Identification of cough-variant asthma phenotypes based on clinical and pathophysiologic data.

BACKGROUND: Cough-variant asthma (CVA) may respond differently to antiasthmatic treatment. There are limited data on the heterogeneity of CVA. OBJECTIVE: We aimed to classify patients with CVA using cluster analysis based on clinicophysiologic parameters and to unveil the underlying molecular pathways of these phenotypes with transcriptomic data of sputum cells. METHODS: We applied k-mean clustering to 342 newly physician-diagnosed patients with CVA from a prospective multicenter observational cohort using 10 prespecified baseline clinical and pathophysiologic variables. The clusters were compared according to clinical features, treatment response, and sputum transcriptomic data. RESULTS: Three stable CVA clusters were identified. Cluster 1 (n = 176) was characterized by female predominance, late onset, normal lung function, and a low proportion of complete resolution of cough (60.8%) after antiasthmatic treatment. Patients in cluster 2 (n = 105) presented with young, nocturnal cough, atopy, high type 2 inflammation, and a high proportion of complete resolution of cough (73.3%) with a highly upregulated coexpression gene network that related to type 2 immunity. Patients in cluster 3 (n = 61) had high body mass index, long disease duration, family history of asthma, low lung function, and low proportion of complete resolution of cough (54.1%). TH17 immunity and type 2 immunity coexpression gene networks were both upregulated in clusters 1 and 3. CONCLUSION: Three clusters of CVA were identified with different clinical, pathophysiologic, and transcriptomic features and responses to antiasthmatics treatment, which may improve our understanding of pathogenesis and help clinicians develop individualized cough treatment in asthma.

Genome-wide association analyses identified novel susceptibility loci for pulmonary embolism among Han Chinese population.

BACKGROUND: A large proportion of pulmonary embolism (PE) heritability remains unexplained, particularly among the East Asian (EAS) population. Our study aims to expand the genetic architecture of PE and reveal more genetic determinants in Han Chinese. METHODS: We conducted the first genome-wide association study (GWAS) of PE in Han Chinese, then performed the GWAS meta-analysis based on the discovery and replication stages. To validate the effect of the risk allele, qPCR and Western blotting experiments were used to investigate possible changes in gene expression. Mendelian randomization (MR) analysis was employed to implicate pathogenic mechanisms, and a polygenic risk score (PRS) for PE risk prediction was generated. RESULTS: After meta-analysis of the discovery dataset (622 cases, 8853 controls) and replication dataset (646 cases, 8810 controls), GWAS identified 3 independent loci associated with PE, including the reported loci FGG rs2066865 (p-value = 3.81 × 10-14), ABO rs582094 (p-value = 1.16 × 10-10) and newly reported locus FABP2 rs1799883 (p-value = 7.59 × 10-17). Previously reported 10 variants were successfully replicated in our cohort. Functional experiments confirmed that FABP2-A163G(rs1799883) promoted the transcription and protein expression of FABP2. Meanwhile, MR analysis revealed that high LDL-C and TC levels were associated with an increased risk of PE. Individuals with the top 10% of PRS had over a fivefold increased risk for PE compared to the general population. CONCLUSIONS: We identified FABP2, related to the transport of long-chain fatty acids, contributing to the risk of PE and provided more evidence for the essential role of metabolic pathways in PE development.

Characteristics of different asthma phenotypes associated with cough: a prospective, multicenter survey in China.

BACKGROUND: Asthma is a heterogeneous disease with variable symptoms, which presents with cough either as the sole or predominant symptom with or without wheezing. We compared the clinical and pathophysiological characteristics of cough predominant asthma (CPA), cough variant asthma (CVA) and classic asthma (CA) in order to determine any differential phenotypic traits. METHODS: In 20 clinics across China, a total of 2088 patients were finally recruited, including 327 CVA, 1041 CPA and 720 CA patients. We recorded cough and wheezing visual analogue scale, Leicester cough questionnaire (LCQ) and asthma control test scores. Fractional exhaled nitric oxide (FeNO), induced sputum cell counts, and capsaicin cough challenge were also measured and compared. RESULTS: CPA patients more frequently presented with cough as the initial symptom, and laryngeal symptoms (p < 0.001), had less symptoms related with rhinitis/sinusitis and gastroesophageal reflux (p < 0.05) than CA patients. Comorbidities including rhinitis and gastroesophageal reflux were similar, while the proportion of COPD and bronchiectasis was higher in CA patients. There were no differences in FeNO levels, sputum eosinophil and neutrophil counts, FEV1 (%pred) decreased from CVA to CPA to CA patients (p < 0.001). Cough sensitivity was higher in CVA and CPA compared to CA (p < 0.001), and was positively correlated with LCQ scores. CONCLUSIONS: CVA, CPA and CA can be distinguished by the presence of laryngeal symptoms, cough sensitivity and airflow obstruction. Asthma-associated chronic cough was not associated with airway inflammation or comorbidities in our cohort. Trial registration The Chinese Clinical Trial Registration Center, ChiCTR-POC-17011646, 13 June 2017.

Associations between comorbidities and annual incidence plus frequency of asthma exacerbation hospitalisation during the past year: data from CARN study.

PURPOSE: While asthma comorbidities are associated with higher health care utilisation, lower quality of life and poorer asthma control, the impact of asthma comorbidities on hospitalisation for asthma exacerbation (H-AX) remains less recognised. We aim to analyse the impact of asthma comorbidities on H-AX. METHODS: Based on a national survey on asthma control and disease perception (CARN 2015 study), we analysed the impact of comorbidities on annual incidence and frequency of H-AX in China. Information on demographic characteristics, asthma comorbidities and annual incidence and frequency of H-AX were presented in this study. RESULTS: Among 3875 ambulatory asthma patients, 75.9% (2941/3875) had comorbidities, and 26.4% (1017/3858) experienced H-AX during past year. After adjusting for confounding factors such as demographic data, smoking status and asthma control, COPD [OR = 2.189, 95% CI (1.673, 2.863)] and coronary heart disease [OR = 1.387, 95% CI (1.032, 1.864)] were associated with higher annual incidence, while allergic rhinitis [OR = 0.692, 95% CI (0.588, 0.815)] was associated with lower annual incidence, of H-AX. In terms of frequency, allergic rhinitis [OR = 1.630, 95% CI (1.214, 2.187)], COPD [OR = 1.472, 95% CI (1.021, 2.122)] and anxiety [OR = 2.609, 95% CI (1.051, 6.477)] showed statistically significant correlation with frequent H-AX. CONCLUSIONS: COPD and coronary heart disease were associated with higher annual incidence, while allergic rhinitis was associated with lower annual incidence of H-AX. Allergic rhinitis, COPD and anxiety were associated with frequent H-AX. Comorbidities may have an important role in the risk and frequency of annual hospitalisations due to asthma exacerbation. The goal of asthma control should rely on a multi-disciplinary treatment protocol.

Associated risk factors with disease severity and antiviral drug therapy in patients with COVID-19.

BACKGROUND: Due to the latent onset of novel coronavirus disease 2019 (COVID-19), it is important to identify patients with increased probabilities for disease progression early in order to implement timely medical strategies. This study aimed to identify the factors associated with increased COVID-19 severity and evaluate the current antiviral drugs, especially in severe patients. METHODS: This was a retrospective observational study performed at the No. 7 Hospital of Wuhan (Wuhan, China) with hospitalized patients confirmed with COVID-19 from January 11 to March 13, 2020. Multivariable logistic regression analysis was used to identify the associated factors of severe COVID. Treatments of antivirus drugs were collected and evaluated. RESULTS: Of the 550 patients, 292 (53.1%) were female and 277 (50.4%) were > 60 years old. The most common symptom was fever (n = 372, 67.7%), followed by dry cough (n = 257, 46.7%), and dyspnea (n = 237, 43.1%), and fatigue (n = 224, 40.7%). Among the severe patients, 20.2% required invasive ventilator support and 18.0% required non-invasive ventilator. The identified risk factors for severe cases were: age ≥ 60 years (odds ratio (OR) =3.02, 95% confidence interval (CI): 1.13-8.08, P = 0.028), D-dimer > 0.243 µg/ml (OR = 2.734, 95%CI: 1.012-7.387, P = 0.047), and low oxygenation index (OR = 0.984, 95%CI: 0.980-0.989, P < 0.001). In severe cases, the benefits (relief of clinical symptoms, clinical outcome, and discharge rate) of arbidol alone was 73.3%, which was better than ribavirin (7/17, 41.2%, P = 0.029). CONCLUSIONS: Age > 60 years, D-dimer > 0.243 µg/ml, and lower oxygenation index were associated with severe COVID-19. Arbidol might provide more clinical benefits in treating patients with severe COVID-19 compared with ribavirin.

Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China.

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been widely spread. We aim to investigate the clinical characteristic and allergy status of patients infected with SARS-CoV-2. METHODS: Electronic medical records including demographics, clinical manifestation, comorbidities, laboratory data, and radiological materials of 140 hospitalized COVID-19 patients, with confirmed result of SARS-CoV-2 viral infection, were extracted and analyzed. RESULTS: An approximately 1:1 ratio of male (50.7%) and female COVID-19 patients was found, with an overall median age of 57.0 years. All patients were community-acquired cases. Fever (91.7%), cough (75.0%), fatigue (75.0%), and gastrointestinal symptoms (39.6%) were the most common clinical manifestations, whereas hypertension (30.0%) and diabetes mellitus (12.1%) were the most common comorbidities. Drug hypersensitivity (11.4%) and urticaria (1.4%) were self-reported by several patients. Asthma or other allergic diseases were not reported by any of the patients. Chronic obstructive pulmonary disease (COPD, 1.4%) patients and current smokers (1.4%) were rare. Bilateral ground-glass or patchy opacity (89.6%) was the most common sign of radiological finding. Lymphopenia (75.4%) and eosinopenia (52.9%) were observed in most patients. Blood eosinophil counts correlate positively with lymphocyte counts in severe (r = .486, P < .001) and nonsevere (r = .469, P < .001) patients after hospital admission. Significantly higher levels of D-dimer, C-reactive protein, and procalcitonin were associated with severe patients compared to nonsevere patients (all P < .001). CONCLUSION: Detailed clinical investigation of 140 hospitalized COVID-19 cases suggests eosinopenia together with lymphopenia may be a potential indicator for diagnosis. Allergic diseases, asthma, and COPD are not risk factors for SARS-CoV-2 infection. Older age, high number of comorbidities, and more prominent laboratory abnormalities were associated with severe patients.

Molecular characterization of two novel sub-sublineages of pigeon paramyxovirus type 1 in China.

Pigeon paramyxovirus type 1 (PPMV-1) infection is enzootic in pigeon flocks and poses a potential risk to the poultry industry in China. To gain insight into the biological characteristics and transmission routes of circulating PPMV-1 in pigeons, 13 PPMV-1 isolates from domestic pigeons isolated during 2011-2015 in Guangxi province, China, were characterized using a pathogenicity assessment and phylogenetic analysis. All PPMV-1 isolates were mesogenic or lentogenic strains and had a mean death time (MDT) in 9-day-old SPF chicken embryos and a intracerebral pathogenicity index (ICPI) values of 54-154 h and 0.00-0.90, respectively. Analysis of the F and HN gene sequences of the PPMV-1 isolates and the Newcastle Disease (ND) vaccine strain La Sota, revealed that the nucleotide sequence similarity of the F and HN genes were all < 85% between the PPMV-1 isolates and La Sota, significantly lower than those > 98% among the PPMV-1 isolates. The amino acids sequence of the F protein at the cleavage site of the 13 PPMV-1 isolates was 112RRQKR↓F117, characteristic of virulent Newcastle disease virus (NDV). All 13 isolates were classified as sublineage 4b by phylogenetic analysis and evolutionary distances, based on the F gene sequences. It was also found that the 13 isolates were divided into two novel sub-groups of sublineage 4b, sub-sublineages 4biig and 4biih. Since these two novel sub-sublineages had two different geographic sources, we speculated that they represent two different transmission routes of PPMV-1 in China. Phylogenetic analysis of these isolates will help to elucidate the sources of the transmission and evolution of PPMV-1 and may help to control PPMV-1 infection in the pigeon industry in China.

[Effects of estrogen on ACE-Ang II-AT1 axis in ovariectomy and hypoxic pulmonary hypertension rats].

OBJECTIVE: To explore the effects of estrogen (E2) on angiotensin converting enzyme-angiotensin II-angiotensin type 1 receptor (ACE-Ang II-AT1) axis in hypoxic pulmonary hypertension rats. METHODS: A total of 60 healthy female Sprague-Dawdley (SD) rats were divided randomly into 6 groups (n = 10 each) of sham operation, pure ovariectomy (OVX), pure hypoxia,OVX+hypoxia,OVX+E2 and OVX+hypoxia+E2. Abdominal cavity was opened for sham operation group and bilateral ovaries were left intact without any other procedure. The pure OVX group underwent oophorectomy. The pure hypoxia group were placed into a low-oxygen environment (24 hour, 8 weeks). The OVX+hypoxia group were placed into a low-oxygen environment after bilateral oophorectomy. The OVX+E2 group received a subcutaneous injection of E2 (20 µg×kg(-1)×d(-1)) after bilateral oophorectomy. The OVX+hypoxia+E2 group had an injection of E2 and was placed into a low-oxygen environment after bilateral oophorectomy. The rats were feed continuously for 8 weeks to establish hypoxic pulmonary hypertension model. The mean pulmonary artery pressure (mPAP) was measured after bloodletting. Then right ventricle hypertrophy index (RVHI) and hematoxylin-eosin pulmonary artery remodeling (HPSR) were observed. And electron microscope was employed to observe pulmonary arteriolar ultrastructure. The methods of radio-immunity assay, ultraviolet spectroscopy, Western blot and reverse transcription PCR were used to measure the levels of CE,Ang II and AT1 in sera, lung and pulmonary artery. RESULTS: The vascular walls of pure hypoxia and OVX+hypoxia groups became thickened and lumen narrowed.mPAP and RVHI were (32.4 ± 2.2) mmHg (1 mmHg = 0.133 kPa),0.331 ± 0.032 and (37.9 ± 1.6) mmHg,0.433 ± 0.033. Both were significantly higher than those of Sham operation group ((12.6 ± 1.8) mmHg,0.233 ± 0.029) (both P < 0.05); the above parameters of OVX+Hypoxia+E2 group changed little. And mPAP ((26.1 ± 1.4) mmHg) was significantly higher than that in sham operation group (P < 0.05) while the difference in RVHI between OVX+ Hypoxia+ E2 (0.267 ± 0.040) and sham operation groups had no statistical significance (P > 0.05). Compared with Sham operation group, the expression levels of ACE,Ang II and AT1 in pure OVX, pure hypoxia and OVX+ hypoxia groups rose markedly (all P < 0.05).However, the OVX+E2 and OVX+ hypoxia+E2 groups had no obvious change (all P > 0.05). CONCLUSION: The intervention effect of E2 for hypoxic pulmonary hypertension may be partly mediated by the down-regulated expressions of ACE and AT1 in lung tissue resulting in the reduced activity of ACE-AngII-AT1 axis.

Bioinformatics and Machine Learning Methods Identified MGST1 and QPCT as Novel Biomarkers for Severe Acute Pancreatitis.

Severe acute pancreatitis (SAP) is a life-threatening gastrointestinal emergency. The study aimed to identify biomarkers and investigate molecular mechanisms of SAP. The GSE194331 dataset from GEO database was analyzed using bioinformatics. Differentially expressed genes (DEGs) associated with SAP were identified, and a protein-protein interaction network (PPI) was constructed. Machine learning algorithms were used to determine potential biomarkers. Gene set enrichment analysis (GSEA) explored molecular mechanisms. Immune cell infiltration were analyzed, and correlation between biomarker expression and immune cell infiltration was calculated. A competing endogenous RNA network (ceRNA) was constructed, and biomarker expression levels were quantified in clinical samples using RT-PCR. 1101 DEGs were found, with two modules most relevant to SAP. Potential biomarkers in peripheral blood samples were identified as glutathione S-transferase 1 (MGST1) and glutamyl peptidyltransferase (QPCT). GSEA revealed their association with immunoglobulin regulation, with QPCT potentially linked to pancreatic cancer development. Correlation between biomarkers and immune cell infiltration was demonstrated. A ceRNA network consisting of 39 nodes and 41 edges was constructed. Elevated expression levels of MGST1 and QPCT were verified in clinical samples. In conclusion, peripheral blood MGST1 and QPCT show promise as SAP biomarkers for diagnosis, providing targets for therapeutic intervention and contributing to SAP understanding.

Identifying an immunogenic cell death-related gene signature contributes to predicting prognosis, immunotherapy efficacy, and tumor microenvironment of lung adenocarcinoma.

BACKGROUND: Immunogenic cell death (ICD) is a regulated form of cell death that triggers an adaptive immune response. The objective of this study was to investigate the correlation between ICD-related genes (ICDGs) and the prognosis and the immune microenvironment of patients with lung adenocarcinoma (LUAD). METHODS: ICD-associated molecular subtypes were identified through consensus clustering. Subsequently, a prognostic risk model comprising 5 ICDGs was constructed using Lasso-Cox regression in the TCGA training cohort and further tested in the GEO cohort. Enriched pathways among the subtypes were analyzed using GO, KEGG, and GSVA. Furthermore, the immune microenvironment was assessed using ESTIMATE, CIBERSORT, and ssGSEA analyses. RESULTS: Consensus clustering divided LUAD patients into three ICDG subtypes with significant differences in prognosis and the immune microenvironment. A prognostic risk model was constructed based on 5 ICDGs and it was used to classify the patients into two risk groups; the high-risk group had poorer prognosis and an immunosuppressive microenvironment characterized by low immune score, low immune status, high abundance of immunosuppressive cells, and high expression of tumor purity. Cox regression, ROC curve analysis, and a nomogram indicated that the risk model was an independent prognostic factor. The five hub genes were verified by TCGA database, cell sublocalization immunofluorescence analysis, IHC images and qRT-PCR, which were consistent with bioinformatics analysis. CONCLUSIONS: The molecular subtypes and a risk model based on ICDGs proposed in our study are both promising prognostic classifications in LUAD, which may provide novel insights for developing accurate targeted cancer therapies.

Serum Albumin for Short-Term Poor Prognosis in Patients With Acute Pulmonary Embolism: A Clinical Study Based on a Database.

The relationship between serum albumin (ALB) and short-term prognosis in patients with acute pulmonary embolism (APE) remains unclear. We investigated the predictive value of ALB for short-term prognosis in APE patients using our hospital pulmonary embolism (PE) database (384 patients consecutively collected). Logistic regression analysis and nomograms were applied to construct the predictive model, and validation was assessed. A total of 340 APE patients were included, with a 30-day all-cause mortality rate of 8.5%. The incidence of hypoalbuminemia was 15.9%. The odds ratio (OR) for short-term mortality in patients with high ALB was 0.89 (0.886, 95% CI: 0.812-0.967). Additionally, we created a nomogram for individualized mortality risk prediction. Receiver operating characteristic (ROC) curve analysis showed that the diagnostic area under the curve (AUC) of ALB was 0.758 (95% CI 0.683-0.833), and the best cut-off value was 33.85 g/L. Optimal simplified Pulmonary Embolism Severity Index (sPESI) (ALB combined sPESI) AUC was 0.835 (95% CI 0.775-0.896). Baseline hypoalbuminemia may be an independent prognostic indicator of short-term mortality in patients with APE.

Evaluation of asthma control and patient's perception of asthma: findings and analysis of a nationwide questionnaire-based survey in China.

BACKGROUND: Little is known about asthma control and perception of asthma among asthmatic patients on a national scale in China due to the difficulty of conducting a survey of the large, vastly distributed population of the country. We know that the medical insurance system may not evenly cover all patients and that socioeconomic status varies greatly across cities. OBJECTIVE: This study marks the first survey conducted on a national scale that was aimed at obtaining baseline information on asthma control and patients' perceptions of asthma and providing a point of reference for future studies. METHODS: This face-to-face, questionnaire-based survey was conducted from April 2007 to March 2008 in 3069 asthmatic patients from the respiratory outpatient clinics of 36 general hospitals located in 10 geographically dispersed cities. RESULTS: Per the Global Initiative for Asthma (GINA) guidelines, 28.7% and 45.0% of our patients achieved complete or partial asthma control, respectively. Of patients in the study, only 21.8% had used a peak flow meter (PFM) and 6.6% of these patients used it daily. Inhaled corticosteroids (ICS) plus a long-acting ß2 agonist and ICS were the two most common medication regimens and were used in 45.6% and 30.4% of patients, respectively. Asthma had a significant effect on patients' life and work. A considerable number of hospitalizations, emergency department visits and sick days were also observed. CONCLUSIONS: Despite improvements in asthma control and ICS and PFM compliance compared with past literature, the current level of asthma control countrywide continues to fall short of the goals set in the GINA.

[Altered expressions of alkane monooxygenase and hypoxia inducible factor-1α expression in lung tissue of rat hypoxic pulmonary hypertension].

OBJECTIVE: To explore the altered expressions of alkane monooxygenase (AlkB) and hypoxia-inducible factor-1α (HIF-1α) in a rat model of hypoxic pulmonary arterial hypertension. METHODS: Twenty Wistar rats were divided randomly into normal control and hypoxia groups after 1-week adaptive feeding. Hypoxia group was raised in a homemade organic glass tank with a 24-h continuous supply of air and nitrogen atmospheric mixed gas. And the oxygen concentration of (10.0 ± 0.5)% was controlled by oxygen monitoring control system. The control group was maintained in room air. Both groups stayed in the same room with the same diet. After 8 weeks, the level of mean pulmonary pressure (mPAP) was measured by right-heart catheterization, right ventricular hypertrophy index (RVHI) calculated by the ratio of right ventricle to left ventricle plus septum and hypoxic pulmonary vascular remodeling (HPSR) observed under microscope. And the levels of AlkB and HIF-1α mRNA and protein in lungs were measured by reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot. RESULTS: At 8 weeks post-hypoxia, compared with the control group [11.0 ± 0.7 mm Hg (1 mm Hg = 0.133 kPa), 0.210 ± 0.035], the levels of mPAP and RVHI in hypoxia group (33.3 ± 1.3 mm Hg, 0.448 ± 0.013) increased significantly (both P < 0.05), the expressions of AlkB mRNA and protein in pulmonary tissue decreased significantly (0.338 ± 0.085 vs 0.688 ± 0.020, P < 0.01) (0.483 ± 0.052 vs 0.204 ± 0.010, P < 0.01), and the expressions of HIF-1α mRNA and protein increased significantly (0.790 ± 0.161 vs 0.422 ± 0.096, P < 0.01) (0.893 ± 0.080 vs 0.346 ± 0.008, P < 0.01). CONCLUSION: The down-regulation of AlkB in lung tissue may increase the activity of HIF-1 to participate in the occurrence and development of pulmonary hypertension.

[Meta-analysis of risk factors for all-cause mortality of pulmonary thromboembolism].

OBJECTIVE: To evaluate the causes of death and risk factors of pulmonary thromboembolism. METHODS: Pubmed, English Medical Current Contents, Chinese Conference Data and Chinese Biomedical Database were searched from January 1995 up to May 2011. And the references of these studies were also examined. Observational studies were assessed according to suggestion of quality assessment with references. Randomized control trials (RCT) were assessed with Jadad scale. Software RevMan 5.1 was used to examin the heterogeneity of trials. The fixed or random effect model was employed to pool the risk ratio and 95%CI. The results were expressed with risk ratio and 95%CI. RESULTS: Thirty-five studies with a total number of 19 613 cases of pulmonary thromboembolism (PTE) were included for final analysis. The average mortality rate was (10.7 ± 7.6)% (range 0.5%-30.0%). And the following factors increased the total mortality of pulmonary embolism: right ventricular hypokinesis or dysfunction (2.18(1.64-2.89), P = 0.000), elevated D-dimer (5.19(1.93-13.96), P = 0.001), elevated cardiac troponin (cTnI) (4.01(2.77-5.81), P = 0.000), hypotension (2.76(1.25-6.09), P = 0.010), malignancy (2.65(2.01-3.50), P = 0.000), congestive heart failure (1.90(1.62-2.22), P = 0.000), chronic lung disease (1.40(1.18-1.66), P = 0.000), tachycardia (1.65(1.23-2.20), P = 0.000), immobility (1.74(1.36-2.21), P = 0.000) and age > 65 years (1.24 (1.13-1.37), P = 0.000), etc. When multiple factors co-existed, the risk of death became more obvious. CONCLUSION: Elevated D-dimer, elevated cTnI, hypotension, malignancy, right ventricular hypokinesis or dysfunction, immobility, congestive heart failure, tachycardia, chronic lung disease, age > 65 years influence the mortality rate of pulmonary embolism.

[Inhibitory effects of celecoxib combined with capecitabine on H22 hepatoma mice and its mechanism].

OBJECTIVE: To evaluate the inhibitory effect and its mechanism of celecoxib combined with capecitabine on the growth of implanted H22 hepatoma in mice. METHODS: Tumor model was established by hypodermical injection of H22 cells in BALB/c nude mice. Forty mice were equally randomly divided into 4 groups: control group, celecoxib group (receiving 100 mg/kg celecoxib), capecitabine group (receiving 755 mg/kg capecitabine), and combined treatment group (receiving 100 mg/kg of celecoxib and 755 mg/kg of capecitabine). From the third post-implantation day, each mouse was given relevant drug (or normal saline) by oral gavage. Fifteen days later, all mice were sacrificed and the tumor tissues were measured. The mRNA and protein levels of nuclear factor kappa-B (NF-ΚB) p65 and cyclooxygenase (COX)-2 in tumor tissues were detected by the quantitative polymerase chain reaction (qPCR)and Western blotting, respectively. RESULTS: The tumor inhibition rate was 30.2% in celecoxib group and 49.9% in capecitabine group, which was significantly lower than that (75.4%) in the combined treatment group (P<0.01,P<0.05, respectively). qPCR showed a significant decrease of the mRNA expression of COX-2 in celecoxib group and combined treatment group when compared with control group (P<0.001), but no significant change in NF-ΚB p65.Capecitabine had no significant effects on the mRNA expression of COX-2 and NF-ΚB p65. Western blotting showed that celecoxib and combined treatment significantly inhibited the protein expression of COX-2 and NF-ΚB p65(P<0.05), but not capecitabine. CONCLUSION: Celecoxib can enhance the antitumor effect of capecitabine by inhibiting the expressions of COX-2 and NF-ΚB p65 in mice bearing H22 implanted tumor.

[Association of genetic polymorphisms of angiotensin converting enzyme and matrix metallo proteinase-1 with idiopathic pulmonary fibrosis].

OBJECTIVE: To investigate the correlation between angiotensin converting enzyme (ACE) and matrix metallo proteinase (MMP)-1 gene polymorphisms and the risk of idiopathic pulmonary fibrosis (IPF) in a Han Chinese population from Hebei Province. METHODS: Eighty-four IPF patients and 100 controls were enrolled from the Second Hospital of Hebei Medical University. Polymerase chain reaction (PCR) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) were used to detect ACE gene insertion/deletion (I/D) polymorphism and MMP-1 polymorphism respectively. The MMP-1 polymorphism was genotyped by DNA sequence analysis. Radioimmunoassay and ELISA were used to analyzed AngII, MMP-1 and TIMP-1 levels in IPF patients and healthy controls. RESULTS: There was a significant difference between the 2 groups in allele and genotype frequency distribution of ACE Insertion/Deletion polymorphism; frequency distribution of DD genotype and D allele of IPF patients were higher than those of the healthy control group (χ(2) = 11.227, 4.318, P < 0.05). There was no difference from different genders and ages on allele and genotype frequency distribution of ACE Insertion/Deletion polymorphism. (χ(2) = 0.03 - 1.069, P > 0.05). There was no significant difference between the 2 groups in genotype and allele frequency distribution of MMP-1 1G/2G polymorphism (χ(2) = 0.94 and 0.001, P > 0.05). The AngII levels from DD genotype of both IPF patients and healthy controls were the highest, followed by the DI genotype and the II genotype. The AngII level of any genotype for ACE Insertion/Deletion polymorphism in the IPF group was higher than that in the healthy control group (all P < 0.05). The serum level of AngII, MMP-1 and TIMP-1, as well as MMP-1/TIMP-1 ratio in the IPF group were higher than those in the healthy control group (all P < 0.05). CONCLUSIONS: The ACE polymorphism might be associated with IPF, and the serum level of AngII was affected not only by the genetic background of ACE insertion/deletion polymorphism but also the environmental factors. The MMP-1 1G/2G polymorphism might be weakly associated with IPF.

[Effects of PM2.5 exposure on Klebsiella pneumoniae clearance in the lungs of rats].

OBJECTIVE: To investigate the effects of PM2.5 exposure on susceptibility to Klebsiella infection and bacterial clearance, and to discuss its possible mechanisms. METHODS: Eighty-six healthy male SD rats were randomly divided into 4 groups: a control group, a Klebsiella pneumoniae infection group(infection group), a PM2.5 group and a PM2.5+ Klebsiella pneumoniae infection group (combined group) .We developed a rat model in which the animals were given Klebsiella pneumoniae, PM2.5 exposure and PM2.5 exposure followed by infection with Klebsiella pneumoniae respectively. The clinical scores were evaluated. The total mortality of each group was assessed. Bacterial load in the BALF was quantified and the infection rate of each group was assessed.Lung histopathological changes were detected by HE staining. The concentrations of IL-6 and TNF-α in serum were detected by ELISA. Cells in the BALF were counted for each group by microscopy. The changes of tracheal membrane epithelial cells were observed by scanning electron microscope. RESULTS: The total mortality in the combined group (n = 14) was higher than that in the control group (n = 0), infection group(n = 4) and PM2.5 group(n = 4). The infected cases in the combined infection group (n = 13) was higher than that in the infection group (n = 6). The total number of WBC in BALF in the combined group on the first day[(11.96 ± 0.56)×10(5)/L] and seventh day [(15.68 ± 0.81)×10(5)/L] was higher than that in the control group, the infection group and the PM2.5 group. The neutrophil number in BALF in the combined group on the first day[(5.76 ± 0.44)×10(5)/L] and seventh day [(9.41 ± 0.64)×10(5)/L] was higher than that in the control group, the infection group and the PM2.5 group. The lung pathological changes were much more severe in the combined group as compared to those in the control, the infection and the PM2.5 groups. Concentrations of TNF-α in serum in the combined group on the first day [(829 ± 90) ng/L] and the seventh day [(1055 ± 91) ng/L] were higher than those in the control group and the PM2.5 group. Concentrations of IL-6 in serum in the combined group on the first day [(1.26 ± 0.16) ng/L] and seventh day [(1.95 ± 0.18) ng/L] was higher than those in the control, the infection and the PM2.5 groups. Tracheal cilia in the PM2.5 group showed signs of disorderly arrangement, adhesion and ecclasis. CONCLUSIONS: PM2.5 exposure increased the susceptibility of the rats to Klebsiella pneumoniae infection and decreased bacterial clearance.Its mechanism may be related to impairment of the bronchial mucociliary system and interaction of cytokines.

Efficacy and safety of macitentan for pulmonary hypertension: A meta-analysis.

INTRODUCTION: Our purpose of this study is to evaluate the effect and safety of macitentan in the treatment of pulmonary hypertension (PH). METHODS: We retrieved the safety and efficacy of macitentan treatment for PH using PubMed, the Cochrane Library, EMBASE databases and clinicaltrials.gov. The Cochrane Risk of Bias Tool was used for literature screening and quality assessment. Data analysis was conducted using RevMan 5.4.1 and Stata/SE 15.1 software. Results are presented as standardization mean differences (SMDs) and odds ratio (OR). RESULTS: Meta-analysis of seven randomized controlled trial (RCT) studies and four non-RCT studies with 2769 patients was included, involving 723 in the macitentan group and 599 in the placebo group. The results of the study showed that macitentan had effectively decreased pulmonary vascular resistance (PVR) (SMD = -0.53, 95% CI: -0.77--0.29, p < 0.05), cardiac index (CI) (SMD = 0.60, 95% CI: 0.37-0.83, p < 0.05) and N-terminal pro-brain natriuretic peptide (NT-proBNP) (SMD = -0.22, 95% CI: -0.40--0.03, p < 0.05). Furthermore, macitentan also significantly reduced PVR (SMD = -0.58, 95% CI: -0.80--0.35, p < 0.05), 6-min walk distance (6WMD) (SMD = 0.33, 95% CI: 0.15-0.50, p < 0.05), CI (SMD = 0.48, 95% CI: 0.28-0.69, p < 0.05), mean pulmonary arterial pressure (mPAP) (SMD = -0.43, 95% CI: -0.64--0.23, p < 0.05) and NT-proBNP (SMD = -0.55, 95% CI: -1.07--0.03, p < 0.05) between baseline and follow-up. The adverse reactions to macitentan were mild, with headache, anaemia and bronchitis. Other efficacy and safety outcomes did not reach statistical differences. CONCLUSION: Macitentan therapy for PH is effective and safe. The effectiveness on PVR, mPAP, mean right atrial pressure (mRAP), mortality and other indicators still needs to be further confirmed.

Stroke risk of COPD patients and death risk of COPD patients following a stroke: A systematic review and meta-analysis.

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is closely related to the development and progression of cardiovascular disease. The purpose of this study is to clarify the answers to the following questions through systematic evaluation: the risk of stroke in COPD patients; the risk of stroke in acute exacerbations of COPD (AECOPD) patients; and the risk of death after stroke in COPD patients. METHODS: Two reviewers independently searched EMbase, PubMed, and the Cochrane Library for relevant literature from the date of creation to February 17, 2023, for studies relating COPD to stroke patients. Of the 8039 publications retrieved, we identified 27 articles that met our selection criteria. Fixed-effects or random-effects models were used to calculate ORs and 95% confidence intervals for the combined risk. RESULTS: combining studies on stroke risk in COPD patients by random-effects model suggested that COPD was an independent risk factor for stroke-associated pneumonia (OR 1.40, 95% CI: 1.24-1.59, I2 = 98.4%, P = .000), with significant heterogeneity in the results, and subgroup analysis did not find a source of heterogeneity. In the combined 7 AECOPD studies, a significantly higher risk of stroke was found (OR 1.53, 95% CI: 1.44-1.63, I2 = 49.2%, P = .066). In the combined 6 short- term prognostic studies, the relationship between COPD and risk of death was not highly significant (OR 1.12, 95% CI: 1.08-1.16, I2 = 37.4%, P = .131). In 10 long-term observational prognosis studies, COPD was suggested to be associated with death after stroke by combining data using a random-effects model (OR 1.20, 95% CI: 1.13-1.27, I2 = 56.8%, P = .014), and there was moderate heterogeneity in the combination, with subgroup analysis showing that stroke type may be a source of heterogeneity and the risk of death from ischemic stroke: OR 1.23, 95% CI: 1.17-1.29, I2 = 45.0%, P = .191 and the risk of death from both types of stroke: OR 1.12, 95% CI: 1.07-1.18, I2 =18.9%, P = .291. CONCLUSION: COPD is an independent risk factor for stroke. The risk of stroke is significantly increased, especially during AECOPD. In addition, the association between COPD and short-term death in stroke patients is insignificant, while it is more associated with fatal events in the long-term prognosis.