Cluster analysis of clinical phenotypic heterogeneity in obstructive sleep apnea assessed using photoplethysmography.

BACKGROUND: We evaluated heterogeneity in clinical phenotypes among patients with obstructive sleep apnea syndrome (OSAHS) using photoplethysmography (PPG) in cluster analysis. METHODS: All enrolled patients underwent polysomnography (PSG) monitoring while wearing a PPG device. Pulse wave signals were recorded with a modified pulse oximetry probe in the PPG device. The pulse wave-derived cardiac risk composite parameter (CRI) and eight derived signal parameters were used to assess OSAHS phenotype. We defined a high cardiovascular risk OSAHS group (CRI ≥0.5) and low cardiovascular risk OSAHS group (CRI <0.5). K-means clustering was performed for analysis of clinical phenotype heterogeneity in OSAHS by combining the CRI and its derived signals. RESULTS: The OSAHS group had high cardiovascular risk for sex, age, body mass index, systolic and diastolic blood pressure, apnea hypopnea index, and obstructive arousal index and higher risk of developing hypertension, diabetes, and cerebrovascular comorbidities. The low cardiovascular risk OSAHS group had higher blood oxygen levels. Three clinical phenotypes were identified in CRI clustering: 1) typical OSAHS with high risk of hypertension (characterized by middle age, obesity, hypertension with severe OSAHS); 2) older women and mild OSAHS; 3) older men and mild OSAHS. Three subtypes were obtained based on the eight cardiac risk-derived parameters: 1) hypoxia combined with decreased pulse wave amplitude variation; 2) decreased vascular pulse wave amplitude combined with decreased pulse frequency; 3) arrhythmia combined with hypoxia. CONCLUSIONS: Establishing OSAHS clinical phenotypes with the CRI and derived parameters using PPG may help in establishing multi-dimensional assessment of cardiovascular risk in OSAHS.

Metagenomic next-generation sequencing indicates more precise pathogens in patients with pulmonary infection: A retrospective study.

Background: Timely identification of causative pathogens is important for the diagnosis and treatment of pulmonary infections. Metagenomic next-generation sequencing (mNGS), a novel approach to pathogen detection, can directly sequence nucleic acids of specimens, providing a wide range of microbial profile. The purpose of this study was to evaluate the diagnostic performance of mNGS in the bronchoalveolar lavage fluid (BALF) of patients with suspected pulmonary infection. Methods: From April 2019 to September 2021, 502 patients with suspected pneumonia, who underwent both mNGS of BALF and conventional microbiological tests (CMTs), were classified into different groups based on comorbidities. The diagnostic performances of mNGS and CMTs were compared. Comprehensive clinical analysis was used as the reference standard. Results: The diagnostic accuracy and sensitivity of mNGS were 74.9% (95% confidence interval [CI], 71.7-78.7%) and 72.5% (95% CI, 68.2-76.8%) respectively, outperformed those of CMTs (36.9% diagnostic accuracy, 25.4% sensitivity). For most pathogens, the detection rate of mNGS was higher than that of CMTs. Polymicrobial infections most often occurred in immunocompromised patients (22.1%). Only 2.3% patients without underlying diseases developed polymicrobial infections. Additionally, the spectrums of pathogens also varied among the different groups. We found the positive predictive values (PPV) to be dependent upon both the pathogen of interest as well as the immunologic status of the patient (e.g., the PPV of Mycobacterium tuberculosis was 94.9% while the PPV of Pneumocystis jirovecii in immunocompetent individuals was 12.8%). This information can help physicians interpret mNGS results. Conclusion: mNGS of BALF can greatly enhance the accuracy and detection rate of pathogens in patients with pulmonary infections. Moreover, the comorbidities and types of pathogens should be taken consideration when interpreting the results of mNGS.

Study on the Management of the Health Status of Patients with Stable Chronic Obstructive Pulmonary Disease Treated with Double Bronchodilator.

Objective: To investigate the patients with stable chronic obstructive pulmonary disease (COPD) to understand the use of double bronchodilator therapy and influencing factors. Methods: The patients with stable COPD who used double bronchodilators were continuously enrolled in our hospital. The information of demographic characteristics, medical history, physical examination, drug use, and correct treatment methods after using inhaled drugs were collected by standardized questionnaire. Measurement data between groups were compared by using the independent sample t-test, and counting data between groups were compared by using the chi-square test. Results: A total of 102 patients were included in the analysis. The proportion of patients with stable COPD who correctly used dual bronchodilators was 59.8% (61 patients). In the GOLD classification, the correct use rate of C-level patients was 69.8%, which was significantly higher than the used correct rate of D-level patients (49.0%) (P=0.032). In the age group, the correct use rate of patients <65 years old was 72.1%, which was significantly higher than that of patients ≥65 years old (50.8%) (P=0.031). In addition, education level, duration of drug use, and drug type may also affect the correct use of drugs, but no significant statistical significance was found between the groups of these three factors (P > 0.05). Conclusion: There is still a gap between the treatment of dual bronchodilators in patients with stable COPD and the guidelines, so the management of COPD should be strengthened. Besides, the correct use rate could be affected by the GOLD classification and age.

GLCCI1 gene body methylation in peripheral blood is associated with asthma and asthma severity.

BACKGROUND AND AIMS: Epigenetic changes play a role in the occurrence of asthma. In this study, we evaluated the methylation status of glucocorticoid-induced transcript 1 (GLCCI1) and assessed its associations with asthma and asthma severity. MATERIALS AND METHODS: Peripheral blood mononuclear cells were harvested from 33 severe asthma patients, 84 mild-moderate asthma patients and 79 healthy controls of Han nationality. GLCCI1 methylation were screened using the MassArray Epityper platform (Agena). We also conducted mRNA sequencing of GLCCI1-knockout mice to further explore possible functions of this gene. RESULTS: We found 5 GLCCI1 methylation sites independently correlated with asthma (adjusted p < 0.05) and perform well in asthma prediction with optimum area under the curve (AUC) value was 0.846 (p < 0.0001). In asthmatic group, only one sites independently associates with severe asthma. Area under the curve in predicting severe asthma is comparable with forced expiratory volume in 1 s predicted (AUC 0.865 and 0.857, p = 0.291). Spearman correlate analysis denoted GLCCI1 low methylation is associates with its low expression in asthma PBMCs. Its reduced level may influence PI3k-Akt and MAPK pathways by the results of RNA sequencing of GLCCI1-knockout mice (adjusted p value < 0.01). CONCLUSIONS: Our research indicates a low GLCCI1 methylation level in asthma with certain sites are lower in severe asthma group. These GLCCI1 methylation sites may be contributed to detect asthma and asthma severity.

GLCCI1 reduces collagen deposition and airway hyper-responsiveness in a mouse asthma model through binding with WD repeat domain 45B.

Asthma is a serious public health problem worldwide, without effective therapeutic methods. Our previous study indicated that glucocorticoid-induced transcript 1 gene (GLCCI1) knockout reduces the sensitivity to glucocorticoid in asthmatic mouse. Here, we explored the role and action mechanism of GLCCI1 in asthma development. In ovalbumin-sensitized mice, airway resistance and tissue damage increased, the production of inflammatory cytokines were up-regulated, GLCCI1 expression was reduced and autophagy was activated. Increasing of GLCCI1 inhibited human and mouse airway epithelial cell (AEC) autophagy, while decreasing of GLCCI1 promoted autophagy. Furthermore, we found that GLCCI1 bound with WD repeat domain 45B (WDR45B) and inhibited its expression. Increasing of WDR45B partly reversed the inhibition of GLCCI1 to autophagy-related proteins expression and autophagosome formation in vitro. Increasing of WDR45B in vivo reversed the improvement of GLCCI1 on airway remodelling in asthma and the inhibition to autophagy level in lung tissues. Overall, our data showed that GLCCI1 improved airway remodelling in ovalbumin-sensitized mice through inhibiting autophagy via combination with WDR45B and inhibiting its expression. Our results proved a new idea for asthma treatment.

Glucocorticoid induced transcript 1 represses airway remodeling of asthmatic mouse via inhibiting IL-13/periostin/TGF-ß1 signaling.

Asthma is characterized by airway remodeling. Glucocorticoid induced transcript 1 (GLCCI1) was reported to be associated with the development of asthma, while its exact mechanism is still not clear. In our study, ovalbumin (OVA) combined with aluminum hydroxide were used to establish asthmatic mouse model. ELISA assay was fulfilled to ensure the concentration of inflammatory factors in both bronchoalveolar lavage fluid and serum. The pathological changes and collagen deposition in lung tissues were analyzed using H&E staining and Masson staining, respectively. The expression of proteins was measured using western blot, and the expression of GLCCI1 mRNA was ensured by qRT-PCR. Here, we demonstrated that OVA-induced inflammation, lung structural remodeling and collagen deposition in asthmatic mice was notably improved by hydroprednisone treatment or GLCCI1 overexpressing. The expression of GLCCI1 was decreased, while IL-13, periostin and TGF-ß1 were increased in the lung tissue of asthmatic mice. Importantly, upregulation of GLCCI1 suppressed the expression of IL-13, periostin and TGF-ß1, phosphorylation of Smad2 and Smad3, and extracellular matrix (ECM) deposition-related proteins expression. IL-13-induced upregulation of periostin and TGF-ß1 expression, phosphorylation of Smad2 and Smad3, and ECM deposition in airway epithelial cells (AECs) was repressed by GLCCI1 increasing. Furthermore, our results showed that overexpression of GLCCI1 repressed the effect of IL-13 on AECs via inhibiting periostin expression. Overall, our data revealed that GLCCI1 limited the airway remodeling in mice with asthma through inhibiting IL-13/periostin/TGF-ß1 signaling pathway. Our data provided a novel target for asthma treatment.

GLCCI1 rs37973 is associated with the response of adrenal hormone to inhaled corticosteroids in asthma.

BACKGROUND: Previous studies have demonstrated that glucocorticoid-induced transcript 1 gene (GLCCI1) rs37973 mutant genotype is associated with poor inhaled corticosteroid (ICS) response in asthmatics. As human airway relaxation is regulated by circulation epinephrine, which can be enhanced by corticosteroid. It is unknown whether or not GLCCI1 rs37973 is associated with circulation epinephrine and cortisol concentrations in asthma. The aim of this study is to evaluate these relationships. METHODS: A total of 182 asthmatics and 180 healthy controls were recruited for the study. 30 mild-to-moderate asthmatics received fluticasone propionate (125 µg, bid) treatment for 12 weeks. GLCCI1 rs37973 genotyping was performed with the iPlex MassARRAY genotyping platform. The plasma concentrations of cortisol and epinephrine of each participant were detected by enzyme linked immunosorbent assay (ELISA) kits. RESULTS: GLCCI1 rs37973 homozygotes mutant genotype GG had a higher plasma epinephrine concentration (median concentration 27.032 pg/ml, nGG = 36; median concentration 23.149 pg/ml, nAA+AG = 146; P = 0.015) and cortisol concentration (median concentration 1.141 ng/ml, nGG = 36; median concentration 0.921 ng/ml, nAA+AG = 146; P = 0.013). Both epinephrine concentration and cortisol concentration in plasma were positively correlated with FEV1 (r = 0.889 and r = 0.821, respectively. nasthma = 182). For asthmatics treated with ICS, rs37973 was associated with change in plasma epinephrine and cortisol concentration in a recessive model (AA + AG vs GG), with GG had less improvement in epinephrine concentration [ΔEPIAA+AG = 6.843 (9.26) pg/ml, nAA+AG = 26; ΔEPIGG = -1.666 (6.52) pg/ml, nGG = 4; P = 0.018] and cortisol concentration [ΔCORAA+AG = 0.3040 (0.21) ng/ml, nAA+AG = 26; ΔCORGG = -0.066 (0.24) ng/ml, nGG = 4; P = 0.009]. CONCLUSIONS: Our study suggested that the poor ICS response in GLCCI1 rs37973 mutant genotype might be related to the less increased amplitudes of plasma epinephrine and cortisol in asthmatic patients. TRIAL REGISTRATION: ChiCTR-RCC-13003634 www.chictr.org.cn. Active since September 27, 2013.

Effects of Glucocorticoid-Induced Transcript 1 Gene Deficiency on Glucocorticoid Activation in Asthmatic Mice.

BACKGROUND: Glucocorticoid (GC) is the first-line therapy for asthma, but some asthmatics are insensitive to it. Glucocorticoid-induced transcript 1 gene (GLCCI1) is reported to be associated with GCs efficiency in asthmatics, while its exact mechanism remains unknown. METHODS: A total of 30 asthmatic patients received fluticasone propionate for 12 weeks. Forced expiratory volume in 1 s (FEV1) and GLCCI1 expression were detected. Asthma model was constructed in wild-type and GLCCI1 knockout (GLCCI1-/-) mice. Glucocorticoid receptor (GR) and mitogen-activated protein kinase phosphatase 1 (MKP-1) expression were detected by polymerase chain reaction and Western blotting (WB). The phosphorylation of p38 mitogen-activated protein kinase (MAPK) was also detected by WB. RESULTS: In asthmatic patients, the change of FEV1 was well positively correlated with change of GLCCI1 expression (r = 0.430, P = 0.022). In animal experiment, GR and MKP-1 mRNA levels were significantly decreased in asthmatic mice than in control mice (wild-type: GR: 0.769 vs. 1.000, P = 0.022; MKP-1: 0.493 vs. 1.000, P < 0.001. GLCCI1-/-: GR: 0.629 vs. 1.645, P < 0.001; MKP-1: 0.377 vs. 2.146, P < 0.001). Hydroprednisone treatment significantly increased GR and MKP-1 mRNA expression levels than in asthmatic groups; however, GLCCI1-/- asthmatic mice had less improvement (wild-type: GR: 1.517 vs. 0.769, P = 0.023; MKP-1: 1.036 vs. 0.493, P = 0.003. GLCCI1-/-: GR: 0.846 vs. 0.629, P = 0.116; MKP-1: 0.475 vs. 0.377, P = 0.388). GLCCI1-/- asthmatic mice had more obvious phosphorylation of p38 MAPK than wild-type asthmatic mice (9.060 vs. 3.484, P < 0.001). It was still higher even though after hydroprednisone treatment (6.440 vs. 2.630, P < 0.001). CONCLUSIONS: GLCCI1 deficiency in asthmatic mice inhibits the activation of GR and MKP-1 and leads to more obvious phosphorylation of p38 MAPK, leading to a decremental sensitivity to GCs. TRIAL REGISTRATION: ChiCTR.org.cn, ChiCTR-RCC-13003634; http://www.chictr.org.cn/showproj.aspx?proj=5926.

Inhibition of SERPINE2/protease nexin-1 by a monoclonal antibody attenuates airway remodeling in a murine model of asthma.

SERPINE2, also known as protease nexin-1 (PN-1), is a serine protease inhibitor produced by many cell types and has pleiotropic biological functions. It has been reported that SERPINE2/PN-1 is involved in tissue remodeling of fibrotic diseases including idiopathic pulmonary fibrosis and cardiac fibrosis. However, the potential role of SERPINE2/PN-1 in asthmatic airway remodeling has remained barely investigated so far. In this study, BALB/c male mice were sensitized and challenged by ovalbumin to generate murine models of airway remodeling. Anti-SERPINE2 monoclonal antibody was intraperitoneally injected into these mice during the ovalbumin challenge while IgG antibody was used as a vehicle control. The results revealed that the expression of SERPINE2/PN-1 was significantly upregulated in the lung extracts of ovalbumin-challenged mice, and this upregulation was inhibited by dexamethasone. Sustained ovalbumin stimulation increased the thickness of airway wall and α-SMA positive areas in lung, which was attenuated by the treatment with SERPINE2 antibody. In addition, SERPINE2 antibody partially blocked the phosphorylation of ERK, and reduced the upregulation of MMP-9 and TIMP-1 expressions in asthmatic mice. These findings suggest that SERPINE2/PN-1 may play a role in the pathologic development of airway remodeling. Monoclonal antibody against SERPINE2 may have the potential as an effective pharmacotherapy for asthmatic airway remodeling.

GLCCI1 Variation Is Associated with Asthma Susceptibility and Inhaled Corticosteroid Response in a Chinese Han Population.

BACKGROUND AND AIMS: GLCCI1 variations are found to be associated with response to glucocorticoid therapy in non-Hispanic white subjects with asthma. However, there are also other relevant studies that were not consistent with this finding. In this study we aimed to evaluate the association of GLCCI1 variations with asthma susceptibility and inhaled corticosteroid (ICS) response in a Chinese adult Han population. METHODS: We genotyped 24 single nucleotide polymorphisms of GLCCI1 in 182 asthmatic patients and 180 healthy controls. Furthermore, we analyzed the association of GLCCI1 variations with ICS response in 30 mild-to-moderate asthmatics. RESULTS: rs11976862 homozygote mutant genotype GG was nominally associated with increased asthma risk (OR = 2.435, 95% CI: 1.221-4.854, p = 0.01148, p(corr) = 0.0127). Recessive model of rs37972, rs37973 and rs11976862 showed that the rare alleles were correlated with less improvement in FEV1 after fluticasone treatment for 12 weeks (p = 0.004, p = 0.009 and p = 0.039, respectively). The GLCCI1 mRNA expression level decreased obviously in asthmatics than in healthy controls (0.037663 ± 0.0216833 vs. 0.046352 ± 0.0235812, p = 0.000). For asthmatics, GLCCI1 mRNA expression level significantly increased after fluticasone treatment for 12 weeks (0.067641 ± 0.031547 vs. 0.030048 ± 0.014613, p = 0.000). Moreover, changes of GLCCI1 mRNA expression were significantly related with rs37973 and rs11976862 in a recessive model (p = 0.014 and p = 0.033, respectively). CONCLUSIONS: GLCCI1 variations are associated with asthma susceptibility and ICS response in a Chinese Han adult population. GLCCI1 variations may affect ICS response by modulating GLCCI1 expression.

High-intensity training induces EIB in rats through neuron transdifferentiation of adrenal medulla chromaffin cells.

A high prevalence of exercise-induced bronchoconstriction (EIB) can be found in elite athletes, but the underlying mechanisms remain elusive. Airway responsiveness, NGF and epinephrine (EPI) levels, and chromaffin cell structure in high- (HiTr) and moderate-intensity training (MoTr) rats with or without ovalbumin (OVA) sensitization were measured in a total of 120 male Sprague-Dawley rats. The expression of NGF-associated genes in rat adrenal medulla was tested. Both HiTr and OVA intervention significantly increased airway resistance to aerosolized methacholine measured by whole body plethysmography. HiTr significantly increased inflammatory reaction in the lung with a major increase in peribronchial lymphocyte infiltration, whereas OVA significantly increased the infiltration of various inflammatory cells with an over 10-fold increase in eosinophil level in bronchoalveolar lavage. Both HiTr and OVA intervention upregulated circulating NGF level and peripherin level in adrenal medulla, but downregulated phenylethanolamine N-methyl transferase level in adrenal medulla and circulating EPI level. HiTr + OVA and HiTr + ExhEx (exhaustive exercise) interventions significantly enhanced most of the HiTr effects. The elevated NGF level was significantly associated with neuronal conversion of adrenal medulla chromaffin cells (AMCC). The levels of p-Erk1/2, JMJD3, and Mash1 were significantly increased, but the levels of p-p38 and p-JNK were significantly decreased in adrenal medulla in HiTr and OVA rats. Injection of NGF antiserum and moderate-intensity training reversed these changes observed in HiTr and/or OVA rats. Our study suggests that NGF may play a vital role in the pathogenesis of EIB by inducing neuron transdifferentiation of AMCC via MAPK pathways and subsequently decreasing circulating EPI.

Metastatic hepatic clear cell carcinoma presenting as lump in the hilum of the lung: a case report and review of the literature.

We report a case of a 52-year-old Chinese woman with a history of primary hepatic cell carcinoma who presented with chest pain, cough, expectoration and bloody phlegm. Chest computer tomography (CT) revealed a 6.2 cm × 6.8 cm shallow lobulated irregular shaped mass in the hilum of the right lung. Bronchoscopy and CT guided lung biopsy was performed. Histopathological and immunohistochemical examinations of biopsies revealed the diagnosis of lung metastatic hepatic clear cell carcinoma. This case is thought to be extremely rare.