Development And Validation Of A Novel E2f1 Mouse Model To Evaluate The Cell-Type Specific Contribution Of E2f1 To Age-Associated Neurodegeneration

Increased expression of cell cycle proteins, including the transcription factor E2F1, is observed in a variety of aging-associated neurodegenerative diseases. E2F1 modulates the G1-S phase transition of the cell cycle, apoptosis, and inflammation, and its upregulation in neurodegenerative diseases may contribute to pathology by promoting all of these processes, leading to neuronal dysfunction/death. Thus, reducing E2F1 levels in neurons may mitigate the progression of neurodegeneration. However, E2F1tm1/tm1 mice exhibit central nervous system (CNS) pathology, with contradictory studies suggesting that E2F1 loss impairs or improves memory as measured by novel object recognition assays. Given that neuronal and synaptic function are affected by inherent neuronal processes and that neuroimmune interactions are regulated by CNS-resident innate immune cells, specifically microglia, we generated a conditional floxed E2F1 mouse (E2F1fx/fx) to study cell-type specific roles of E2F1. We then developed a novel constitutive E2F1 knockout (E2F1-/-) mouse to 1) reevaluate E2F1-mediated CNS pathology and neurocognitive behaviors to confirm the presence of CNS-associated phenotypes in our E2F1-/- mouse and 2) characterize inflammatory mediator release from E2F1-/- macrophages in response to differing doses of lipopolysaccharide (LPS) with and without priming to acquire a better understanding of E2F1’s role in inflammation. We found that E2F1 loss in E2F1-/- mice did not cause some of the reported E2F1tm1/tm1-associated CNS and peripheral pathologies, while discovering a novel E2F1-/- related phenotype: megakaryocytic hyperplasia. We also found that E2F1-/- macrophages exhibited anti-inflammatory (reduced IL-6 and TNF-alpha release) and pro-inflammatory (increased CCL-2 release) responses dependent on LPS dose and priming condition. These results suggest that aspects of mouse model design may account for altered neuron/synapse health observed in E2F1tm1/tm1 mice which may not be dependent on E2F1 loss alone, and that E2F1 has beneficial and detrimental functions in inflammation depending on its roles in initiation and resolution of inflammation. Further exploration of E2F1’s role in neuronal health and neuroinflammatory response should provide insight into not only the cell-type specific therapeutic development for neurodegenerative diseases but also the novel roles of E2F1 in innate immune memory

Sans titres: Anthologie collective Français 335 (automne 2011)

http://deepblue.lib.umich.edu/bitstream/2027.42/89432/1/sans_titres.pd

Development and Validation of a Novel E2F1 Mouse Model to Evaluate the Cell-Type Specific Contribution of E2F1 to Age-Associated Neurodegeneration

Increased expression of cell cycle proteins, including the transcription factor E2F1, is observed in a variety of aging-associated neurodegenerative diseases. E2F1 modulates the G1-S phase transition of the cell cycle, apoptosis, and inflammation, and its upregulation in neurodegenerative diseases may contribute to pathology by promoting all of these processes, leading to neuronal dysfunction/death. Thus, reducing E2F1 levels in neurons may mitigate the progression of neurodegeneration. However, E2F1tm1/tm1 mice exhibit central nervous system (CNS) pathology, with contradictory studies suggesting that E2F1 loss impairs or improves memory as measured by novel object recognition assays. Given that neuronal and synaptic function are affected by inherent neuronal processes and that neuroimmune interactions are regulated by CNS-resident innate immune cells, specifically microglia, we generated a conditional floxed E2F1 mouse (E2F1fx/fx) to study cell-type specific roles of E2F1. We then developed a novel constitutive E2F1 knockout (E2F1-/-) mouse to 1) reevaluate E2F1-mediated CNS pathology and neurocognitive behaviors to confirm the presence of CNS-associated phenotypes in our E2F1-/- mouse and 2) characterize inflammatory mediator release from E2F1-/- macrophages in response to differing doses of lipopolysaccharide (LPS) with and without priming to acquire a better understanding of E2F1’s role in inflammation. We found that E2F1 loss in E2F1-/- mice did not cause some of the reported E2F1tm1/tm1-associated CNS and peripheral pathologies, while discovering a novel E2F1-/- related phenotype: megakaryocytic hyperplasia. We also found that E2F1-/- macrophages exhibited anti-inflammatory (reduced IL-6 and TNF-alpha release) and pro-inflammatory (increased CCL-2 release) responses dependent on LPS dose and priming condition. These results suggest that aspects of mouse model design may account for altered neuron/synapse health observed in E2F1tm1/tm1 mice which may not be dependent on E2F1 loss alone, and that E2F1 has beneficial and detrimental functions in inflammation depending on its roles in initiation and resolution of inflammation. Further exploration of E2F1’s role in neuronal health and neuroinflammatory response should provide insight into not only the cell-type specific therapeutic development for neurodegenerative diseases but also the novel roles of E2F1 in innate immune memory

Does branched-chain amino acid supplementation improve pulmonary rehabilitation effect in COPD?

International audienceBackgroundMuscle wasting is frequent in chronic obstructive lung disease (COPD) and associated with low branched-chain amino acids (BCAA). We hypothesized that BCAA supplementation could potentiate the effect of a pulmonary rehabilitation program (PRP) by inducing muscular change.Materials and methodsSixty COPD patients (GOLD 2–3) were involved in an ambulatory 4-week PRP either with BCAA oral daily supplementation or placebo daily supplementation in a randomized double-blind design. Maximal exercise test including quadriceps oxygenation measurements, functional exercise test, muscle strength, lung function tests, body composition, dyspnea and quality of life were assessed before and after PRP.ResultsFifty-four patients (64.9 ± 8.3 years) completed the protocol. In both groups, maximal exercise capacity, functional and muscle performances, quality of life and dyspnea were improved after 4-week PRP (p ≤ 0.01). Changes in muscle oxygenation during the maximal exercise and recovery period were not modified after 4-week PRP in BCAA group. Contrarily, in the placebo group the muscle oxygenation kinetic of recovery was slowed down after PRP.ConclusionThis study demonstrated that a 4-week PRP with BCAA supplementation is not more beneficial than PRP alone for patients. A longer duration of supplementation or a more precise targeting of patients would need to be investigated to validate an effect on muscle recovery and to demonstrate other beneficial effects

Adverse events during treatment of nontuberculous mycobacterial lung disease: do they really matter?

28th International Congress of the European-Respiratory-Society (ERS), Paris, FRANCE, SEP 15-19, 2018International audienceTreatment of nontuberculous mycobacterial lung disease (NTM LD) is long and hampered with frequent adverse events. Side effects may explain the poor prognosis associated with this disease. Our hypothesis was that adverse events might be responsible of premature discontinuation of treatment, thus leading to an increased mortality. We conducted a retrospective study including adult patients treated for NTM LD at 5 French hospitals between January 1st 2010 and December 31st 2015. Patients with cystic fibrosis were excluded. 71 patients were included, of which 45 had a pulmonary disease due to Mycobacterium avium complex and 15 due to M. xenopi. All patients fulfilled the ATS clinical and microbiological criteria for NTM LD. While treated, 72% of patients presented at least one reported side effect, of which 65% were gastro-intestinal and 21% were ophthalmologic. 14 patients stopped prematurely their treatment while initial therapy was modified in 22 cases due to poor tolerance. Adverse events were more common in patients who had been previously treated for NTM LD (p=0.02). Early treatment cessation was associated with the absence of sputum conversion (p=0.014) but not with mortality (p=0.237). Occurrence of adverse events was not associated with mortality. 15 patients died, among them 6 were under treatment. Mortality was associated with use of systemic steroids and existence of comorbidities, especially pulmonary or cardiovascular ones, as well as extra pulmonary cancers. Side effects of drugs used to treat NTM LD are common and responsible for early cessation of treatment that may result in a lack of sputum conversion. However, they did not affect mortality in our cohort

Treatment Discontinuation Following Bariatric Surgery in Obstructive Sleep Apnea: a Controlled Cohort Study

International audienceUncontrolled studies looking at the discontinuation of obstructive sleep apnea (OSA) treatment after bariatric surgery (BS) have suggested that surgery improves OSA. However, this discontinuation of OSA treatment by BS patients has never been compared to a matched population without BS. The objectives of this study are to evaluate whether BS increases OSA treatment discontinuation compared to that in matched patients without BS and to identify predictive factors of OSA treatment discontinuation in BS patients. The study took place in an ambulatory, tertiary hospital

Randomised trial of first-line bronchial artery embolisation for non-severe haemoptysis of mild abundance

Background Whereas first-line bronchial artery embolisation (BAE) is considered standard of care for the management of severe haemoptysis, it is unknown whether this approach is warranted for non-severe haemoptysis.Research question To assess the efficacy on bleeding control and the safety of first-line BAE in non-severe haemoptysis of mild abundance.Study design and methods This multicentre, randomised controlled open-label trial enrolled adult patients without major comorbid condition and having mild haemoptysis (onset <72 hours, 100–200 mL estimated bleeding amount), related to a systemic arterial mechanism. Patients were randomly assigned (1:1) to BAE associated with medical therapy or to medical therapy alone.Results Bleeding recurrence at day 30 after randomisation (primary outcome) occurred in 4 (11.8%) of 34 patients in the BAE strategy and 17 (44.7%) of 38 patients in the medical strategy (difference −33%; 95% CI −13.8% to −52.1%, p=0.002). The 90-day bleeding recurrence-free survival rates were 91.2% (95% CI 75.1% to 97.1%) and 60.2% (95% CI 42.9% to 73.8%), respectively (HR=0.19, 95% CI 0.05 to 0.67, p=0.01). No death occurred during follow-up and no bleeding recurrence needed surgery.Four adverse events (one major with systemic emboli) occurred during hospitalisation, all in the BAE strategy (11.8% vs 0%; difference 11.8%, 95% CI 0.9 to 22.6, p=0.045); all eventually resolved.Conclusion In non-severe haemoptysis of mild abundance, BAE associated with medical therapy had a superior efficacy for preventing bleeding recurrences at 30 and 90 days, as compared with medical therapy alone. However, it was associated with a higher rate of adverse events.Trial registration number NCT0127819