Mitochondrie, stress oxydant et protection musculaire

Molecular diffusion and microcirculation in the capillary network result in a distribution of phases in a single voxel in the presence of magnetic field gradients. This distribution produces a spin-echo attenuation. The authors have developed a magnetic resonance (MR) method to image such intravoxel incoherent motions (IVIMs) by using appropriate gradient pulses. Images were generated at 0.5 T in a high-resolution, multisection mode. Diffusion coefficients measured on images of water and acetone phantoms were consistent with published values. Images obtained in the neurologic area from healthy subjects and patients were analyzed in terms of an apparent diffusion coefficient (ADC) incorporating the effect of all IVIMs. Differences were found between various normal and pathologic tissues. The ADC of in vivo water differed from the diffusion coefficient of pure water. Results were assessed in relation to water compartmentation in biologic tissues (restricted diffusion) and tissue perfusion. Nonuniform slow flow of cerebrospinal fluid appeared as a useful feature on IVIM images. Observation of these motions may significantly extend the diagnostic capabilities of MR imaging.

Intravoxel incoherent motion (IVIM) imaging is a method the authors developed to visualize microscopic motions of water. In biologic tissues, these motions include molecular diffusion and microcirculation of blood in the capillary network. IVIM images are quantified by an apparent diffusion coefficient (ADC), which integrates the effects of both diffusion and perfusion. The aim of this work was to demonstrate how much perfusion contributes to the ADC and to present a method for obtaining separate images of diffusion and perfusion. Images were obtained at 0.5 T with high-resolution multisection sequences and without the use of contrast material. Results in a phantom made of resin microspheres demonstrated the ability of the method to separately evaluate diffusion and perfusion. The method was then applied in patients with brain and bone tumors and brain ischemia. Clinical results showed significant promise of the method for tissue characterization by perfusion patterns and for functional studies in the evaluation of the microcirculation in physiologic and pathologic conditions, as, for instance, in brain ischemia.

Neurologic Features in SARS-CoV-2 Infection In a consecutive series of 64 patients with Covid-19 and ARDS, 58 of whom underwent neurologic examination, severe agitation and corticospinal signs were...

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OBJECTIVES: . The aims of this study were to determine the incidence and prevalence of inflammatory myopathies (IMs), their epidemiological tendencies over time and their possible key determinants. METHODS: . All original articles in English or French regarding the prevalence and/or incidence of IMs were searched. The methods of case ascertainment, epidemiological analysis and diagnostic criteria were systematically analysed. RESULTS: . Forty-six articles published between 1966 and 2013 were found in which the incidence of IMs as a whole ranged from 1.16 to 19/million/year and their prevalence ranged from 2.4 to 33.8 per 100 000 inhabitants. Methodological heterogeneities limited comparisons, although certain epidemiological tendencies were highlighted. The relative incidence of DM may follow a latitudinal gradient in the northern hemisphere that may be explained by the immunomodulatory action of ultraviolet radiation. The prevalence of sporadic inclusion body myositis (sIBM) was correlated with the frequency of HLA-DR3. Juvenile myositis onset was non-random over seasons and/or time, consistent with a role of infectious diseases, although other environmental factors may be involved. Disparities according to sex, age and geographical origin were also found. The frequency of IM increased over time, which may reflect progress in diagnostic performance, although there is still a need to increase the level of awareness with regard to these diseases, especially sIBM, as attested by its considerably delayed diagnosis. CONCLUSION: . This first systematic literature review confirms the rarity of IM and may highlight certain genetic and environmental determinants of IM. There is a need for uniformity in diagnostic and classification criteria as well as more exhaustive case ascertainment to refine IM epidemiology.

OBJECTIVE: To determine whether systemic oxidative stress status is associated with cognitive decline. DESIGN: A longitudinal population-based study. SETTING: A cohort study of older subjects in Nantes, France. PARTICIPANTS: A total of 1166 high cognitive functioning subjects aged 60 to 70 in the Etude du Vieillissement Arteriel (EVA) cohort with a 4 year follow-up. MEASUREMENTS: Subjects completed a baseline interview and a global cognitive test (Mini-Mental Status Examination (MMSE)). Blood samples were obtained at baseline to determine plasma levels of selenium, carotenoids, thiobarbituric acid reactant substances (TBARS), an indicator of lipoperoxidation, and red blood cell vitamin E. Risk of cognitive decline, defined as a loss of 3 points in MMSE score between baseline and the 4 year follow-up, was assessed by oxidative stress level. RESULTS: Subjects with the highest levels of TBARS show an increased risk of cognitive decline (adjusted odds ratio (OR) = 2.25; confidence interval (CI) 95% = 1.26-4.02). This result is reinforced in the lower antioxidant status subgroup. Subjects with low levels of selenium have an increased risk of cognitive decline (OR = 1.58; CI 95% = 1.08-2.31) after adjustment for various confounding factors. CONCLUSIONS: These results suggest that increased levels of oxidative stress and/or antioxidant deficiencies may pose risk factors for cognitive decline. The direct implication of oxidative stress in vascular and neurodegenerative mechanisms that lead to cognitive impairment should be further explored.

Cancer can occur in patients with inflammatory myopathies. This association is mainly observed in dermatomyositis, and myositis-specific antibodies have allowed us to delineate patients at an increased risk. Malignancy is also reported in patients with necrotizing autoimmune myopathies, but the risk remains elusive. Anti-signal recognition particle or anti-HMGCR antibodies have been specifically associated with necrotizing autoimmune myopathies. We aimed at screening the incidence of cancer in necrotizing autoimmune myopathies. A group of patients (n = 115) with necrotizing autoimmune myopathies with or without myositis-specific antibodies was analysed. Malignancy occurred more frequently in seronegative necrotizing autoimmune myopathies patients and in HMGCR-positive patients compared to anti-signal recognition particle positive patients. Synchronous malignancy was diagnosed in 21.4% and 11.5% of cases, respectively, and incidence of cancer was higher compared to the general population in both groups. No specific type of cancer was predominant. Patients suffering from a synchronous cancer had a decreased median survival time. Cancer screening is necessary in seronegative necrotizing autoimmune myopathies and in HMGCR-positive patients but not in anti-signal recognition particle-positive patients.

IMPORTANCE: It has not been established whether noninvasive ventilation (NIV) reduces the need for invasive mechanical ventilation in patients who develop hypoxemic acute respiratory failure after abdominal surgery. OBJECTIVE: To evaluate whether noninvasive ventilation improves outcomes among patients developing hypoxemic acute respiratory failure after abdominal surgery. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized, parallel-group clinical trial conducted between May 2013 and September 2014 in 20 French intensive care units among 293 patients who had undergone abdominal surgery and developed hypoxemic respiratory failure (partial oxygen pressure <60 mm Hg or oxygen saturation [SpO2] ≤90% when breathing room air or <80 mm Hg when breathing 15 L/min of oxygen, plus either [1] a respiratory rate above 30/min or [2] clinical signs suggestive of intense respiratory muscle work and/or labored breathing) if it occurred within 7 days after surgical procedure. INTERVENTIONS: Patients were randomly assigned to receive standard oxygen therapy (up to 15 L/min to maintain SpO2 of 94% or higher) (n = 145) or NIV delivered via facial mask (inspiratory pressure support level, 5-15 cm H2O; positive end-expiratory pressure, 5-10 cm H2O; fraction of inspired oxygen titrated to maintain SpO2 ≥94%) (n = 148). MAIN OUTCOMES AND MEASURES: The primary outcome was tracheal reintubation for any cause within 7 days of randomization. Secondary outcomes were gas exchange, invasive ventilation-free days at day 30, health care-associated infections, and 90-day mortality. RESULTS: Among the 293 patients (mean age, 63.4 [SD, 13.8] years; n=224 men) included in the intention-to-treat analysis, reintubation occurred in 49 of 148 (33.1%) in the NIV group and in 66 of 145 (45.5%) in the standard oxygen therapy group within+ 7 days after randomization (absolute difference, -12.4%; 95% CI, -23.5% to -1.3%; P = .03). Noninvasive ventilation was associated with significantly more invasive ventilation-free days compared with standard oxygen therapy (25.4 vs 23.2 days; absolute difference, -2.2 days; 95% CI, -0.1 to 4.6 days; P = .04), while fewer patients developed health care-associated infections (43/137 [31.4%] vs 63/128 [49.2%]; absolute difference, -17.8%; 95% CI, -30.2% to -5.4%; P = .003). At 90 days, 22 of 148 patients (14.9%) in the NIV group and 31 of 144 (21.5%) in the standard oxygen therapy group had died (absolute difference, -6.5%; 95% CI, -16.0% to 3.0%; P = .15). There were no significant differences in gas exchange. CONCLUSIONS AND RELEVANCE: Among patients with hypoxemic respiratory failure following abdominal surgery, use of NIV compared with standard oxygen therapy reduced the risk of tracheal reintubation within 7 days. These findings support use of NIV in this setting. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01971892.

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Amyotrophic lateral sclerosis (ALS) is the most common fatal motor neuron disease in adults. Numerous studies indicate that ALS is a systemic disease that affects whole body physiology and metabolic homeostasis. Using a mouse model of the disease (SOD1(G86R)), we investigated muscle physiology and motor behavior with respect to muscle metabolic capacity. We found that at 65 days of age, an age described as asymptomatic, SOD1(G86R) mice presented with improved endurance capacity associated with an early inhibition in the capacity for glycolytic muscle to use glucose as a source of energy and a switch in fuel preference toward lipids. Indeed, in glycolytic muscles we showed progressive induction of pyruvate dehydrogenase kinase 4 expression. Phosphofructokinase 1 was inhibited, and the expression of lipid handling molecules was increased. This mechanism represents a chronic pathologic alteration in muscle metabolism that is exacerbated with disease progression. Further, inhibition of pyruvate dehydrogenase kinase 4 activity with dichloroacetate delayed symptom onset while improving mitochondrial dysfunction and ameliorating muscle denervation. In this study, we provide the first molecular basis for the particular sensitivity of glycolytic muscles to ALS pathology.

BACKGROUND: Patients liberated from invasive mechanical ventilation are at risk of extubation failure, including inability to breathe without a tracheal tube (airway failure) or without mechanical ventilation (non-airway failure). We sought to identify respective risk factors for airway failure and non-airway failure following extubation. METHODS: The primary endpoint of this prospective, observational, multicenter study in 26 intensive care units was extubation failure, defined as need for reintubation within 48 h following extubation. A multinomial logistic regression model was used to identify risk factors for airway failure and non-airway failure. RESULTS: Between 1 December 2013 and 1 May 2015, 1514 patients undergoing extubation were enrolled. The extubation-failure rate was 10.4% (157/1514), including 70/157 (45%) airway failures, 78/157 (50%) non-airway failures, and 9/157 (5%) mixed airway and non-airway failures. By multivariable analysis, risk factors for extubation failure were either common to airway failure and non-airway failure: intubation for coma (OR 4.979 (2.797-8.864), P < 0.0001 and OR 2.067 (1.217-3.510), P = 0.003, respectively, intubation for acute respiratory failure (OR 3.395 (1.877-6.138), P < 0.0001 and OR 2.067 (1.217-3.510), P = 0.007, respectively, absence of strong cough (OR 1.876 (1.047-3.362), P = 0.03 and OR 3.240 (1.786-5.879), P = 0.0001, respectively, or specific to each specific mechanism: female gender (OR 2.024 (1.187-3.450), P = 0.01), length of ventilation > 8 days (OR 1.956 (1.087-3.518), P = 0.025), copious secretions (OR 4.066 (2.268-7.292), P < 0.0001) were specific to airway failure, whereas non-obese status (OR 2.153 (1.052-4.408), P = 0.036) and sequential organ failure assessment (SOFA) score ≥ 8 (OR 1.848 (1.100-3.105), P = 0.02) were specific to non-airway failure. Both airway failure and non-airway failure were associated with ICU mortality (20% and 22%, respectively, as compared to 6% in patients with extubation success, P < 0.0001). CONCLUSIONS: Specific risk factors have been identified, allowing us to distinguish between risk of airway failure and non-airway failure. The two conditions will be managed differently, both for prevention and curative strategies. TRIAL REGISTRATION: ClinicalTrials.gov, NCT 02450669 . Registered on 21 May 2015.

The aim of this study was to investigate the antioxidant role of zinc (Zn) in the Cd-exposed testes of Wistar rats. Subchronic exposure to Cd (CdCl(2), 40 mg/l, per os) for 30 days resulted in a significant reduction in growth rate (-11%) and relative weights of testes (-36%) and seminal vesicles (-80%). Treated rats displayed a decrease in testicular and plasma testosterone levels, respectively (-70%, P<0.05; -48%, P<0.05), epididymal sperm count (-22%, P<0.05), and spermatozoa motility (-35%, P<0.05). In contrast, Cd increased the malondialdehyde (+46%, P<0.05), metallothionein (+200%, P<0.05), and 8-oxodGuo concentrations (+71%, P<0.05) in the testis. In the gonad, Cd decreased the GPx (-30%, P<0.05), CAT (-32%, P<0.05), mitochondrial Mn-SOD (-34%, P<0.05), and cytosolic CuZn-SOD (-32%, P<0.05) activities. Zinc supplementation (ZnCl(2), 40 mg/l, per os) in the Cd-exposed rats restored the activities of GPx, CuZn-SOD, and Mn-SOD in the testes to the levels of the control group. Moreover, zinc administration was capable of reducing the elevated levels of malondialdehyde in the testis. Interestingly, zinc supplementation attenuated DNA oxidation induced by Cd in the gonad and restored the testosterone level and sperm count to the levels of the control group. Zinc administration minimized oxidative damage and reversed the impairment of spermatogenesis and testosterone production induced by Cd in the rat testis.

The N-terminal region of the prion protein PrP(C) contains a series of octapeptide repeats. This region has been implicated in the binding of divalent metal ions, particularly copper. PrP(C) has been suggested to be involved in copper transport and metabolism and in cell defense mechanisms against oxidative insult, possibly through the regulation of the intracellular CuZn superoxide dismutase activity (CuZn-SOD) or a SOD-like activity of PrP(C) itself. However, up to now the link between PrP(C) expression and copper metabolism or SOD activity has still to be formally established; particularly because conflicting results have been obtained in vivo. In this study, we report a link between PrP(C), copper binding, and resistance to oxidative stress. Radioactive copper ((64)Cu) was used at a physiological concentration to demonstrate that binding of copper to the outer plasma cell membrane is related to the level of PrP(C) expression in a cell line expressing a doxycycline-inducible murine PrP(C) gene. Cellular PIPLC pretreatment indicated that PrP(C) was not involved in copper delivery at physiological concentrations. We also demonstrated that murine PrP(C) expression increases several antioxidant enzyme activities and glutathione levels. Prion protein may be a stress sensor sensitive to copper and able to initiate, following copper binding, a signal transduction process acting on the antioxidant systems to improve cell defenses.

The final results of the EDELWEISS-I dark matter search using cryogenic heat-and-ionization Ge detectors are presented. The final data sample corresponds to an increase by a factor 5 in exposure relative to the previously published results. A recoil energy threshold of 13 keV or better was achieved with three 320 g detectors working simultaneously over four months of stable operation. Limits on the spin-independent cross section for the scattering of a weakly interacting massive particle on a nucleon are derived from an accumulated fiducial exposure of $62\text{ }\text{ }\mathrm{kg}\text{ }\mathrm{d}$.

OBJECTIVE: Our aim was to evaluate a fluorescence-based enhanced-reality system to assess intestinal viability in a laparoscopic mesenteric ischemia model. MATERIALS AND METHODS: A small bowel loop was exposed, and 3 to 4 mesenteric vessels were clipped in 6 pigs. Indocyanine green (ICG) was administered intravenously 15 minutes later. The bowel was illuminated with an incoherent light source laparoscope (D-light-P, KarlStorz). The ICG fluorescence signal was analyzed with Ad Hoc imaging software (VR-RENDER), which provides a digital perfusion cartography that was superimposed to the intraoperative laparoscopic image [augmented reality (AR) synthesis]. Five regions of interest (ROIs) were marked under AR guidance (1, 2a-2b, 3a-3b corresponding to the ischemic, marginal, and vascularized zones, respectively). One hour later, capillary blood samples were obtained by puncturing the bowel serosa at the identified ROIs and lactates were measured using the EDGE analyzer. A surgical biopsy of each intestinal ROI was sent for mitochondrial respiratory rate assessment and for metabolites quantification. RESULTS: Mean capillary lactate levels were 3.98 (SD = 1.91) versus 1.05 (SD = 0.46) versus 0.74 (SD = 0.34) mmol/L at ROI 1 versus 2a-2b (P = 0.0001) versus 3a-3b (P = 0.0001), respectively. Mean maximal mitochondrial respiratory rate was 104.4 (±21.58) pmolO2/second/mg at the ROI 1 versus 191.1 ± 14.48 (2b, P = 0.03) versus 180.4 ± 16.71 (3a, P = 0.02) versus 199.2 ± 25.21 (3b, P = 0.02). Alanine, choline, ethanolamine, glucose, lactate, myoinositol, phosphocholine, sylloinositol, and valine showed statistically significant different concentrations between ischemic and nonischemic segments. CONCLUSIONS: Fluorescence-based AR may effectively detect the boundary between the ischemic and the vascularized zones in this experimental model.

Factor acetyltransferase activity associated with several histone acetyltransferases plays a key role in the control of transcription. Here we report that hGCN5, a well known histone acetyltransferase, specifically interacts with and acetylates the human immunodeficiency virus type 1 (HIV-1) transactivator protein, Tat. The interaction between Tat and hGCN5 is direct and involves the acetyltransferase and the bromodomain regions of hGCN5, as well as a limited region of Tat encompassing the cysteine-rich domain of the protein. Tat lysines 50 and 51, target of acetylation by p300/CBP, were also found to be acetylated by hGCN5. The acetylation of these two lysines by p300/CBP has been recently shown to stimulate Tat transcriptional activity and accordingly, we have found that hGCN5 can considerably enhance Tat-dependent transcription of the HIV-1 long terminal repeat. These data highlight the importance of the acetylation of lysines 50 and 51 in the function of Tat, since different histone acetyltransferases involved in distinct signaling pathways, GCN5 and p300/CBP, converge to acetylate Tat on the same site.

Inflammation is a cellular and molecular response to infection and/or tissues injury. While a suited inflammatory response in intensity and time allows for killing pathogens, clearing necrotic tissue, and healing injury; an excessive inflammatory response drives various diseases in which inflammation and tissues damages/stress self-sustain each other. Microbes have been poorly implied in non-resolving inflammation, emphasizing the importance of endogenous regulation of inflammation. Mitochondria have been historically identified as the main source of cellular energy, by coupling the oxidation of fatty acids and pyruvate with the production of high amount of adenosine triphosphate by the electron transport chain. Mitochondria are also the main source of reactive oxygen species. Interestingly, research in the last decade has highlighted that since its integration in eukaryote cells, this organelle of bacterial origin has not only been tolerated by immunity, but has also been placed as a central regulator of cell defense. In intact cells, mitochondria regulate cell responses to critical innate immune receptors engagement. Downstream intracellular signaling pathways interact with mitochondrial proteins and are tuned by mitochondrial functioning. Moreover, upon cell stress or damages, mitochondrial components are released into the cytoplasm or the extra cellular milieu, where they act as danger signals when recognized by innate immune receptors. Finally, by regulating the energetic state of immunological synapse between dendritic cells and lymphocytes, mitochondria regulate the inflammation fate toward immunotolerance or immunogenicity. As dysregulations of these processes have been recently involved in various diseases, the identification of the underlying mechanisms might open new avenues to modulate inflammation.

Very intense neutrino beams and large neutrino detectors will be needed in order to enable the discovery of CP violation in the leptonic sector. We propose to use the proton linac of the European Spallation Source currently under construction in Lund, Sweden, to deliver, in parallel with the spallation neutron production, a very intense, cost effective and high performance neutrino beam. The baseline program for the European Spallation Source linac is that it will be fully operational at 5 MW average power by 2022, producing 2 GeV 2.86 ms long proton pulses at a rate of 14 Hz. Our proposal is to upgrade the linac to 10 MW average power and 28 Hz, producing 14 pulses/s for neutron production and 14 pulses/s for neutrino production. Furthermore, because of the high current required in the pulsed neutrino horn, the length of the pulses used for neutrino production needs to be compressed to a few μs with the aid of an accumulator ring. A long baseline experiment using this Super Beam and a megaton underground Water Cherenkov detector located in existing mines 300–600 km from Lund will make it possible to discover leptonic CP violation at 5 σ significance level in up to 50% of the leptonic Dirac CP-violating phase range. This experiment could also determine the neutrino mass hierarchy at a significance level of more than 3 σ if this issue will not already have been settled by other experiments by then. The mass hierarchy performance could be increased by combining the neutrino beam results with those obtained from atmospheric neutrinos detected by the same large volume detector. This detector will also be used to measure the proton lifetime, detect cosmological neutrinos and neutrinos from supernova explosions. Results on the sensitivity to leptonic CP violation and the neutrino mass hierarchy are presented.

This cross-sectional study aimed to investigate, during a short period between 2000 and 2001, in a large population of patients with chronic hepatitis C, the epidemiological characteristics of hepatitis C virus (HCV) genotypes in France. Data from 26 referral centres, corresponding to 1769 patients with chronic hepatitis C were collected consecutively during a 6-month period. HCV genotyping in the 5'-non-coding region (NCR) was performed in each center using the line probe assay (LiPA, in 63% of cases), sequencing (25%) or primer-specific polymerase chain reaction (PCR) (12%). HCV genotypes 1a, 1b, 2, 3, 4, 5, non-subtyped 1 and mixed infection were found in 18, 27, 9, 21, 9, 3, 11 and 1% of our population, respectively. HCV genotype distribution was associated with gender, age, source and duration of infection, alanine aminotransferase (ALT) levels, cirrhosis, alcohol consumption, hepatitis B virus (HBV) and human immunodeficiency virus (HIV) coinfection. In multivariate analysis, only the source of infection was the independent factor significantly associated with genotype (P = 0.0001). In conclusion, this study shows a changing pattern of HCV genotypes in France, with i.v. drug abuse as the major risk factor, an increase of genotype 4, and to a lesser extent 1a and 5, and a decrease of genotypes 1b and 2. The modification of the HCV genotype pattern in France in the next 10 years may require new therapeutic strategies, and further survey studies.

Observing double beta decay with no neutrinos in the final state, would signal the existence of lepton number violating processes and hint at the neutrino being a Majorana particle. The impressive effort represented by the NEMO-3 experiment sets important constraints on the Majorana mass of neutrinos and lepton-number violating processes.