Prevalence and risk factors of asthma in dairy farmers: Ancillary analysis of AIRBAg.

BACKGROUND: Prolonged occupational agricultural exposure is associated with an increase in asthma diagnosis. This study aimed to identify the prevalence and risk factors for asthma in dairy farmers. METHODS: AIRBAg was a cross-sectional study including 1203 representative dairy farmers. They completed a self-administered questionnaire and underwent a health respiratory check-up. Referral to a pulmonologist was made for any participant with wheezing, dyspnoea, chronic bronchitis, a chronic cough or a FEV1/FEV6 ratio<80%. They underwent further examinations such as spirometry with a reversibility test. Controls (non-asthmatic dairy farmers and non-farm employees) were matched to each asthma case for sex and age (±5 years). The odds ratios (OR) between asthma and different risk factors were estimated using conditional multivariate logistic regression models. RESULTS: Active asthma was diagnosed in 107 (8.9%) farmers. Compared with control dairy farmers, there was a positive association with family history of allergy (OR = 8.68; 95% CI [4.26-17.69]), personal history of eczema (OR = 3.39; 95% CI [1.61-7.13]), hay manipulation (OR = 5.36, 95% CI [1.59-18.01]), and a negative association with farm area (OR = 0.92; 95% CI [0.85-0.99]) and handling treated seeds (OR = 0.47; 95% CI [0.23-0.95]). Compared with control non-farm employees, there was a positive association between asthma and family history of allergy (OR = 95.82, 95% CI [12.55-731.47]). CONCLUSIONS: The prevalence of active asthma in dairy farmers was somewhat higher than the rate observed in the general population but may be controlled by reducing exposure to airborne organic contaminants through occupational adaptions on farms.

ING2 tumor suppressive protein translocates into mitochondria and is involved in cellular metabolism homeostasis.

ING2 (Inhibitor of Growth 2) is a tumor suppressor gene that has been implicated in critical biological functions (cell-cycle regulation, replicative senescence, DNA repair and DNA replication), most of which are recognized hallmarks of tumorigenesis occurring in the cell nucleus. As its close homolog ING1 has been recently observed in the mitochondrial compartment, we hypothesized that ING2 could also translocate into the mitochondria and be involved in new biological functions. In the present study, we demonstrate that ING2 is imported in the inner mitochondrial fraction in a redox-sensitive manner in human cells and that this mechanism is modulated by 14-3-3η protein expression. Remarkably, ING2 is necessary to maintain mitochondrial ultrastructure integrity without interfering with mitochondrial networks or polarization. We observed an interaction between ING2 and mtDNA under basal conditions. This interaction appears to be mediated by TFAM, a critical regulator of mtDNA integrity. The loss of mitochondrial ING2 does not impair mtDNA repair, replication or transcription but leads to a decrease in mitochondrial ROS production, suggesting a detrimental impact on OXPHOS activity. We finally show using multiple models that ING2 is involved in mitochondrial respiration and that its loss confers a protection against mitochondrial respiratory chain inhibition in vitro. Consequently, we propose a new tumor suppressor role for ING2 protein in the mitochondria as a metabolic shift gatekeeper during tumorigenesis.

Transferrin saturation is independently associated with the severity of obstructive sleep apnea syndrome and hypoxia among obese subjects.

INTRODUCTION & AIMS: Obstructive sleep apnea syndrome (OSAS) is a frequent complication of obesity. Intermittent chronic hypoxia which frequently results from OSAS could modulate the systemic control of iron metabolism and alter serum iron parameters, especially among obese patients. AIMS: to evaluate whether serum parameters of iron bioavailability and storage (primary), as well as age, waist circumference, arterial hypertension and tobacco use (secondary) are associated with OSAS severity and/or hypoxia. METHODS: design: a single-center retrospective study with prospective data collection; inclusion criteria: consecutive patients referred for initial assessment for obesity underwent nocturnal respiratory polygraphy and iron status serum assessment within a 3-month period. The adjusted analyzes were performed using ANOVA and reported as adjusted means and 95% confidence interval (95% CI). RESULTS: 13 men and 56 women were included. OSAS prevalence: 72% (n = 50). Ferritin (mean ± SD, 260 ± 276 vs. 111 ± 89 µg/l, p = 0.01) and transferrin saturation (31 ± 10 vs. 24 ± 9%, p = 0.002) were significantly higher in case of moderate/severe OSAS than in absent/mild OSAS, independently from gender and tobacco use. Serum iron (19.4 µg/l [CI95%, 16.5-22.3] vs. 16.2 µg/l ([14.1-18.2], p = 0.056) and transferrin saturation (31.5% [26.3-36.7]) vs. 25.3% [21.6-29.1], p = 0.043) were higher when time under oxygen saturation <90% was >15%. Age (mean ± SD, 51 ± 11 vs. 41 ± 12 yr, p = 0.001), waist circumference (136 ± 18 vs. 123 ± 12 cm, p = 0.003), arterial hypertension (59% (n = 13/22) vs. 23% (n = 11/47), p = 0.004) and tobacco use (64% (n = 14/22) vs. 32% (n = 15/47), p = 0.01) were significantly greater in moderate/severe OSAS than in absent/mild OSAS. CONCLUSIONS: Transferrin saturation was associated with OSAS severity and time under hypoxia. This suggests a relationship between OSAS-induced hypoxia and iron metabolism among obese patients.

What are the best indicators to assess malnutrition in idiopathic pulmonary fibrosis patients? A cross-sectional study in a referral center.

OBJECTIVES: Little is known about the indicators to assess malnutrition in patients with idiopathic pulmonary fibrosis (IPF). This study aimed to determine the following: 1) the prevalence of malnutrition in IPF patients; 2) the nutritional indicators predictive of low fat-free mass (FFM) as measured by bioimpedance analysis; 3) the IPF patients' characteristics associated with low FFM. METHODS: The IPF patients were consecutively recruited in a referral center for rare pulmonary diseases. Malnutrition was defined as a fat-free mass index (FFMI) = FFM (kg) / (height [m]2) <17 (men) or <15 (women). Nutritional assessment included body mass index (BMI), mid-arm circumference (MAC), triceps skinfold thickness, analogue food intake scale, and serum albumin and transthyretin. The primary endpoint was FFMI. Area under the receiver operating characteristic curve (AUC) assessed low FFMI prediction from nutritional indicators. Multivariable logistic regression determined variables associated with low FFMI. RESULTS: Eighty-one patients were consecutively recruited. Low FFMI prevalence was 28% (23 of 81). BMI AUC was 0.91 (95% confidence interval [CI], 0.84‒0.97) and MAC AUC was 0.85 (0.76‒0.94). Multivariable analysis associated BMI (odds ratio [OR] 0.26 [95% CI, 0.12-0.54], P = 0.0003), male sex (OR 0.02 [0.00-0.33], P = 0.005), and smoking (OR 0.10 [0.01-0.75], P = 0.024) with a lower risk of malnutrition. CONCLUSIONS: Malnutrition occurred in nearly one-third of IPF patients. Malnutrition screening should become systematic based on BMI and MAC, which are good clinical indicators of low FFMI. We propose a practical approach to screen malnutrition in IPF patients.

Prevalence and risk factors of chronic obstructive pulmonary disease in dairy farmers: AIRBAg study.

BACKGROUND: The AIRBAg study was designed to assess the prevalence of chronic obstructive pulmonary disease (COPD) in dairy farmers and to define its associated risk factors. METHODS: Between March 2012 and February 2017 randomly selected dairy farmers in the French region of Brittany were asked to complete a self-administered questionnaire and undergo an occupational health check-up with electronic mini-spirometry and standard spirometry. Those having one or more of the following features: chronic cough, chronic bronchitis, wheezing, dyspnea and/or a ratio FEV1/FEV6 < 80% were then referred to a pulmonologist for further check-up including spirometry with a reversibility test. Each COPD case was matched with three controls (dairy farmers and non-farm employees), for sex and age ( ±â€¯5 years). Conditional multivariate logistic regression models were used to estimate the odds ratios between COPD occurrence and various risk factors. RESULTS: The 1203 farmers examined included 525 (43.6%) who were "at risk of bronchial obstruction" and 432 (35.9%) of these saw the pulmonologist. This screening identified 16 (1.3%) cases of COPD, including eight non-smokers and five with an FEV1 < 80% of predicted values. Their average age was 54.6 ( ±â€¯7.7) years and 10 of them were men. None complained of illness before the study. Multivariate analyses revealed no significant occupational risk factors for COPD. CONCLUSIONS: This unexpected result may be because Breton dairy farms began to modernize early (1950s), giving rise to conditions with much lower exposure to airborne contaminants.

Risk of venous thromboembolism in association with factor V leiden in cancer patients - The EDITH case-control study.

BACKGROUND: Cancer and factor V Leiden mutation are both risk factors for venous thromboembolism (VTE). Cancer critically increases the thrombotic risk whereas Factor V Leiden is the most common pro-thrombotic mutation. The impact of the factor V Leiden on the risk of VTE in cancer patients remains uncertain. OBJECTIVE: To assess the impact of factor V Leiden mutation in cancer-associated thrombosis. METHODS: The EDITH hospital-based case-control study enrolled 182 patients with cancer and VTE as well as 182 control patients with cancer, matched for gender, age and cancer location, between 2000 and 2012, in the University Hospital of Brest. All cases and controls were genotyped for the factor V Leiden mutation and interviewed with a standardized questionnaire. RESULTS: Twenty one of 182 (11.5%) patients with cancer-associated thrombosis carried the factor V Leiden mutation and 4 of 182 (2.2%) controls with cancer but no venous thrombosis. In multivariate analysis including cancer stage and family history of VTE, cancer patients with factor V Leiden mutation had a seven-fold increased risk of venous thromboembolism (adjusted odds ratio [OR], 7.04; 95% CI, 2.01-24.63). CONCLUSION: The pro-thrombotic Factor V Leiden mutation was found to be an independent additional risk factor for venous thromboembolism in cancer patients and might therefore be considered in the individual thrombotic risk assessment.

Phagocytosis depends on TRPV2-mediated calcium influx and requires TRPV2 in lipids rafts: alteration in macrophages from patients with cystic fibrosis.

Whereas many phagocytosis steps involve ionic fluxes, the underlying ion channels remain poorly defined. As reported in mice, the calcium conducting TRPV2 channel impacts the phagocytic process. Macrophage phagocytosis is critical for defense against pathogens. In cystic fibrosis (CF), macrophages have lost their capacity to act as suppressor cells and thus play a significant role in the initiating stages leading to chronic inflammation/infection. In a previous study, we demonstrated that impaired function of CF macrophages is due to a deficient phagocytosis. The aim of the present study was to investigate TRPV2 role in the phagocytosis capacity of healthy primary human macrophage by studying its activity, its membrane localization and its recruitment in lipid rafts. In primary human macrophages, we showed that P. aeruginosa recruits TRPV2 channels at the cell surface and induced a calcium influx required for bacterial phagocytosis. We presently demonstrate that to be functional and play a role in phagocytosis, TRPV2 might require a preferential localization in lipid rafts. Furthermore, CF macrophage displays a perturbed calcium homeostasis due to a defect in TRPV2. In this context, deregulated TRPV2-signaling in CF macrophages could explain their defective phagocytosis capacity that contribute to the maintenance of chronic infection.

Mutational Landscape of DDR2 Gene in Lung Squamous Cell Carcinoma Using Next-generation Sequencing.

BACKGROUND: Lung cancer represents the leading cause of cancer-related death worldwide. Despite great advances in lung cancer management with the recent emergence of molecular targeted therapies for non-squamous non-small-cell lung cancer, no dramatic improvements have been achieved in lung squamous cell carcinoma (SCC). Mutations in discoidin domain receptor 2 (DDR2) gene were recently identified as promising molecular targets in this histology. The aim of this study is to describe the DDR2 mutational landscape of lung SCC and investigate the associated clinical factors. METHODS: Next-generation sequencing of the DDR2 gene was performed on 271 samples of lung SCC. Patients followed in our institution from January 2011 to August 2014 were retrospectively selected for data collection. Other driver gene alterations (EGFR, KRAS, BRAF, HER2, and PI3KCA) were analyzed using pyrosequencing. RESULTS: A total of 11 patients harboring a DDR2 mutation was detected among the 271 sequenced lung SCC samples (4%). We describe 10 unreported mutations, comprising a novel DDR2 exon 7 splice mutant. DDR2 mutations were not mutually exclusive with other driver gene alterations. One hundred thirty-six patients were included for clinical comparison and logistic regression analysis. No difference was detected between DDR2-mutant and DDR2 wild-type lung SCC regarding clinical characteristics or survival. CONCLUSION: DDR2 mutations were observed in 4% of cases of lung SCC of European descent. DDR2-mutated tumors can exhibit other driver gene alterations. No clinical characteristics were significantly associated with DDR2 mutation.

Acute eosinophilic pneumonia following artenimol-piperaquine exposure.

Acute eosinophilic pneumonia (AEP) has been reported following chloroquine or mefloquine exposure, both structurally related to piperaquine. We report a case of AEP with typical CT scan patterns, hypereosinophilia in blood (9.8 109/l), and bronchoalveolar lavage (78% of 600 000 cells/ml), 10 days after artenimol-piperaquine exposure in a 26-year-old man.

Soluble CD14 acts as a DAMP in human macrophages: origin and involvement in inflammatory cytokine/chemokine production.

The innate immune system is able to detect bacterial LPS through the pattern recognition receptor CD14, which delivers LPS to various TLR signaling complexes that subsequently induce intracellular proinflammatory signaling cascades. In a previous study, we showed the overproduction of the soluble form of CD14 (sCD14) by macrophages from patients with cystic fibrosis (CF). CF is an autosomal recessive disorder that is caused by mutations in the gene that encodes the CFTR protein and is characterized by persistent inflammation. Macrophages play a significant role in the initial stages of this disease due to their inability to act as suppressor cells, leading to chronic inflammation in CF. In this work, we investigated the origin of sCD14 by human macrophages and studied the effect of sCD14 on the production of inflammatory cytokine/chemokine. Our data indicate that sCD14 stimulate proinflammatory cytokine/chemokine production in a manner that is independent of LPS but dependent on the TLR-4/CD14 membrane complex, NF-κB, and the inflammasome. Therefore, sCD14, overproduced by CF macrophages, originates primarily from the endocytosis/exocytosis process and should be considered to be a danger-associated molecular pattern. This elucidation of the origin and inflammation-induced mechanisms associated with sCD14 contributes to our understanding of maintained tissue inflammation.-Lévêque, M., Simonin-Le Jeune, K., Jouneau, S., Moulis, S., Desrues, B., Belleguic, C., Brinchault, G., Le Trionnaire, S., Gangneux, J.-P., Dimanche-Boitrel, M.-T., Martin-Chouly, C. Soluble CD14 acts as a DAMP in human macrophages: origin and involvement in inflammatory cytokine/chemokine production.

Opportunistic Pulmonary Bordetella hinzii Infection after Avian Exposure.

We report 2 cases of pulmonary Bordetella hinzii infection in immunodeficient patients. One of these rare cases demonstrated the potential transmission of the bacteria from an avian reservoir through occupational exposure and its persistence in humans. We establish bacteriologic management of these infections and suggest therapeutic options if needed.

Repeated therapeutic thoracentesis to manage complicated parapneumonic effusions.

PURPOSE OF REVIEW: In complicated parapneumonic effusion (CPPE), antibiotics and evacuation of the infected pleural fluid are mandatory. The first-line evacuation treatment is still controversial. The aim of this article is to highlight the usefulness of repeated therapeutic thoracentesis (RTT) as a first-line treatment. RECENT FINDINGS: In the most recent study on RTT in CPPE, disposable pleural needles were used and the median number of thoracentesis was 3. The success rate was 81%, and only 4% of the patients were referred for thoracic surgery. The 1-year survival rate was 88%. On multivariate analysis, the observation of microorganisms in the pleural fluid after Gram staining and first thoracentesis volume at least 450 ml was associated with a higher risk of RTT failure. RTT is less invasive and can target different loculated pleural collections. Patients are less confined to beds between each procedure, and could even be ambulatory managed. The use of intrapleural fibrinolytics in association with DNase could most likely enhance the efficacy of RTT. SUMMARY: RTT is efficient and well tolerated in the management of CPPE, including pleural empyema, and could be proposed as a first-line therapy for CPPE. This technique could be used in association with intrapleural fibrinolytics and DNase.

EFGR-mutant lung adenocarcinoma and Li-Fraumeni syndrome: report of two cases and review of the literature.

We report two cases of non-smoker patients diagnosed with EGFR-mutated lung adenocarcinoma and bearing germinal TP53 gene mutation, also known as Li-Fraumeni syndrome (LFS). We describe for the first time an EGFR-TKI resistance mutation in this population. Finally, we provide an analysis of discerning epidemiological data obtained from the IARC database and from all the published cases of EGFR-mutated lung cancer in TP53 germline mutation carriers.

[Management of COPD exacerbations: from primary care to hospitalization]. / Prise en charge des exacerbations: de la ville à l'hôpital.

The Société de pneumologie de langue française defines acute exacerbation of chronic obstructive pulmonary disease (AE COPD) as an increase in daily respiratory symptoms, basically duration ≥ 48h or need for treatment adjustment. Etiology of EA COPD are mainly infectious, viral (rhinovirus, influenzae or parainfluenzae virus, coronavirus, adenovirus and respiratory syncytial virus) or bacterial (Haemophilus influenzae, Streptococcus pneumoniae, or Moraxella catarrhalis). Pollutant exposure can also lead to AE COPD, such as NO2, SO2, ozone or particulates (PM10 and PM2.5). In 30% the etiology remains unknown. Differential diagnoses of AE COPD include infectious pneumonia, pneumothorax, acute heart failure and pulmonary embolism. Presences of signs of severity impose hospitalization: signs of respiratory distress, shock, acute confusion but also fragile patients, insufficient home support or absence of response to initial treatment. AE COPD treatments consist on increase in bronchodilators, chest physiotherapy, and antibiotics if sputum is frankly purulent. Systemic corticosteroids should not be systematic. Recommended dose is 0.5 mg/kg on short course (5-7 days). During hospitalization, oxygen supplementation and thromboprophylaxis could be prescribed. The main interest in non-invasive ventilation is persistent hypercapnia despite optimal medical management. During ambulatory management or hospitalization, clinical assessment at 48-72 h is mandatory.

[Long-term macrolide treatment in adult chronic bronchial diseases: benefits and limits]. / Macrolides au long cours et pathologie bronchique chronique de l'adulte : intérêts et limites.

Decreased frequency of pulmonary exacerbations, mainly related to immunomodulatory effects of macrolide antibiotics, has been demonstrated in bronchiectasis and chronic obstructive pulmonary diseases (COPD). Due to its tolerance, azithromycin is the antibiotic of choice for maintenance therapy at the dose of 250 mg per day or 500 mg × 3 per week (for body weight >55 kg). Maintenance therapy with macrolide could be proposed in selected patients with bronchiectasis or COPD with more than 3 acute exacerbations in the previous year or decreased lung function despite compliance with optimum treatment. The risk of sudden cardiac death with azithromycin is rare and controversial. It should be avoided in patients with a high baseline risk of cardiovascular disease, QT>450 msec, pulse rate>100 bpm and potential drug interactions, particularly those known to cause QT prolongation. It is recommended to search for hearing deficit (audiometry) and sputum culture positive for mycobacteria. Patients must also be aware that it can rapidly lead to macrolide resistance in commensal or pathogenic flora. Follow-up evaluation every 3 month can be proposed with medical history (hearing deficit) and electrocardiography. After one year, the treatment should be stopped in the absence of reduction in the frequency of exacerbations.

Iterative thoracentesis as first-line treatment of complicated parapneumonic effusion.

RATIONALE: Optimal management of complicated parapneumonic effusions (CPPE) remains controversial. OBJECTIVES: to assess safety and efficacy of iterative therapeutic thoracentesis (ITTC), the first-line treatment of CPPE in Rennes University Hospital. METHODS: Patients with CPPE were identified through our computerized database. We retrospectively studied all cases of CPPE initially managed with ITTC in our institution between 2001 and 2010. ITTC failure was defined by the need for additional treatment (i.e. surgery or percutaneous drainage), or death. RESULTS: Seventy-nine consecutive patients were included. The success rate was 81% (n = 64). Only 3 patients (4%) were referred to thoracic surgery. The one-year survival rate was 88%. On multivariate analysis, microorganisms observed in pleural fluid after Gram staining and first thoracentesis volume ≥450 mL were associated with ITTC failure with adjusted odds-ratios of 7.65 [95% CI, 1.44-40.67] and 6.97 [95% CI, 1.86-26.07], respectively. The main complications of ITTC were iatrogenic pneumothorax (n = 5, 6%) and vasovagal reactions (n = 3, 4%). None of the pneumothoraces required chest tube drainage, and no hemothorax or re-expansion pulmonary edema was observed. CONCLUSIONS: Although not indicated in international recommendations, ITTC is safe and effective as first-line treatment of CPPE, with limited invasiveness.

Ambulatory management of large spontaneous pneumothorax with pigtail catheters.

STUDY OBJECTIVE: There is no consensus about the management of large spontaneous pneumothoraces. Guidelines recommend either needle aspiration or chest tube drainage and most patients are hospitalized. We assess the efficiency of ambulatory management of large spontaneous pneumothoraces with pigtail catheters. METHODS: From February 2007 to January 2011, all primary and secondary large spontaneous pneumothoraces from Lorient's hospital (France) were managed with pigtail catheters with a 1-way valve. The patients were discharged immediately and then evaluated every 2 days according to a specific algorithm. RESULTS: Of the 132 consecutive patients (110 primary, 22 secondary), 103 were exclusively managed as outpatients, with full resolution of the pneumothorax by day 2 or 4, which represents an ambulatory success rate of 78%. Mean time (SD) of drainage was 3.4 days (1.8). Seven patients were initially hospitalized but quickly discharged and had full resolution by day 2 or 4, leading to a total success rate of 83%. The use of analgesics was low. The 1-year recurrence rate was 26%. If successful, this outpatient management is potentially cost saving, with a mean cost of $926, assuming up to 2 outpatient visits and 1 chest radiograph, compared with $4,276 if a chest tube was placed and the patient was admitted to the hospital for 4 days. CONCLUSION: Ambulatory management with pigtail catheters with 1-way valves could be a reasonable first-line of treatment for large spontaneous pneumothoraces. Compared with that of other studies, our protocol does not require hospitalization and is cost saving.