Downregulation of ALKBH5 rejuvenates aged human mesenchymal stem cells and enhances their therapeutic efficacy in myocardial infarction.

Despite promising results in myocardial infarction (MI), mesenchymal stem cell (MSC)-based therapy is limited by cell senescence. N6-methyladenosine (m6A) messenger RNA methylation has been reported to be closely associated with cell senescence. Nonetheless, its role in the regulation of MSC senescence remains unclear. We examined the role of ALKB homolog 5 (ALKBH5) in regulating MSC senescence and determined whether ALKBH5 downregulation could rejuvenate aged MSCs (AMSCs) to improve their therapeutic efficacy for MI. RNA methylation was determined by m6A dot blotting assay. MSC senescence was evaluated by senescence-associated ß-galactosidase (SA-ß-gal) staining. A mouse model of acute MI was established by ligation of the left anterior decedent coronary artery (LAD). Compared with young MSCs (YMSCs), m6A level was significantly reduced but ALKBH5 was greatly increased in AMSCs. Overexpression of ALKBH5 reduced m6A modification and accelerated YMSC senescence. Conversely, ALKBH5 knockdown increased m6A modifications and alleviated AMSC senescence. Mechanistically, ALKBH5 regulated the m6A modification and stability of CDKN1C mRNA, which further upregulated CDKN1C expression, leading to MSC senescence. CDKN1C overexpression ameliorated the inhibition of cellular senescence of ALKBH5 siRNA-treated AMSCs. More importantly, compared with AMSCs, shALKBH5-AMSCs transplantation provided a superior cardioprotective effect against MI in mice by improving MSC survival and angiogenesis. We determined that ALKBH5 accelerated MSC senescence through m6A modification-dependent stabilization of the CDKN1C transcript, providing a potential target for MSC rejuvenation. ALKBH5 knockdown rejuvenated AMSCs and enhanced cardiac function when transplanted into the mouse heart following infarction.

Exosomal miR-9-5p derived from iPSC-MSCs ameliorates doxorubicin-induced cardiomyopathy by inhibiting cardiomyocyte senescence.

Doxorubicin (DOX) is a chemotherapeutic agent widely used for tumor treatment. Nonetheless its clinical application is heavily limited by its cardiotoxicity. There is accumulated evidence that transplantation of mesenchymal stem cell-derived exosomes (MSC-EXOs) can protect against Dox-induced cardiomyopathy (DIC). This study aimed to examine the cardioprotective effects of EXOs isolated from human induced pluripotent stem cell-derived MSCs (iPSC-MSCs) against DIC and explore the potential mechanisms. EXOs were isolated from the cultural supernatant of human BM-MSCs (BM-MSC-EXOs) and iPSC-MSCs (iPSC-MSC-EXOs) by ultracentrifugation. A mouse model of DIC was induced by intraperitoneal injection of Dox followed by tail vein injection of PBS, BM-MSC-EXOs, or iPSC-MSC-EXOs. Cardiac function, cardiomyocyte senescence and mitochondrial dynamics in each group were assessed. In vitro, neonatal mouse cardiomyocytes (NMCMs) were subjected to Dox and treated with BM-MSC-EXOs or iPSC-MSC-EXOs. The mitochondrial morphology and cellular senescence of NMCMs were examined by Mitotracker staining and senescence-associated-ß-galactosidase assay, respectively. Compared with BM-MSC-EXOs, mice treated with iPSC-MSC-EXOs displayed improved cardiac function and decreased cardiomyocyte mitochondrial fragmentation and senescence. In vitro, iPSC-MSC-EXOs were superior to BM-MSC-EXOs in attenuation of cardiomyocyte mitochondrial fragmentation and senescence caused by DOX. MicroRNA sequencing revealed a higher level of miR-9-5p in iPSC-MSC-EXOs than BM-MSC-EXOs. Mechanistically, iPSC-MSC-EXOs transported miR-9-5p into DOX-treated cardiomyocytes, thereby suppressing cardiomyocyte mitochondrial fragmentation and senescence via regulation of the VPO1/ERK signal pathway. These protective effects and cardioprotection against DIC were largely reversed by knockdown of miR-9-5p in iPSC-MSC-EXOs. Our results showed that miR-9-5p transferred by iPSC-MSC-EXOs protected against DIC by alleviating cardiomyocyte senescence via inhibition of the VPO1/ERK pathway. This study offers new insight into the application of iPSC-MSC-EXOs as a novel therapeutic strategy for DIC treatment.

MicroRNA-19b-3p dysfunction of mesenchymal stem cell-derived exosomes from patients with abdominal aortic aneurysm impairs therapeutic efficacy.

Senescence of vascular smooth muscle cells (VSMCs) contributes to the formation of abdominal aortic aneurysm (AAA). Although mesenchymal stem cell exosomes (MSC-EXO) have been confirmed to restrict the development of AAA, their biological activity depends largely on the physiological state of the MSCs. This study aimed to compare the effects of adipose-derived MSC-EXO from healthy donors (HMEXO) and AAA patients (AMEXO) on senescence of VSMCs in AAA and explore the underlying mechanisms. An ApoE-/- mouse model of AAA was used to investigate the therapeutic effects of HMEXO, AMEXO or miR-19b-3p-AMEXO on AAA development. This in vitro model of AAA was established by treating VSMCs with Ang II (Angiotensin II). The senescence of VSMCs was determined by senescence-associated ß-galactosidase (SA-ß-gal) staining. The morphology of mitochondria in VSMCs was examined by MitoTracker staining. HMEXO exhibited superior capacity compared with AMEXO to inhibit VSMC senescence and attenuate AAA formation in Ang II-treated ApoE-/- mice. In vitro, both AMEXO and HMEXO inhibited Ang II-induced VSMC senescence via downregulation of mitochondrial fission. Notably, compared with HMEXO, the ability of AMEXO to inhibit VSMC senescence was significantly decreased. miRNA sequencing and the expression of miR-19b-3p was significantly decreased in AMEXO compared with HMEXO. Luciferase assay suggested that MST4 (Mammalian sterile-20-like kinase 4) is a potential target of miR-19b-3p. Mechanistically, miR-19b-3p in HMEXO ameliorated VSMC senescence by inhibiting mitochondrial fission via regulation of the MST4/ERK/Drp1 signaling pathway. Overexpression of miR-19b-3p in AMEXO improved their beneficial effect on AAA formation. Our study reveals that MSC-exosomal miR-19b-3p exerts protective effects against Ang II-induced AAA and VSMC senescence via regulation of the MST4/ERK/Drp1 pathway. The pathological state of AAA patients alters the miRNA components of AMEXO and impairs their therapeutic benefits.

Effects of treatment with montelukast alone, budesonide/formoterol alone and a combination of both in cough variant asthma.

BACKGROUND: Whether cysteinyl-leukotriene receptor antagonists (LTRAs) have a similar antitussive effect to inhaled corticosteroids and long-acting ß2-agonist (ICS/LABA), and that LTRA plus ICS/LABA is superior to LTRAs alone or ICS/LABA alone in treating cough variant asthma (CVA) remain unclear. This study aimed to investigate and compare the efficacy of montelukast alone, budesonide/formoterol alone and the combination of both in the treatment of CVA. METHODS: Ninety-nine CVA patients were assigned randomly in a 1:1:1 ratio to receive montelukast (M group: 10 mg, once daily), budesonide/formoterol (BF group: 160/4.5 µg, one puff, twice daily), or montelukast plus budesonide/formoterol (MBF group) for 8 weeks. The primary outcomes were changes in the cough visual analogue scale (VAS) score, daytime cough symptom score (CSS) and night-time CSS, and the secondary outcomes comprised changes in cough reflex sensitivity (CRS), the percentage of sputum eosinophils (sputum Eos%) and fractional exhaled nitric oxide (FeNO). CRS was presented with the lowest concentration of capsaicin that induced at least 5 coughs (C5). The repeated measure was used in data analysis. RESULTS: The median cough VAS score (median from 6.0 to 2.0 in the M group, 5.0 to 1.0 in the BF group and 6.0 to 1.0 in the MBF group, all p < 0.001), daytime CSS (all p < 0.01) and night-time CSS (all p < 0.001) decreased significantly in all three groups after treatment for 8 weeks. Meanwhile, the LogC5 and sputum Eos% improved significantly in all three groups after 8 weeks treatment (all p < 0.05). No significant differences were found in the changes of the VAS score, daytime and night-time CSSs, LogC5 and sputum Eos% among the three groups from baseline to week 8 (all p > 0.05). The BF and MBF groups also showed significant decreases in FeNO after 8 weeks treatment (p = 0.001 and p = 0.008, respectively), while no significant change was found in the M group (p = 0.457). Treatment with MBF for 8 weeks significantly improved the FEV1/FVC as well as the MMEF% pred and decreased the blood Eos% (all p < 0.05). CONCLUSIONS: Montelukast alone, budesonide/formoterol alone and a combination of both were effective in improving cough symptom, decreasing cough reflex sensitivity and alleviating eosinophilic airway inflammation in patients with CVA, and the antitussive effect and anti-eosinophilic airway inflammation were similar. Trial registration ClinicalTrials.gov, number NCT01404013.

Determinants of response to bronchodilator in patients with cough variant asthma- A randomized, single-blinded, placebo-controlled study.

BACKGROUND: Not all patients with cough variant asthma (CVA) show responsiveness to bronchodilators (RB) in clinic. Whether there are specific clinical and pathophysiological features can indicate RB in patients with CVA needs further investigation. Thus, we aimed to investigate the RB in patients with CVA and associated factors. METHODS: Forty-two CVA patients were randomized in a 2:1 ratio to receive oral bambuterol hydrochloride (10 mg, once daily, for 3 days) or matched placebo, 36 patients (24 with bronchodilator and 12 with placebo) completed the study eventually. RB was considered when cough visual analogue scale (VAS) score decreased 30% or more after 3 days treatment. The baseline clinical and pathophysiological characteristics between patients with RB and patients without RB were compared. CRS was presented with the lowest concentration of capsaicin inducing at least 5 coughing (C5). RESULTS: The responsive rate of patients with bronchodilator was significantly higher than that with placebo (62.5% vs 16.7%, p < 0.01). Patients with RB showed a significant greater mean decline of FEV1% predicted after bronchial provocation (26.7% vs 22.4%, p < 0.05) and higher geometric mean of sputum eosinophils (1.37 vs 0.69, p < 0.05) as compared with these without RB. No significant differences in sputum neutrophil, Log C5 were found between patients with RB and patients without RB. There was a moderate correlation between the decline of FEV1% pred and RB (rs = 0.443, p < 0.05). The regression analysis showed that nocturnal cough was a predictor of RB (OR, 7.33, 95% CI: 1.11-48.26, p = 0.038). No adverse events were reported by all of the patients after the study. CONCLUSION: More than one-third of patients with CVA do not respond to bronchodilator treatment, indicating that the response to bronchodilator should not be a diagnostic requirement of CVA. CVA patients with higher airway responsiveness will more likely respond to bronchodilator. Cough of CVA might be elicited by different mechanisms, which suggests that CVA could be divided into two phenotypes according to the response to bronchodilators.

Eosinophilic airway inflammation is common in subacute cough following acute upper respiratory tract infection.

BACKGROUND AND OBJECTIVE: Patients presenting with refractory postinfectious cough may respond to glucocorticosteroids but it is unclear whether airway eosinophilic inflammation exists in those patients. We aimed to determine the airway inflammation and causes of subacute cough following acute upper respiratory tract infection (AURTI). METHODS: One hundred and sixteen patients with persistent cough lasting 3-8 weeks after upper respiratory tract infection were evaluated with differential cell count in induced sputum, spirometry and methacholine bronchial challenge testing. RESULTS: In patients with subacute cough, sputum eosinophilia (median 8.5%,3.0-73.0%) was identified in 35 (33.6%) patients, 22 (18.5%) without bronchial hyperresponsiveness (BHR) were diagnosed as non-asthmatic eosinophilic bronchitis (NAEB), 13 (14.3%) of whom with BHR were diagnosed as cough variant asthma (CVA). Cough in patients with sputum eosinophilia improved after treatment with corticosteroids. Compared with postinfectious cough (PIC) and NAEB, CVA had significantly higher median eosinophil count in induced sputum (0.5% vs 7.5% vs 20.0%, P < 0.01). MMEF in CVA was significantly lower than PIC and NAEB (P < 0.05). The common causes of subacute cough following acute upper respiratory tract infection (AURTI) were PIC (37.8%), NAEB (18.5%), CVA (14.3%) and upper airway cough syndrome (UACS) (10.1%). Atopic cough (AC) (5.2%) and gastroesophageal reflux-related cough (GERC) (3.4%) were less common in subacute cough following AURTI, while 9 (7.8%) patients had unexplained cough. CONCLUSION: Subacute cough following AURTI can be attributed to different entities, eosinophilic airway inflammation is common. Induced sputum should be considered when evaluating patients with subacute cough following acute upper respiratory tract infection.

Non-invasive positive pressure ventilation can reduce perioperative mortality in acute aortic dissection patients with hypoxemia.

Background: Hypoxemia is a common critical respiratory complication in patients with acute aortic dissection (AAD) before operation and results in adverse outcomes. This study aimed to identify the optimal oxygenation treatment for AAD patients with hypoxemia in the emergency department (ED). Methods: This was a retrospective, observational, cohort study. We retrospectively collected data from 187 adult patients with AAD and hypoxemia who had been admitted to our ED. All patients were divided into nasal cannula group (n=91), Venturi mask group (n=60), and non-invasive positive pressure ventilation (NIPPV) group (n=36). The primary outcome was overall mortality in ED; the secondary outcomes were preoperative intubation rate and postoperative mortality, length of intensive care unit (ICU) stay, length of hospital stay, and length of intubation. Results: Among all patients, those who received NIPPV treatment showed the lowest ED intubation rate (2.78%, P=0.004), shortest postoperative length of ICU stay (median 2.31, P<0.001), postoperative length of intubation (median 25.10, P<0.001), and post-operative length of hospital stay (median 21.00, P<0.001). Kaplan-Meier analysis showed the highest 3-day survival (log-rank 7.387, P=0.03) and 5-day survival (log-rank 14.710, P=0.001) in the NIPPV group. After adjustment, NIPPV therapy was independently associated with the reduced 3-day [adjusted hazard ratio (HR) 0.102, 95% confidence interval (CI): 0.013-0.791, P=0.03] and 5-day (adjusted HR 0.057, 95% CI: 0.008-0.427, P=0.005) mortality in ED. Conclusions: Early utilization of NIPPV in AAD patients with hypoxemia in the ED can effectively decrease pre-operative intubation rate and perioperative mortality, and improve postoperative outcomes.

Ciprofloxacin Accelerates Angiotensin-II-Induced Vascular Smooth Muscle Cells Senescence Through Modulating AMPK/ROS pathway in Aortic Aneurysm and Dissection.

Aortic aneurysm and dissection (AAD) is a cardiovascular disease that poses a severe threat to life and has high morbidity and mortality rates. Clinical and animal-based studies have irrefutably shown that fluoroquinolones, a commonly prescribed antibiotic for treating infections, significantly increase the risk of AAD. Despite this, the precise mechanism by which fluoroquinolones cause AAD remains unclear. Therefore, this study aims to investigate the molecular mechanism and role of Ciprofloxacin definitively-a type of fluoroquinolone antibiotic-in the progression of AAD. Aortic transcriptome data were collected from GEO datasets to detect the genes and pathways expressed differently between healthy donors and AAD patients. Human primary Vascular Smooth Muscle Cells (VSMCs) were isolated from the aorta. After 72 h of exposure to 110ug/ml Ciprofloxacin or 100 nmol/L AngII, either or combined, the senescent cells were identified through SA-ß-gal staining. MitoTracker staining was used to examine the morphology of mitochondria in each group. Cellular Reactive Oxygen Species (ROS) levels were measured using MitoSox and DCFH-DA staining. Western blot assay was performed to detect the protein expression level. We conducted an analysis of transcriptome data from both healthy donors and patients with AAD and found that there were significant changes in cellular senescence-related signaling pathways in the latter group. We then isolated and identified human primary VSMCs from healthy donors (control-VSMCs) and patients' (AAD-VSMCs) aortic tissue, respectively. We found that VSMCs from patients exhibited senescent phenotype as compared to control-VSMCs. The higher levels of p21 and p16 and elevated SA-ß-gal activity demonstrated this. We also found that pretreatment with Ciprofloxacin promoted angiotensin-II-induced cellular senescence in control-VSMCs. This was evidenced by increased SA-ß-gal activity, decreased cell proliferation, and elevation of p21 and p16 protein levels. Additionally, we found that Angiotensin-II (AngII) induced VSMC senescence by promoting ROS generation. We used DCFH-DA and mitoSOX staining to identify that Ciprofloxacin and AngII pretreatment further elevated ROS levels than the vehicle or alone group. Furthermore, JC-1 staining showed that mitochondrial membrane potential significantly declined in the Ciprofloxacin and AngII combination group compared to others. Compared to the other three groups, pretreatment of Ciprofloxacin plus AngII could further induce mitochondrial fission, demonstrated by mitoTracker staining and western blotting assay. Mechanistically, we found that Ciprofloxacin impaired the balance of mitochondrial fission and fusion dynamics in VSMCs by suppressing the phosphorylation of AMPK signaling. This caused mitochondrial dysfunction and ROS generation, thereby elevating AngII-induced cellular senescence. However, treatment with the AMPK activator partially alleviated those effects. Our data indicate that Ciprofloxacin may accelerate AngII-induced VSMC senescence through modulating AMPK/ROS signaling and, subsequently, hasten the progression of AAD.

Transcriptome analysis reveals therapeutic potential of NAMPT in protecting against abdominal aortic aneurysm in human and mouse.

Abdominal Aortic Aneurysm (AAA) is a life-threatening vascular disease characterized by the weakening and ballooning of the abdominal aorta, which has no effective therapeutic approaches due to unclear molecular mechanisms. Using single-cell RNA sequencing, we analyzed the molecular profile of individual cells within control and AAA abdominal aortas. We found cellular heterogeneity, with increased plasmacytoid dendritic cells and reduced endothelial cells and vascular smooth muscle cells (VSMCs) in AAA. Up-regulated genes in AAA were associated with muscle tissue development and apoptosis. Genes controlling VSMCs aberrant switch from contractile to synthetic phenotype were significantly enriched in AAA. Additionally, VSMCs in AAA exhibited cell senescence and impaired oxidative phosphorylation. Similar observations were made in a mouse model of AAA induced by Angiotensin II, further affirming the relevance of our findings to human AAA. The concurrence of gene expression changes between human and mouse highlighted the impairment of oxidative phosphorylation as a potential target for intervention. Nicotinamide phosphoribosyltransferase (NAMPT, also named VISFATIN) signaling emerged as a signature event in AAA. NAMPT was significantly downregulated in AAA. NAMPT-extracellular vesicles (EVs) derived from mesenchymal stem cells restored NAMPT levels, and offered protection against AAA. Furthermore, NAMPT-EVs not only repressed injuries, such as cell senescence and DNA damage, but also rescued impairments of oxidative phosphorylation in both mouse and human AAA models, suggesting NAMPT supplementation as a potential therapeutic approach for AAA treatment. These findings shed light on the cellular heterogeneity and injuries in AAA, and offered promising therapeutic intervention for AAA treatment.

TRAF3IP2 drives mesenchymal stem cell senescence via regulation of NAMPT-mediated NAD biosynthesis.

The cellular senescence of mesenchymal stem cells (MSCs) limits their application in regenerative medicine. This study aimed to clarify the role of TNF receptor-associated factor 3 interacting protein 2 (TRAF3IP2), a pro-inflammatory cytoplasmic adaptor protein, in regulating MSC senescence and to explore the potential mechanisms. Methods: MSC senescence was determined by senescence-associated ß-galactosidase (SA-ß-gal) staining. The expression of TRAF3IP2 and senescence-related proteins was detected by Western blotting. The nicotinamide adenine dinucleotide (NAD+) level and nicotinamide phosphoribosyl transferase (NAMPT) expression in MSCs was measured. Results: Compared with that in MSCs isolated from young donors (YMSCs), the expression of TRAF3IP2 was greatly increased in MSCs derived from aged donors (AMSCs). Overexpression of TRAF3IP2 accelerated YMSC senescence whereas downregulation significantly rescued cellular senescence. The protein level of NAMPT and the level of NAD+ were significantly decreased in AMSCs compared with YMSCs. Mechanistically, TRAF3IP2 induced MSC senescence via downregulation of NAMPT expression and NAD + level by inhibiting the AMPK signaling pathway. These effects were partially reversed by treatment with an AMPK or NAMPT activator. Conclusion: We revealed that TRAF3IP2 accelerated MSC senescence via downregulation of NAMPT-mediated NAD biosynthesis by mediation of the AMPK pathway, highlighting a novel means to rejuvenate senescent MSCs.

Psychometric properties of the metacognitions about smartphone use questionnaire (MSUQ) in Chinese college students.

AIMS: Over the last ten years, several studies investigating the role of metacognitions in addictive behaviors, including technological addictions, have been published. Problematic Smartphone use has been conceptualized as a behavioural addiction and a psychometrically sound self-report measure to assess metacognitions about PSU has been recently published. The objective of this study was to evaluate some psychometric properties (e.g., factor structure, reliability, and validity) of the Chinese Metacognitions about Smartphone Use Questionnaire (Chinese MSUQ). METHODS: A sample of 698 undergraduates (F = 54.70%, mean age = 19.89 ±â€¯1.38 years) were enrolled in China. An exploratory factor analysis was first performed in a randomly allocated subsample of 349 participants. A confirmatory factor analysis was then computed on a second subsample of 349 participants to test its fitting with the identified factor structure. Internal consistency and predictive validity were verified. RESULTS: The result of exploratory factor analysis showed a 2-factor structure, which consists of positive metacognitions concerning emotional and cognitive regulation and social advantages of smartphone use (MSUQ-PM) and negative metacognitions about uncontrollability and cognitive harm of smartphone use (MSUQ-NM). The confirmatory factor analysis indicated that the 2-factor structure of Chinese MSUQ had appropriate fit. Cronbach's Alphas ranged from 0.90 to 0.92. Additionally, regression analysis showed that MSUQ-PM and MSUQ-NM positively predicted PSU. Notably, MSUQ-NM is a stronger predictor of PSU compared with MSUQ-PM, with a rescaled importance of 86.36%. CONCLUSIONS: The Chinese MSUQ has appropriate psychometric properties, suggesting it is a reliable instrument to assess metacognitions about smartphone use in the Chinese context.

Response to bronchodilator and clinical, pathophysiological features in patients with nonasthmatic eosinophilic bronchitis.

INTRODUCTION: Whether nonasthmatic eosinophilic bronchitis (NAEB) shows response to bronchodilator (RB) remains unclear. OBJECTIVES: To investigate the RB and its relationship with clinical and pathophysiological features in NAEB. METHODS: Fifty-one patients with NAEB were assigned in a 2:1 ratio to receive oral bambuterol hydrochloride (n = 34, 10 mg, once daily, for 3 days) or matched placebo (n = 17) randomly, of whom 48 patients (32 with bronchodilator and 16 with placebo) completed the study. Sputum induction, spirometry and cough reflex sensitivity were measured. RB was considered when cough Visual analogue scale (VAS) score decreased 30% or more after treatment. Cough reflex sensitivity was defined as the lowest concentration of capsaicin inducing five coughings or more (C5), and presented as Log C5. RESULTS: The responsive rate of patients with bronchodilator was significantly higher than that with placebo (34.4% vs 6.3%, P < 0.05). The VAS score decreased significantly in patients with bronchodilator (median: 6.0-3.0, P < 0.01). There was a significantly higher median Log C5 (2.7 vs 1.3, P < 0.05), and a higher trend of decline in FEV1 % predicted and MMEF% predicted after bronchial provocation in patients with RB as compared with patients without RB. No significant differences in baseline percentages of sputum eosinophil were found between patients with RB and that without RB. CONCLUSIONS: One third of patients with NAEB respond well to bronchodilator treatment, which are related with lower cough reflex sensitivity and increased airway responsiveness. The relationship between NAEB and asthma needs to be investigated further.

Duration of treatment with inhaled corticosteroids in nonasthmatic eosinophilic bronchitis: a randomized open label trial.

BACKGROUND: Nonasthmatic eosinophilic bronchitis (NAEB) responds well to inhaled corticosteroids (ICS), while recurrence is common after discontinuing treatment. There are no data available to show whether treatment duration of ICS in patients with NAEB is related to recurrence. We aim to evaluate the effect of different duration of treatment with ICS on relapse of NAEB. METHODS: A total of 101 patients with NAEB were recruited to the open label, randomized, parallel-group trial. Patients were randomized to receive 1-month, 2-month, or 4-month treatment with inhaled budesonide (200 µg, twice daily). Sputum induction, cough visual analogue scale (VAS), and cough symptom score (CSS) were conducted at baseline and after completion of treatment. The patients were followed up for 1 year after treatment. The primary outcome was the relapse rate of NAEB in 1 year. RESULTS: ICS significantly decreased cough VAS, CSS, and sputum eosinophilia among these groups. There were no statistically significant between-group differences in cough VAS, CSS scores, and sputum eosinophil counts at the end of treatment, and no significant between-group differences in those changes from baseline to post-treatment. Significantly, more participants in the 1-month treatment group experienced a recurring episode of NAEB than those in the 3-month treatment group (41.9% versus 12.0%, p = 0.0137) at 1-year follow-up. The 2-month treatment group showed a lower tendency, with a relapse rate of 20.0% (p = 0.0644). CONCLUSIONS: Our results suggest that inhaled corticosteroids should be administrated for at least 2 months to reduce the relapse of NAEB. CLINICAL TRIAL REGISTRATION: The study was registered on ClinicalTrials.gov (NCT02002715). The reviews of this paper are available via the supplemental material section.

The duration of cough in patients with H1N1 influenza.

BACKGROUND: Cough is one of common symptoms of influenza, the cough duration and prevalence of postinfectious cough (PIC) after viral upper respiratory tract infection has not been well described. OBJECTIVES: We aim to investigate the duration of cough and prevalence of PIC and its relation with acute symptoms, airway inflammation and cough sensitivity in patients with H1N1 influenza. METHODS: Patients with acute symptoms of H1N1 influenza were enrolled and followed up until cough relived. Spirometry, induced sputum test, capsaicin challenge test were conducted in patients with PIC. Cough sensitivity was presented as logarithm of provocative concentration inducing five or more coughs (logC5). RESULTS: A total of 141 cases with H1N1 influenza were enrolled. In patients with H1N1 influenza, 97.2% of them complained cough. The duration of cough was as following: <1 week (73.0%); 1-2 weeks (7.8%); 2-3 weeks (7.8%); ≥3 weeks (8.5%). Twelve (8.5%) patients had cough lasting more than 3 weeks (PIC), 4 (2.8%) patients developed chronic cough (>8 weeks). Acute symptoms, spirometry, bronchial responsiveness and sputum differential cell count were similar between patients with PIC and those without PIC, however, there was a higher prevalence of previous PIC (58.3% vs 14.7%, P < 0.05) and elevated cough sensitivity (lgC5: 1.18 ± 0.58 vs 2.73 ± 0.33, P < 0.01) in patients with PIC as compared with the patients without PIC. CONCLUSIONS: Acute cough is common in patients with H1N1 PIC, only a few of patients develop chronic cough. Acute symptoms cannot predict PIC which is related with previous PIC and increased cough sensitivity.

Validity of Fractional Exhaled Nitric Oxide in Diagnosis of Corticosteroid-Responsive Cough.

BACKGROUND: Whether fractional exhaled nitric oxide (FeNO) measurement alone or combined with sputum eosinophil and atopy is useful in predicting corticosteroid-responsive cough (CRC) and non-CRC (NCRC) is not clear. METHODS: A total of 244 patients with chronic cough and 59 healthy subjects as control were enrolled. The causes of chronic cough were confirmed according to a well-established diagnostic algorithm. FeNO measurement and induced sputum for differential cell were performed in all subjects. RESULTS: CRC occurred in 139 (57.0%) patients and NCRC occurred in 105. The FeNO level in CRC significantly correlated with sputum eosinophils (rs = 0.583, P < .01). The median (quarter) of FeNO level in CRC was significantly higher than NCRC (32.0 ppb [19.0-65.0 ppb] vs 15.0 ppb [11.0-22.0 ppb], P < .01). FeNO of 31.5 ppb had a sensitivity and specificity of 54.0% and 91.4%, respectively, in predicting CRC from chronic cough, with a positive predictive value of 89.3% and a negative predictive value of 60.0%. If the patients had a combination of low level of FeNO ( < 22.5 ppb), normal sputum eosinophil ( < 2.5%), and absence of atopy, the sensitivity and specificity would be 30.3% and 93.5% for predicting NCRC. CONCLUSIONS: In our cohort, a high level (≥ 31.5 ppb) of FeNO indicates more likelihood of CRC, but the sensitivity is insufficient to rule out a diagnosis of CRC. A combination of low-level FeNO, normal sputum eosinophil, and absence of atopy suggests a lower likelihood of CRC.

Will nonasthmatic eosinophilic bronchitis develop into chronic airway obstruction?: a prospective, observational study.

OBJECTIVE: The long-term prognosis of nonasthmatic eosinophilic bronchitis (NAEB) is still unclear. The aim of this study was to observe the frequency of relapse among patients with NAEB and the likelihood of NAEB developing into chronic airflow obstruction over time. METHODS: Patients with NAEB were followed for at least 1 year between 2003 and 2013. During this period, we evaluated clinical symptoms, sputum eosinophil count, spirometry, and bronchial hyperresponsiveness. A linear mixed model was adopted to determine the relationship between time and lung function. RESULTS: A total of 234 patients with NAEB were identified, of whom 141 were followed for > 1 year (median, 4.1 years). Up to 59.6% of patients had a relapse after treatment. Both allergic rhinitis (OR, 4.37; 95% CI, 1.049-18.203; P = .043) and sputum eosinophilia after 4 weeks of treatment with inhaled corticosteroids (OR, 9.493; 95% CI, 2.381-37.850; P = .001) were risk factors for relapse. Among the 141 patients, mild asthma developed in eight (5.7%). During the follow-up period, no progressive decline in FVC, FEV1, and FEV1/FVC were observed (P > .05). Although the proportion of small airway dysfunction (maximum midexpiratory flow [MMEF] < 65%) significantly increased at the last visit in all groups (all P < .05), only the relapse group showed an MMEF decline at the end of follow-up (P < .05) in the linear mixed model. CONCLUSIONS: More than 50% of patients with NAEB have repeated episodes associated with persistent sputum eosinophilia after treatment and allergic rhinitis. In the current cohort, chronic airway obstruction does not develop despite small airway dysfunction increases over time.

Epidemiology of cough in relation to China.

Cough is one of the most common complaints for which patients seek medical attention. Misdiagnosis and mistreatment of cough exist commonly in China. The prevalence of acute cough caused by upper airway infection fluctuates between 9% and 64% in the community, for chronic cough, the prevalence >10% in most surveys, ranging from 7.2%-33%. The common causes of chronic cough are upper airway cough syndrome (previously called as post nasal drip syndrome [PNDS]), cough variant asthma (CVA), gastroesophageal reflux related cough (GERD) and eosinophilic bronchitis (EB). There is a regional discrepancy regarding the prevalence of common causes of cough and distribution of gender among China, UK, USA, the most common cause of chronic cough in China are CVA, followed by UACS, EB and atopic cough (AC), the male is almost equal to female in numbers in China. The risk factors for cough includes cold air, smoking, environmental pollutants, noxious substances and allergens, and unreasonable diet habits.