NO-releasing xanthine KMUP-1 bonded by simvastatin attenuates bleomycin-induced lung inflammation and delayed fibrosis

Background and purposePulmonary fibrosis (PF) is a progressing lung injury initiated by pulmonary inflammation (PI). Bleomycin (BLM) is the most common pathogenesis of PF through early PI and extensive extracellular matrix deposition. This study is aimed to determine whether NO-releasing KMUP-1 inhibits PI and PF, and if so, the benefits of KMUP-1S resulted from simvastatin (SIM)-bonding to KMUP-1.Experiment approachC57BL/6 male mice were intra-tracheally administered BLM (4 U/kg) at day 0. KMUP-1 (1–5 mg/kg), KMUP-1S (2.5 mg/kg), SIM (5 mg/kg), Plus (KMUP-1 2.5 mg/kg + SIM 2.5 mg/kg), and clarithromycin (CAM, 10 mg/kg) were orally and daily administered for 7 and 28 days, respectively, to mice, sacrificed at day-7 and day-28 to isolate the lung tissues, for examining the inflammatory and fibrotic signaling and measuring the cell population and MMP-2/MMP-9 activity in broncholaveolar lavage fluid (BAL).Key resultsKMUP-1 and KUP-1S significantly decreased neutrophil counts in BAL fluid. Fibroblastic foci were histologically assessed by H&E and Masson's trichrome stain and treated with KMUP-1 and references. Lung tissues were determined the contents of collagen and the expressions of TGF-β, α-SMA, HMGB1, CTGF, eNOS, p-eNOS, RhoA, Smad3, p-Smad3, MMP-2 and MMP-9 by Western blotting analyses, respectively. These changes areregulated by NO/cGMP and inhibited by various treatments. KMUP-1 and KMUP-1S predominantly prevented HMGB1/MMP-2 expression at day-7 and reduced TGF-β/phosphorylated Smad3 and CTGF at day-28.Conclusions and implicationsKMUP-1 and KMUP-S restore eNOS, inhibit iNOS/ROCKII/MMP-2/MMP-9, attenuate histologic collagen disposition and reduce BALF inflammatory cells, potentially useful for the treatment of BLM-lung PF.     

The Early Cognitive Development of Children at High Risk of Developing an Eating Disorder

Diagnosis of an eating disorder (ED) has been associated with differences in cognition. Recent evidence suggests that differences may be present prior to onset. Children at familial high risk for ED show cognitive differences at ages 8–10 years. Research is required to investigate differences in cognitive development at various time points. This is the first study to investigate cognitive development in children at high risk at 18 months (Griffiths Mental Development Scale; n = 982) and 4 years old (Wechsler Preschool and Primary Scale of Intelligence—Revised; n = 582), in comparison with children not at risk, using a general population sample, the Avon Longitudinal Study of Parents and Children. Children of women with lifetime anorexia nervosa revealed difficulties in social understanding, visual‐motor function, planning and abstract reasoning. Cognitive differences observed here have also been observed in clinical groups. This suggests difficulties may be present prior to onset, potentially affecting risk status for development of ED. Findings contribute to an understanding of aetiology, and design of prevention/intervention strategies. Copyright © 2013 The Authors. European Eating Disorders Review published by John Wiley & Sons Ltd.     

Gastroesophageal reflux disease and patterns of reflux in patients with idiopathic pulmonary fibrosis using hypopharyngeal multichannel intraluminal impedance

Idiopathic pulmonary fibrosis (IPF) is a diffuse fibrotic lung disease of unknown etiology. The association between IPF and gastroesophageal reflux disease (GERD) has been suggested. The objective of this study was to determine the prevalence of GERD and assess the proximity of reflux events in patients with histologically proven IPF using hypopharyngeal multichannel intraluminal impedance (HMII). This is a retrospective review of prospectively collected data from patients with histologically confirmed IPF (via lung biopsy) who underwent objective esophageal physiology testing including high‐resolution manometry and HMII. Defective lower esophageal sphincter (LES) was defined as either LES pressure of <5.0 mmHg, total length of LES of <2.4 cm, or intra‐abdominal length of LES of <0.9 cm. Abnormal esophageal motility was considered present when failed swallows ≥30% and/or mean wave amplitude <30 mmHg was present. HMII used a specialized impedance catheter to directly measure laryngopharyngeal reflux (LPR) and full column reflux (reflux 2 cm distal to the upper esophageal sphincter). Based on the previous study of healthy subjects, abnormal proximal exposure was considered present when LPR ≥1/day and/or full column reflux ≥5/day were present. From October 2009 to June 2011, 46 patients were identified as having pulmonary fibrosis and sufficient HMII data. Of 46, 10 patients were excluded because of concomitant connective tissue diseases, and 8 patients were excluded because they had undergone lung transplantation, which may impact the patterns of reflux. The remaining 28 patients with histologically confirmed IPF (male 16, female 12) were included in this study. Mean age and BMI were 60.4 years (range, 41–78) and 28.4 (range, 21.1–38.1), respectively. All patients except one were symptomatic; 23 (82%) patients had concomitant typical GERD symptoms such as heartburn, whereas 4 (14%) patients had isolated pulmonary symptoms such as cough. Esophageal mucosal injury such as esophagitis and Barrett's esophagus was found in 17 (71%) patients, whereas hiatal hernia was found in 19 (73%) patients. Abnormal proximal exposure, which occurred almost exclusively in the upright position, was present in 54% (15/28) of patients. There was no significant difference in clinical symptoms, objective findings of GERD, and pulmonary functions such as forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and diffusing capacity of the lung for carbon monoxide (DLCO) between patients with and without abnormal proximal exposure. Although the total number of reflux events was significantly higher in patients with abnormal proximal exposure, a large number of patients had a negative DeMeester score regardless of whether abnormal proximal exposure was present (patients with, 80%; those without, 85%). Patients with abnormal proximal exposure more likely had a defective LES compared with those without (93% vs. 75%). Fourteen patients (56%) had abnormal esophageal motility including aperistaltic esophagus (n = 9). This first study of HMII in patients with IPF demonstrated that GERD is highly prevalent (>70%), and abnormal proximal reflux events such as LPR and full column reflux are common despite a frequently negative DeMeester score. HMII may be beneficial in the work‐up of GERD in patients with IPF.     

The acoustic cough monitoring and manometric profile of cough and throat clearing

Cough and throat clearing might be difficult to differentiate when trying to detect them acoustically or manometrically. The aim of this study was to assess the accuracy of acoustic monitoring for detecting cough and throat clearing, and to also determine whether these two symptoms present with different manometric profiles on esophageal pressure topography. Ten asymptomatic volunteers (seven females, mean age 31.1) were trained to simulate cough and throat clearing in a randomized order every 6 minutes during simultaneous acoustic monitoring and high‐resolution manometry. The accuracy of automated acoustic analysis and two blinded reviewers were compared. The pattern of the events and the duration of the pressure changes were assessed using the 30 mmHg isobaric contour. There were 50 cough and 50 throat‐clearing events according to the protocol. The sensitivity and specificity of automated acoustic analysis was 84% and 50% for cough, while the blinded analysis using sound revealed a sensitivity and specificity of 94% and 92%. The manometric profile of both cough and throat clearing was similar in terms of qualitative findings; however, cough was associated with a greater number of repetitive pressurizations and a more vigorous upper esophageal sphincter contraction compared with throat clearing. The acoustic analysis software has a moderate sensitivity and poor specificity to detect cough. The profile of cough and throat clearing in pressure topography revealed a similar qualitative pattern of pressurization with more vigorous pressure changes and a greater rate of repetitive pressurizations in cough.     

支气管扩张症-慢性阻塞性肺疾病重叠综合征临床特点分析

目的分析总结支气管扩张症-慢性阻塞性肺疾病重叠综合征(ECOS)患者的临床特点,提高对该病的认识,指导临床工作。方法回顾性分析2018年1〜12月在成都市双流区第一人民医院呼吸与危重医学科住院的490例确诊为慢性阻塞性肺疾病急性加重期患者的临床资料,将通过高分辨CT诊断为BCOS的患者45例为ECOS组,同时在剩余的患者中随机选择(采用随机数表法)同期入住呼吸与危重医学科的单纯慢性阻塞性肺疾病(COPD)患者45例作为对照组,分别比较2组患者在一般资料、临床表现、肺功能、实验室检査、住院时间及费用、出院后6个月内急性加重次数及再入院率等方面的差异。结果2组患者在年龄、性别、吸烟指数、体质量指数、住院前基础用药方面差异无统计学意义。BCOS组与COPD组比较,其临床症状更重,实验室检查提示白细胞计数、降钙素原阳性率更高,动脉血氧分压值及氧合指数下降更明显,痰培养阳性率更高,肺功能受损更显著,住院时间更长,住院费用更高,出院6个月内急性加重次数更多。结论BCOS患者发病率较高,临床症状更重,肺功能受损更明显,住院时间及费用明显升高,临床应更加重视此类患者,早诊断,早治疗,以更好的改善患者预后。