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.
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.
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.
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).
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.
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.
Early in life, cystic fibrosis (CF) patients are infected with microorganisms. The role of macrophages has largely been underestimated in literature, whereas the focus being mostly on neutrophils and ...epithelial cells. Macrophages may however play a significant role in the initiating stages of this disease, via an inability to act as a suppressor cell. Yet macrophage dysfunction may be the first step in cascade of events leading to chronic inflammation/infection in CF. Moreover, reports have suggested that CFTR contribute to altered inflammatory response in CF by modification of normal macrophage functions.
In order to highlight possible intrinsic macrophage defects due to impaired CFTR, we have studied inflammatory cytokines secretions, recognition of pathogens and phagocytosis in peripheral blood monocyte-derived macrophages from stable adult CF patients and healthy subjects (non-CF).
In CF macrophage supernatants, concentrations of sCD14, IL-1β, IL-6, TNF-α and IL-10 were strongly raised. Furthermore expression of CD11b and TLR-5 were sorely decreased on CF macrophages. Beside, no difference was observed for mCD14, CD16, CD64, TLR-4 and TLR1/TLR-2 expressions. Moreover, a strong inhibition of phagocytosis was observed for CF macrophages. Elsewhere CFTR inhibition in non-CF macrophages also led to alterations of phagocytosis function as well as CD11b expression.
Altogether, these findings demonstrate excessive inflammation in CF macrophages, characterized by overproduction of sCD14 and inflammatory cytokines, with decreased expression of CD11b and TLR-5, and impaired phagocytosis. This leads to altered clearance of pathogens and non-resolution of infection by CF macrophages, thereby inducing an exaggerated pro-inflammatory response.
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.
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.
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.
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.
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.
Background
Adaptive servo-ventilation (ASV) is used to treat complex sleep apnea syndrome (CompSAS), but with variable success. Factors influencing success are poorly understood. ASV devices ...determine their output based upon characteristics of a given breath and on proprietary algorithms that assume a periodic breathing pattern. Periodic breathing patterns produce elevated narrow band low-frequency cardiopulmonary coupling (eNB-LFC). Therefore, we hypothesized that ASV success would correlate with elevated proportions of periodic breathing as marked by eNB-LFC on cardiopulmonary coupling (CPC) analysis.
Methods
This was a retrospective study of 106 consecutive patients presenting to an academic tertiary care sleep center with CompSAS between July 2008 and July 2009 who underwent ASV titration with polysomnographic signals amenable to CPC analysis.
Results
The study included 89 males (84 %) and 17 females (16 %), with mean age of 63.3 years. Median diagnostic apnea–hypopnea index (AHI) was 38 (21, 56)/h, and on continuous positive airway pressure (CPAP), the median residual AHI (CompSAS) was 36.5 (23, 58)/h, with central apneas occurring on average 22.5 (13, 39)/h. ASV brought AHI to 11.0 ± 13.0, with success in 81.1 % of patients, as defined by an AHI of <10/h. NB-LFC was elevated (>0) in 45.3 %; however, the percentage of eNB-LFC did not correlate with ASV treatment success (
p
= 0.518). No clinical factors were found to be associated with ASV success.
Conclusion
ASV was successful in 81 % of patients with CompSAS. However, eNB-LFC calculated from CPC, a marker for periodic breathing, did not correlate with ASV success and therefore may not be a useful tool to predict ASV success.
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.
To assess the impact of factor V Leiden mutation in cancer-associated thrombosis.
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.
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).
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.
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