndrome (ARDS), however, the presence of DAD in the clinical criteria of ARDS patients by Berlin definition is little known. This study is designed to investigate the role of DAD in ARDS patients who underwent open lung biopsy. METHODS: We retrospectively reviewed all ARDS patients who met the Berlin definition and underwent open lung biopsy from January 1999 to January 2014 in a referred medical center. DAD is characterized by hyaline membrane formation, lung edema, inflammation, hemorrhage and alveolar epithelial cell injury. Clinical data including baseline characteristics, severity of ARDS, clinical and pathological diagnoses, and survival outcomes were analyzed. RESULTS: A total of 1838 patients with ARDS were identified and open lung biopsies were performed on 101 patients (5.5 %) during the study period. Of these 101 patients, the severity of ARDS on diagnosis was mild of 16.8 %, moderate of 56.5 % and severe of 26.7 %. The hospital mortality rate was not significant difference between the three groups (64.7 % vs 61.4 % vs 55.6 %, p = 0.81). Of the 101 clinical ARDS patients with open lung biopsies, 56.4 % (57/101) patients had DAD according to biopsy results. The proportion of DAD were 76.5 % (13/17) in mild, 56.1 % (32/57) in moderate and 44.4 % (12/27) in severe ARDS and there is no significant difference between the three groups (p = 0.113). Pathological findings of DAD patients had a higher hospital mortality rate than non-DAD patients (71.9 % vs 45.5 %, p = 0.007). Pathological findings of DAD (odds ratio: 3.554, 95 % CI, 1.385-9.12; p = 0.008) and Sequential Organ Failure Assessment score on the biopsy day (odds ratio: 1.424, 95 % CI, 1.187-1.707; p<0.001) were significantly and independently associated with hospital mortality. The baseline demographics and clinical characteristics were not significantly different between DAD and non-DAD patients. CONCLUSIONS: The correlation of pathological findings of DAD and ARDS diagnosed by Berlin definition is modest. A pathological finding of DAD in ARDS patients is associated with hospital mortality and there are no clinical characteristics that could identify DAD patients before open lung biopsy.

Coral-derived compound WA-25 inhibits angiogenesis by attenuating the VEGF/VEGFR2 signaling pathway.

BACKGROUND: WA-25 (dihydroaustrasulfone alcohol, a synthetic derivative of marine compound WE-2) suppresses atherosclerosis in rats by reducing neointima formation. Because angiogenesis plays a critical role in the pathogenesis of atherosclerosis, the present study investigated the angiogenic function and mechanism of WA-25. METHODS: The angiogenic effect of WA-25 was evaluated using a rat aortic ring assay and transgenic zebrafish models were established using transgenic Tg(fli-1:EGFP)y1 and Tg(kdrl:mCherryci5-fli1a:negfpy7) zebrafish embryos. In addition, the effect of WA-25 on distinct angiogenic processes, including matrix metalloproteinase (MMP) expression, endothelial cell proliferation and migration, as well as tube formation, was studied using human umbilical vein endothelial cells (HUVECs). The effect of WA-25 on the endothelial vascular endothelial growth factor (VEGF) signaling pathway was elucidated using qRT-PCR, immunoblot analysis, immunofluorescence and flow cytometric analyses. RESULTS: The application of WA-25 perturbed the development of intersegmental vessels in transgenic zebrafish. Moreover, WA-25 potently suppressed microvessel sprouting in organotypic rat aortic rings. Among cultured endothelial cells, WA-25 significantly and dose-dependently inhibited MMP-2/MMP-9 expression, proliferation, migration and tube formation in HUVECs. Mechanistic studies revealed that WA-25 significantly reduced the VEGF release by reducing VEGF expression at the mRNA and protein levels. In addition, WA-25 reduced surface VEGF receptor 2 (VEGFR2/Flk-1) expression by repressing the VEGFR2 mRNA level. Finally, an exogenous VEGF supply partially rescued the WA-25-induced angiogenesis blockage in vitro and in vivo. CONCLUSIONS: WA-25 is a potent angiogenesis inhibitor that acts through the down-regulation of VEGF and VEGFR2 in endothelial cells. GENERAL SIGNIFICANCE: WA-25 may constitute a novel anti-angiogenic drug that acts by targeting endothelial VEGF/VEGFR2 signaling.