0307 : QSOX1 has a protective role in the myocardium face to acute stress

IntroductionQSOX1 was identified as a plasma biomarker of acute heart failure (AHF). QSOX1 being a sulfhydryl oxidase, our aim was to decipher the role of QSOX1 in the heart face to an AHF event.MethodsAHF was provoked by IP injections of Isoproterenol (ISO, 300mg/kg/12h) for 2 days in mice (C57Bl/6 J) whereas control (C) received NaCl 9‰. Mice were killed at day 3, after echocardiography. QSOX1 KO (C57Bl/6 J) mice were generated using a QSOX1tm1a embryonic stem cell clone (KOMP). The KO construct contains a promoter-less lacZ gene under the control of the QSOX1 regulatory sequences. The mRNA levels were analyzed by RT-qPCR. The cellular level of oxidative stress was detected by using DHE. Fibrosis was analysed by Sirius red and collagen mRNA.ResultsAt baseline QSOX1-/- adult mice did not display any cardiac or vascular phenotype. After ISO, lacZ expression dramatically increased in QSOX1+/- hearts with the strongest β-galactosidase staining in the atria. In mice receiving ISO, a pulmonary congestion, BNP (x2 p<0.001) and CD68 (x3, p<0.001) increases were observed only in QSOX1-/-, whereas Galectin 3 increased in both groups. After ISO, the severe cardiac dysfunction in QSOX1-/- mice was associated with signs of enhanced oxidative stress (DHE staining p<0.0001). An early fibrosis was observed by Sirius red analysis and associated with an increase of collagen 1 and 3 mRNAs without difference between WT and QSOX1-/- mice.ConclusionWe provided evidence that the absence of QSOX1 leads to a more serious cardiac dysfunction in response to acute cardiac stress by ISO than in WT counterparts. Hence, our data indicated that QSOX1 protects the heart in response to acute stress

QSOX1 has a protective role in the myocardium face to acute stress

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Moderate Exercise Modulates Inflammatory Responses and Improves Survival in a Murine Model of Acute Pneumonia

International audienceAn association between physical inactivity and worse outcome during infectious disease has been reported. The effect of moderate exercise preconditioning on the immune response during an acute pneumonia in a murine model was evaluated. SETTING: Laboratory experiments. SUBJECTS: C57BL6/j male mice. INTERVENTIONS: Six-week-old C57BL/6J mice were divided in two groups: an exercise group and a control group. In the exercise group, a moderate, progressive, and standardized physical exercise was applied for 8 weeks. It consisted in a daily treadmill training lasting 60 minutes and with an intensity of 65% of the maximal theoretical oxygen uptake. Usual housing recommendation were applied in the control group during the same period. After 8 weeks, pneumonia was induced in both groups by intratracheal instillation of a fixed concentration of a Klebsiella pneumoniae (5 × 103 colony-forming unit) solution. MEASUREMENTS AND MAIN RESULTS: Mice preconditioned by physical exercise had a less sever onset of pneumonia as shown by a significant decrease of the Mouse Clinical Assessment Severity Score and had a significantly lower mortality compared with the control group (27% vs. 83%; p = 0.019). In the exercise group, we observed a significantly earlier but transient recruitment of inflammatory immune cells with a significant increase of neutrophils, CD4+ cells and interstitial macrophages counts compared with control group. Lung tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-10 were significantly decreased at 48 hours after pneumonia induction in the exercise group compared with the control group. CONCLUSIONS: In our model, preconditioning by moderate physical exercise improves outcome by reducing the severity of acute pneumonia with an increased but transient activation of the innate immune response

Evaluation of cardiac output variations with the peripheral pulse pressure to mean arterial pressure ratio

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Spontaneous glutamatergic activity induces a BDNF-dependent potentiation of GABAergic synapses in the newborn rat hippocampus

Spontaneous ongoing synaptic activity is thought to play an instructive role in the maturation of the neuronal circuits. However the type of synaptic activity involved and how this activity is translated into structural and functional changes is not fully understood. Here we show that ongoing glutamatergic synaptic activity triggers a long-lasting potentiation of γ-aminobutyric acid (GABA) mediated synaptic activity (LLPGABA-A) in the developing rat hippocampus. LLPGABA-A induction requires (i) the activation of AMPA receptors and L-type voltage-dependent calcium channels, (ii) the release of endogenous brain-derived neurotrophic factor (BDNF), and (iii) the activation of postsynaptic tropomyosin-related kinase receptors B (TrkB). We found that spontaneous glutamatergic activity is required to maintain a high level of native BDNF in the newborn rat hippocampus and that application of exogenous BDNF induced LLPGABA-A in the absence of glutamatergic activity. These results suggest that ongoing glutamatergic synaptic activity plays a pivotal role in the functional maturation of hippocampal GABAergic synapses by means of a cascade involving BDNF release and downstream signalling through postsynaptic TrkB receptor activation

Noninvasive ventilation in COVID-19 patients aged ≥ 70 years : a prospective multicentre cohort study

Background: Noninvasive ventilation (NIV) is a promising alternative to invasive mechanical ventilation (IMV) with a particular importance amidst the shortage of intensive care unit (ICU) beds during the COVID-19 pandemic. We aimed to evaluate the use of NIV in Europe and factors associated with outcomes of patients treated with NIV. Methods: This is a substudy of COVIP study-an international prospective observational study enrolling patients aged >= 70 years with confirmed COVID-19 treated in ICU. We enrolled patients in 156 ICUs across 15 European countries between March 2020 and April 2021.The primary endpoint was 30-day mortality. Results: Cohort included 3074 patients, most of whom were male (2197/3074, 71.4%) at the mean age of 75.7 years (SD 4.6). NIV frequency was 25.7% and varied from 1.1 to 62.0% between participating countries. Primary NIV failure, defined as need for endotracheal intubation or death within 30 days since ICU admission, occurred in 470/629 (74.7%) of patients. Factors associated with increased NIV failure risk were higher Sequential Organ Failure Assessment (SOFA) score (OR 3.73, 95% CI 2.36-5.90) and Clinical Frailty Scale (CFS) on admission (OR 1.46, 95% CI 1.06-2.00). Patients initially treated with NIV (n = 630) lived for 1.36 fewer days (95% CI - 2.27 to - 0.46 days) compared to primary IMV group (n = 1876). Conclusions: Frequency of NIV use varies across European countries. Higher severity of illness and more severe frailty were associated with a risk of NIV failure among critically ill older adults with COVID-19. Primary IMV was associated with better outcomes than primary NIV

Increased 30-day mortality in very old ICU patients with COVID-19 compared to patients with respiratory failure without COVID-19

Purpose The number of patients >= 80 years admitted into critical care is increasing. Coronavirus disease 2019 (COVID-19) added another challenge for clinical decisions for both admission and limitation of life-sustaining treatments (LLST). We aimed to compare the characteristics and mortality of very old critically ill patients with or without COVID-19 with a focus on LLST. Methods Patients 80 years or older with acute respiratory failure were recruited from the VIP2 and COVIP studies. Baseline patient characteristics, interventions in intensive care unit (ICU) and outcomes (30-day survival) were recorded. COVID patients were matched to non-COVID patients based on the following factors: age (+/- 2 years), Sequential Organ Failure Assessment (SOFA) score (+/- 2 points), clinical frailty scale (+/- 1 point), gender and region on a 1:2 ratio. Specific ICU procedures and LLST were compared between the cohorts by means of cumulative incidence curves taking into account the competing risk of discharge and death. Results 693 COVID patients were compared to 1393 non-COVID patients. COVID patients were younger, less frail, less severely ill with lower SOFA score, but were treated more often with invasive mechanical ventilation (MV) and had a lower 30-day survival. 404 COVID patients could be matched to 666 non-COVID patients. For COVID patients, withholding and withdrawing of LST were more frequent than for non-COVID and the 30-day survival was almost half compared to non-COVID patients. Conclusion Very old COVID patients have a different trajectory than non-COVID patients. Whether this finding is due to a decision policy with more active treatment limitation or to an inherent higher risk of death due to COVID-19 is unclear

The impact of frailty on survival in elderly intensive care patients with COVID-19: the COVIP study

Auteurs : COVIP study groupInternational audienceBackground The COVID-19 pandemic has led highly developed healthcare systems to the brink of collapse due to the large numbers of patients being admitted into hospitals. One of the potential prognostic indicators in patients with COVID-19 is frailty. The degree of frailty could be used to assist both the triage into intensive care, and decisions regarding treatment limitations. Our study sought to determine the interaction of frailty and age in elderly COVID-19 ICU patients. Methods A prospective multicentre study of COVID-19 patients ≥ 70 years admitted to intensive care in 138 ICUs from 28 countries was conducted. The primary endpoint was 30-day mortality. Frailty was assessed using the clinical frailty scale. Additionally, comorbidities, management strategies and treatment limitations were recorded. Results The study included 1346 patients (28% female) with a median age of 75 years (IQR 72–78, range 70–96), 16.3% were older than 80 years, and 21% of the patients were frail. The overall survival at 30 days was 59% (95% CI 56–62), with 66% (63–69) in fit, 53% (47–61) in vulnerable and 41% (35–47) in frail patients ( p < 0.001). In frail patients, there was no difference in 30-day survival between different age categories. Frailty was linked to an increased use of treatment limitations and less use of mechanical ventilation. In a model controlling for age, disease severity, sex, treatment limitations and comorbidities, frailty was independently associated with lower survival. Conclusion Frailty provides relevant prognostic information in elderly COVID-19 patients in addition to age and comorbidities. Trial registration Clinicaltrials.gov: NCT04321265 , registered 19 March 2020