Small airway hyperresponsiveness in COPD: relationship between structure and function in lung slices

The direct relationship between pulmonary structural changes and airway hyperresponsiveness (AHR) in chronic obstructive pulmonary disease (COPD) is unclear. We investigated AHR in relation to airway and parenchymal structural changes in a guinea pig model of COPD and in COPD patients. Precision-cut lung slices (PCLS) were prepared from guinea pigs challenged with lipopolysaccharide or saline two times weekly for 12 wk. Peripheral PCLS were obtained from patients with mild to moderate COPD and non-COPD controls. AHR to methacholine was measured in large and small airways using video-assisted microscopy. Airway smooth muscle mass and alveolar airspace size were determined in the same slices. A mathematical model was used to identify potential changes in biomechanical properties underlying AHR. In guinea pigs, lipopolysaccharide increased the sensitivity of large (>150 μm) airways toward methacholine by 4.4-fold and the maximal constriction of small airways

Incidence and risk factors of deep vein thrombosis after extracorporeal life support

Background: Deep vein thrombosis (DVT) after decannulation of extracorporeal life support (ECLS) is not uncommon. Moreover, the impact of anticoagulation and potential risk factors is unclear. Furthermore, it is unclear if cannula-associated DVT is more common in ECLS patients compared to critically ill patients without ECLS. Methods: All adult patients who were successfully weaned from ECLS and were screened for DVT following decannulation were included in this observational cohort study. The incidence of post-ECLS-DVT was assessed and the cannula-associated DVT rate was compared with that of patients without ECLS after central venous catheter (CVC) removal. The correlation between the level of anticoagulation, risk factors, and post-ECLS-DVT was determined. Results: We included 30 ECLS patients and 53 non-ECLS patients. DVT was found in 15 patients (50%) of which 10 patients had a DVT in a cannulated vein. No correlation between the level of anticoagulation and DVT was found. V-V ECLS mode was the only independent risk factor for post-ECLS-DVT (OR 5.5; 95%CI 1.16–26.41). We found no difference between the ECLS and non-ECLS cohorts regarding cannula-associated DVT rate (33% vs. 32%). Conclusion: Post-ECLS-DVT is a common finding that occurs in half of all patients supported with ECLS. The incidence of cannula-associated DVT was equal to CVC-associated DVT in critically ill patients without ECLS. V-V ECLS was an independent risk factor for post-ECLS-DVT

Adipose triglyceride lipase (ATGL) expression in human skeletal muscle is type I (oxidative) fiber specific

Accumulation of triacylglycerol (TAG) and lipid intermediates in skeletal muscle plays an important role in the etiology of insulin resistance and type 2 diabetes mellitus. Disturbances in skeletal muscle lipid turnover and lipolysis may contribute significantly to this. So far, knowledge on the regulation of muscle lipolysis is limited. Recently the identification of a new lipase was reported: adipose triglyceride lipase (ATGL). ATGL deficient animals show significant lipid accumulation in skeletal muscle, which may indicate that ATGL plays a pivotal role in skeletal muscle lipolysis. However, until now, it is still unknown whether ATGL protein is expressed in human skeletal muscle. Therefore, the aim of the present study was to investigate whether ATGL is expressed at the protein level in human skeletal muscle, and to examine whether its expression is fiber-type specific. To accomplish this, we established an imunohistochemical and immunofluorescent staining procedure to study ATGL protein expression in relation to fiber type in human vastus lateralis muscle of eight male subjects (BMI range: 21.0–34.5 kg/m2 and age: 38–59 years). In the present paper we report for the first time that ATGL protein is indeed expressed in human skeletal muscle. Moreover, ATGL is exclusively expressed in type I (oxidative) muscle fibers, suggesting a pivotal role for ATGL in intramuscular fatty acid handling, lipid storage and breakdown

Multidrug resistance-associated protein-1 (MRP1) genetic variants, MRP1 protein levels and severity of COPD

<p>Abstract</p> <p>Background</p> <p>Multidrug resistance-associated protein-1 (MRP1) protects against oxidative stress and toxic compounds generated by cigarette smoking, which is the main risk factor for chronic obstructive pulmonary disease (COPD). We have previously shown that single nucleotide polymorphisms (SNPs) in <it>MRP1 </it>significantly associate with level of FEV₁in two independent population based cohorts. The aim of our study was to assess the associations of <it>MRP1 </it>SNPs with FEV₁level, MRP1 protein levels and inflammatory markers in bronchial biopsies and sputum of COPD patients.</p> <p>Methods</p> <p>Five SNPs (rs212093, rs4148382, rs504348, rs4781699, rs35621) in <it>MRP1 </it>were genotyped in 110 COPD patients. The effects of <it>MRP1 </it>SNPs were analyzed using linear regression models.</p> <p>Results</p> <p>One SNP, rs212093 was significantly associated with a higher FEV₁level and less airway wall inflammation. Another SNP, rs4148382 was significantly associated with a lower FEV₁level, higher number of inflammatory cells in induced sputum and with a higher MRP1 protein level in bronchial biopsies.</p> <p>Conclusions</p> <p>This is the first study linking <it>MRP1 </it>SNPs with lung function and inflammatory markers in COPD patients, suggesting a role of <it>MRP1 </it>SNPs in the severity of COPD in addition to their association with MRP1 protein level in bronchial biopsies.</p

Remarkable spatial variation in the seroprevalence of Coxiella burnetii after a large Q fever epidemic.

Prior to the 2007-2010 Q fever epidemic in the Netherlands, the seroprevalence of antibodies against Coxiella burnetii in the general population was 1.5%, which is low compared to other countries. We aimed to determine the seroprevalence after the Q fever epidemic among people living in the affected area, compare the seroprevalence with the incidence of Q fever notifications during the 2007-2010 Q fever epidemic, and to identify farm exposures associated with having antibodies against C. burnetii

High-Dose Chemotherapy With Hematopoietic Stem Cell Transplant in Patients With High-Risk Breast Cancer and 4 or More Involved Axillary Lymph Nodes 20-Year Follow-up of a Phase 3 Randomized Clinical Trial:20-Year Follow-up of a Phase 3 Randomized Clinical Trial

Importance: Trials of adjuvant high-dose chemotherapy (HDCT) have failed to show a survival benefit in unselected patients with breast cancer, but long-term follow-up is lacking. Objective: To determine 20-year efficacy and safety outcomes of a large trial of adjuvant HDCT vs conventional-dose chemotherapy (CDCT) for patients with stage III breast cancer. Design, Setting, and Participants: This secondary analysis used data from a randomized phase 3 multicenter clinical trial of 885 women younger than 56 years with breast cancer and 4 or more involved axillary lymph nodes conducted from August 1, 1993, to July 31, 1999. Additional follow-up data were collected between June 1, 2016, and December 31, 2017, from medical records, general practitioners, the Dutch national statistical office, and nationwide cancer registries. Analysis was performed on an intention-to-treat basis. Statistical analysis was performed from February 1, 2018, to October 14, 2019. Interventions: Participants were randomized 1:1 to receive 5 cycles of CDCT consisting of fluorouracil, 500 mg/m 2, epirubicin, 90 mg/m 2, and cyclophosphamide, 500 mg/m 2, or HDCT in which the first 4 cycles were identical to CDCT and the fifth cycle was replaced by cyclophosphamide, 6000 mg/m 2, thiotepa, 480 mg/m 2, and carboplatin, 1600 mg/m 2, followed by hematopoietic stem cell transplant. Main Outcomes and Measures: Main end points were overall survival and safety and cumulative incidence risk of a second malignant neoplasm or cardiovascular events. Results: Of the 885 women in the study (mean [SD] age, 44.5 [6.6] years), 442 were randomized to receive HDCT, and 443 were randomized to receive CDCT. With 20.4 years median follow-up (interquartile range, 19.2-22.0 years), the 20-year overall survival was 45.3% with HDCT and 41.5% with CDCT (hazard ratio, 0.89; 95% CI, 0.75-1.06). The absolute improvement in 20-year overall survival was 14.6% (hazard ratio, 0.72; 95% CI, 0.54-0.95) for patients with 10 or more invoved axillary lymph nodes and 15.4% (hazard ratio, 0.67; 95% CI, 0.42-1.05) for patients with triple-negative breast cancer. The cumulative incidence risk of a second malignant neoplasm at 20 years or major cardiovascular events was similar in both treatment groups (20-year cumulative incidence risk for second malignant neoplasm was 12.1% in the HDCT group vs 16.2% in the CDCT group, P =.10), although patients in the HDCT group more often had hypertension (21.7% vs 14.3%, P =.02), hypercholesterolemia (15.7% vs 10.6%, P =.04), and dysrhythmias (8.6% vs 4.6%, P =.005). Conclusions and Relevance: High-dose chemotherapy provided no long-term survival benefit in unselected patients with stage III breast cancer but did provide improved overall survival in very high-risk patients (ie, with ≥10 involved axillary lymph nodes). High-dose chemotherapy did not affect long-term risk of a second malignant neoplasm or major cardiovascular events. Trial Registration: ClinicalTrials.gov Identifier: NCT03087409

The impact of a pathologist's personality on the interobserver variability and diagnostic accuracy of predictive PD-L1 immunohistochemistry in lung cancer

OBJECTIVES: Programmed death-ligand 1 (PD-L1) is the only approved predictive biomarker for immunotherapy in non-small cell lung cancer (NSCLC). However, predictive PD-L1 immunohistochemistry is subject to interobserver variability. We hypothesized that a pathologist's personality influences the interobserver variability and diagnostic accuracy of PD-L1 immunoscoring. MATERIALS AND METHODS: Seventeen pathologists performed PD-L1 immunoscoring on 50 resected NSCLC tumors in three categories (<1%;1-49%;≥50%). Also, the pathologists completed a certified personality test (NEO-PI-r), assessing five personality traits: neuroticism, extraversion, openness, altruism and conscientiousness. RESULTS: The overall agreement among pathologists for a series of 47 tumors was substantial (kappa = 0.63). Of these, 23/47 (49%) tumors were entirely negative or largely positive, resulting in a kappa value of 0.93. The remaining 24/47 (51%) tumors had a PD-L1 score around the cutoff value, generating a kappa value of 0.32. Pathologists with high scores for conscientiousness (careful, diligent) had the least interobserver variability (r = 0.6, p = 0.009). Also, they showed a trend towards higher sensitivity (74% vs. 68%, p = 0.4), specificity (86% vs. 82%, p = 0.3) and percent agreement (83% vs. 79%, p = 0.3), although not significant. In contrast, pathologists with high scores for neuroticism (sensitive, anxious) had significantly lower specificity (80% vs. 87%, p = 0.03) and percent agreement (78% vs. 85%, p = 0.03). Also, a trend towards high interobserver variability (r = -0.3, p = 0.2) and lower sensitivity (68% vs. 74%, p = 0.3) was observed, although not significant. Pathologists with relatively high scores for conscientiousness scored fewer tumors PD-L1 positive at the ≥ 1% cut-off (r = -0.5, p = 0.03). In contrast, pathologists with relatively high scores for neuroticism score more tumors PD-L1 positive at ≥ 1% (r = 0.6, p = 0.017) and ≥ 50% cut-offs (r = 0.6, p = 0.009). CONCLUSIONS: This study is the first to demonstrate the impact of a pathologist's personality on the interobserver variability and diagnostic accuracy of immunostaining, in the context of PD-L1 in NSCLC. Larger studies are needed for validation of these findings

Smoking cessation and bronchial epithelial remodelling in COPD: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Chronic Obstructive Pulmonary Disease (COPD) is associated with bronchial epithelial changes, including squamous cell metaplasia and goblet cell hyperplasia. These features are partially attributed to activation of the epidermal growth factor receptor (EGFR). Whereas smoking cessation reduces respiratory symptoms and lung function decline in COPD, inflammation persists. We determined epithelial proliferation and composition in bronchial biopsies from current and ex-smokers with COPD, and its relation to duration of smoking cessation.</p> <p>Methods</p> <p>114 COPD patients were studied cross-sectionally: 99 males/15 females, age 62 ± 8 years, median 42 pack-years, no corticosteroids, current (n = 72) or ex-smokers (n = 42, median cessation duration 3.5 years), postbronchodilator FEV₁63 ± 9% predicted. Squamous cell metaplasia (%), goblet cell (PAS/Alcian Blue⁺) area (%), proliferating (Ki-67⁺) cell numbers (/mm basement membrane), and EGFR expression (%) were measured in intact epithelium of bronchial biopsies.</p> <p>Results</p> <p>Ex-smokers with COPD had significantly less epithelial squamous cell metaplasia, proliferating cell numbers, and a trend towards reduced goblet cell area than current smokers with COPD (p = 0.025, p = 0.001, p = 0.081, respectively), but no significant difference in EGFR expression. Epithelial features were not different between short-term quitters (<3.5 years) and current smokers. Long-term quitters (≥3.5 years) had less goblet cell area than both current smokers and short-term quitters (medians: 7.9% vs. 14.4%, p = 0.005; 7.9% vs. 13.5%, p = 0.008; respectively), and less proliferating cell numbers than current smokers (2.8% vs. 18.6%, p < 0.001).</p> <p>Conclusion</p> <p>Ex-smokers with COPD had less bronchial epithelial remodelling than current smokers, which was only observed after long-term smoking cessation (>3.5 years).</p> <p>Trial registration</p> <p>NCT00158847</p