Homozygous COQ7 mutation: a new cause of potentially treatable distal hereditary motor neuropathy.

Distal hereditary motor neuropathy represents a group of motor inherited neuropathies leading to distal weakness. We report a family of two brothers and a sister affected by distal hereditary motor neuropathy in whom a homozygous variant c.3G>T (p.1Met?) was identified in the COQ7 gene. This gene encodes a protein required for coenzyme Q10 biosynthesis, a component of the respiratory chain in mitochondria. Mutations of COQ7 were previously associated with severe multi-organ disorders characterized by early childhood onset and developmental delay. Using patient blood samples and fibroblasts derived from a skin biopsy, we investigated the pathogenicity of the variant of unknown significance c.3G>T (p.1Met?) in the COQ7 gene and the effect of coenzyme Q10 supplementation in vitro. We showed that this variation leads to a severe decrease in COQ7 protein levels in the patient's fibroblasts, resulting in a decrease in coenzyme Q10 production and in the accumulation of 6-demethoxycoenzyme Q10, the COQ7 substrate. Interestingly, such accumulation was also found in the patient's plasma. Normal coenzyme Q10 and 6-demethoxycoenzyme Q10 levels were restored in vitro by using the coenzyme Q10 precursor 2,4-dihydroxybenzoic acid, thus bypassing the COQ7 requirement. Coenzyme Q10 biosynthesis deficiency is known to impair the mitochondrial respiratory chain. Seahorse experiments showed that the patient's cells mainly rely on glycolysis to maintain sufficient ATP production. Consistently, the replacement of glucose by galactose in the culture medium of these cells reduced their proliferation rate. Interestingly, normal proliferation was restored by coenzyme Q10 supplementation of the culture medium, suggesting a therapeutic avenue for these patients. Altogether, we have identified the first example of recessive distal hereditary motor neuropathy caused by a homozygous variation in the COQ7 gene, which should thus be included in the gene panels used to diagnose peripheral inherited neuropathies. Furthermore, 6-demethoxycoenzyme Q10 accumulation in the blood can be used to confirm the pathogenic nature of the mutation. Finally, supplementation with coenzyme Q10 or derivatives should be considered to prevent the progression of COQ7-related peripheral inherited neuropathy in diagnosed patients.

Improved detection of mitochondrial DNA instability in mitochondrial genome maintenance disorders.

PURPOSE: Diseases caused by defects in mitochondrial DNA (mtDNA) maintenance machinery, leading to mtDNA deletions, form a specific group of disorders. However, mtDNA deletions also appear during aging, interfering with those resulting from mitochondrial disorders. METHODS: Here, using next-generation sequencing (NGS) data processed by eKLIPse and data mining, we established criteria distinguishing age-related mtDNA rearrangements from those due to mtDNA maintenance defects. MtDNA deletion profiles from muscle and urine patient samples carrying pathogenic variants in nuclear genes involved in mtDNA maintenance (n = 40) were compared with age-matched controls (n = 90). Seventeen additional patient samples were used to validate the data mining model. RESULTS: Overall, deletion number, heteroplasmy level, deletion locations, and the presence of repeats at deletion breakpoints were significantly different between patients and controls, especially in muscle samples. The deletion number was significantly relevant in adults, while breakpoint repeat lengths surrounding deletions were discriminant in young subjects. CONCLUSION: Altogether, eKLIPse analysis is a powerful tool for measuring the accumulation of mtDNA deletions between patients of different ages, as well as in prioritizing novel variants in genes involved in mtDNA stability.

Serum neprilysin levels are associated with myocardial stunning after ST-elevation myocardial infarction.

BACKGROUND: Left ventricular remodeling following ST-elevation myocardial infarction (STEMI) is associated with poor outcome, including heart failure (HF). Neprilysin inhibition leads to improved outcome in patients with altered left ventricular ejection fraction (LVEF). METHODS: We aimed to assess the association between serum levels of neprilysin and left ventricular (LV) volumes, function and remodeling in STEMI patients with successful myocardial reperfusion and no clinical sign of HF. Sixty-eight patients were admitted for STEMI and had both plasma neprilysin measurement at baseline and 3D transthoracic echocardiogram at baseline and after a median follow-up of 7 months. We compared 3 groups: a group with a low-level of plasma neprilysin (< 125 pg/mL, i.e. the lower limit of detection of the assay) and the two other groups were defined as being below or above the median value of the remaining samples. RESULTS: Median age was 58.5 ± 12.8 years and 56 (82.4%) were men. Median LVEF was 45.0 ± 8.5%. Baseline characteristics were comparable between groups (low-level of neprilysin group [≤125 pg/mL, n = 38], medium-level of neprilysin group [126-450 pg/mL, n = 15] and a high-level group [> 450 pg/mL, n = 15]). At baseline there was a non-significant trend towards lower end-diastolic volume (p = 0.07) but significantly lower LVEF in the high neprilysin group (46.4 ± 8.3%, 47.1 ± 8.1% and 39.1 ± 6.9%, p < 0.01). At follow-up, the magnitude of LVEF increase was significantly more important in the high neprilysin group compared to the other groups (p = 0.022 for relative change in LVEF and 6.6 ± 7.3%, 3.6 ± 9.0% and 11.3 ± 8.4%, p = 0.031 for absolute change in LVEF) resulting in similar LVEF levels at follow-up between all groups (53.0 ± 8.9%, 50.6 ± 9.7% and 50.4 ± 9.9%, p = 0.55). CONCLUSIONS: Initial high neprilysin levels may identify patients with stunned myocardium early after STEMI, with a recovery of contractility leading to improved LVEF at follow-up. Future studies will have to assess the role of neprilysin in the setting of STEMI and the potential benefit of its blockade.

Spironolactone and perioperative atrial fibrillation occurrence in cardiac surgery patients: Rationale and design of the ALDOCURE trial.

BACKGROUND: After artery bypass grafting (CABG), the presence of perioperative AF (POAF) is associated with greater short- and long-term cardiovascular morbidity. Underlying POAF mechanisms are complex and include the presence of an arrhythmogenic substrate, cardiac fibrosis and electrical remodeling. Aldosterone is a key component in this process. We hypothesize that perioperative mineralocorticoid receptor (MR) blockade may decrease the POAF incidence in patients with a left ventricular ejection fraction (LVEF) ≥50% who are referred for CABG with or without aortic valve replacement (AVR). STUDY DESIGN: The ALDOCURE trial (NCT03551548) will be a multicenter, randomized, double-blind, placebo-controlled trial testing the superiority of a low-cost MR antagonist (MRA, spironolactone) on POAF in 1500 adults referred for on-pump elective CABG surgery with or without AVR, without any history of heart failure or atrial arrhythmia. The primary efficacy end point is the occurrence of POAF from randomization to within 5 days after surgery, assessed in a standardized manner. The main secondary efficacy end points include the following: postoperative AF occurring within 5 days after cardiac surgery, perioperative myocardial injury, major cardiovascular events and death occurring within 30 days of surgery, hospital and intensive care unit length of stay, need for readmission, LVEF at discharge and significant ventricular arrhythmias within 5 days after surgery. Safety end points, including blood pressure, serum potassium levels and renal function, will be monitored regularly throughout the trial duration. CONCLUSION: The ALDOCURE trial will assess the effectiveness of spironolactone in addition to standard therapy for reducing POAF in patients undergoing CABG. CLINICAL TRIAL REGISTRATION: NCT03551548.

Primary mitochondrial disorders and mimics: Insights from a large French cohort.

OBJECTIVE: The objective of this study was to evaluate the implementation of NGS within the French mitochondrial network, MitoDiag, from targeted gene panels to whole exome sequencing (WES) or whole genome sequencing (WGS) focusing on mitochondrial nuclear-encoded genes. METHODS: Over 2000 patients suspected of Primary Mitochondrial Diseases (PMD) were sequenced by either targeted gene panels, WES or WGS within MitoDiag. We described the clinical, biochemical, and molecular data of 397 genetically confirmed patients, comprising 294 children and 103 adults, carrying pathogenic or likely pathogenic variants in nuclear-encoded genes. RESULTS: The cohort exhibited a large genetic heterogeneity, with the identification of 172 distinct genes and 253 novel variants. Among children, a notable prevalence of pathogenic variants in genes associated with oxidative phosphorylation (OXPHOS) functions and mitochondrial translation was observed. In adults, pathogenic variants were primarily identified in genes linked to mtDNA maintenance. Additionally, a substantial proportion of patients (54% (42/78) and 48% (13/27) in children and adults, respectively), undergoing WES or WGS testing displayed PMD mimics, representing pathologies that clinically resemble mitochondrial diseases. INTERPRETATION: We reported the largest French cohort of patients suspected of PMD with pathogenic variants in nuclear genes. We have emphasized the clinical complexity of PMD and the challenges associated with recognizing and distinguishing them from other pathologies, particularly neuromuscular disorders. We confirmed that WES/WGS, instead of panel approach, was more valuable to identify the genetic basis in patients with "possible" PMD and we provided a genetic testing flowchart to guide physicians in their diagnostic strategy.

Glucose fluctuation promotes mitochondrial dysfunctions in the cardiomyocyte cell line HL-1.

AIMS: Glycemic variability has been suggested as a risk factor for diabetes complications but the precise deleterious mechanisms remain poorly understood. Since mitochondria are the main source of energy in heart and cardiovascular diseases remain the first cause of death in patients with diabetes, the aim of the study was to evaluate the impact of glucose swings on mitochondrial functions in the cardiomyocyte cell line HL-1. METHODS: HL-1 cells were exposed to low (LG, 2.8 mmol/l), normal (NG, 5.5 mmol/l), high (HG, 25 mmol/l) or intermittent high glucose (IHG, swing between low and high) every 2h during 12h (short-time treatment) or every 12h during 72h (long-time treatment). Anaerobic catabolism of glucose was evaluated by measuring glucose consumption and lactate production, oxidative phosphorylation was evaluated by polarography and ATP measurement, mitochondrial superoxide anions and the mitochondrial membrane potential (MMP) were analysed using fluorescent probes, and the protein oxidation was measured by oxyblot. RESULTS: IHG and HG increased glucose consumption and lactate production compared to LG and NG but without any difference between short- and long-time treatments. After 72h and unlike to LG, NG and HG, we didn't observe any increase of the mitochondrial respiration in the presence of succinate upon IHG treatment. IHG, and to a lesser extent HG, promoted a time-dependent decrease of the mitochondrial membrane potential compared to LG and NG treatments. HG and IHG also increased superoxide anion production compared to LG and NG both at 12 and 72h but with a higher increase for IHG at 72h. At last, both HG and IHG stimulated protein oxidation at 72h compared to LG and NG treatments. CONCLUSIONS: Our results demonstrated that exposure of HL-1 cells to glucose swings promoted time-dependent mitochondrial dysfunctions suggesting a deleterious effect of such condition in patients with diabetes that could contribute to diabetic cardiomyopathy.

Micropipette-guided Drug Administration (MDA) as a non-invasive chronic oral administration method in male rats.

BACKGROUND: In preclinical studies resorting to rodents, the effects of prolonged oral intake of active substances are difficult to evaluate. Indeed, to get closer to clinical reality, oral gavage (OG) is frequently used but the repetition of administrations induces risks of lesions of the digestive tract, and stress for animals which can compromise the quality of the results. NEW METHOD: This study describes the development of a non-invasive oral administration method in male Sprague Dawley rats, as a safe alternative of OG, more faithful to clinical reality and limiting biases in pharmacokinetics and/or pharmacodynamics interpretation. Micropipette-guided Drug Administration (MDA) is based on the administration by micropipette of a sufficiently palatable vehicle for the animals to voluntarily take its contents. RESULTS: MDA was not demonstrated as less stressful than OG. A pharmacokinetics equivalence between MDA and OG was demonstrated for pregabalin administration but not for aripiprazole. Despite the use of a sweet vehicle, the MDA method does not result in weight gain or significant elevation of blood glucose and fructosamines level. Regarding the time needed to administrate the solution, the MDA method is significantly faster than OG. COMPARISON WITH EXISTING METHOD(S): Contrastingly to procedures using food or water, this method allows for a rigorous control of the time and dose administered and is delivered in discrete administration windows which is therefore closer to the clinical reality. This method appears particularly suitable for pharmacological evaluation of hydrophilic compounds. CONCLUSIONS: The MDA procedure represents a respectful and adapted pharmacological administration method to study the effects of chronic oral administration in rats.

Relationship between lifestyle factors and hypertension: a cross-sectional analysis from the Gubbio study.

BACKGROUND: Hypertension (HTN) is a well-established and a major risk factor for cardiovascular disease. Lifestyle behaviours for its prevention and control are recommended within worldwide guidelines. Their relationship with HTN need more investigations. AIM: We aimed to investigate the associations between lifestyle, anthropometric and biological measurements and BP in the Gubbio residential study. METHODS: Cross-sectional analyses were performed using data from Gubbio study. Information concerning lifestyle factors were collected using self-reported questionnaire and were further completed with a baseline clinical examination and blood exams. Three BP measurements were performed following a standard protocol. Age-adjusted and multivariable logistic regressions were used to examine the relationships between lifestyle parameters and HTN separately for each sex. We used heterogeneity test to observe sex differences. RESULTS: There were 3,183 persons included (48% men, 43 ± 17 years old). Mean systolic BP (SBP) was 119 ± 16 mmHg and 10.6% were hypertensives. Age [OR: 129.70 (95%CI: 18.57-905.79) in women and OR: 8.37 (95%CI: 4.01-17.48) (p < 0.0001) in men] and BMI [OR: 2.14 (95%CI: 1.32-3.46) (p = 0.006) in women and OR: 1.81 (95%CI: 1.05-3.12), p = 0.03 in men], were positively associated with SBP in both sexes. Serum uric acid [OR: 3.86 (95%CI: 2.03-7.26), p = 0.04] was positively associated with HTN in women while fasting blood glucose [OR: 3.04 (95%CI: 1.55-5.97), p < 0.001] were associated to HTN only in men. DISCUSSION: In addition to age, BMI is associated with HTN in both sexes while sex differences were observed in the associations between serum uric acid, fasting blood glucose and HTN.

Experimental results using 3-bromopyruvate in mesothelioma: in vitro and in vivo studies.

Over many years we have taken advantage of the special metabolism of cancer cells involving an increased consumption of glucose associated with lactic acid production even in the presence of oxygen, a phenomenon referred to as the "Warburg effect", to counteract cancer cell growth. We have tested 3-bromopyruvate (3-BrPA), an inhibitor of pyruvate-associated reactions. Firstly, we tested this agent, in vitro, in two mesothelioma cell lines. Cellular response would appear to depend on the mode of administration (immediately or 24 h after seeding). Depending on the line, 3-BrPA induced a cytostatic or cytotoxic effect. This effect was accompanied by cell death induction even in cells highly refractory to cisplatin. Mitochondrial apoptotic death appeared to involve both lines; however, a different death pathway such as necrosis cannot be excluded. Interestingly, 3-BrPA leads to a diminution of the expression of the anti-apotptoic protein Mcl-1. We then tested 3-BrPA in vivo. Survival of nude mice bearing human mesothelioma was significantly prolonged (p < 0.0001). Toxicity and clinical studies should be performed to test 3- BrPA as local therapy for patients suffering from pleural or peritoneal mesothelioma. Association with cisplatin should be particularly considered.

Mechanisms involved in cardioprotective effects of pravastatin administered during reoxygenation in human myocardium in vitro.

BACKGROUND: The authors investigated the effect of pravastatin during reoxygenation after myocardial hypoxia and examined the involvement of nitric oxide synthase, mitochondrial permeability transition pore, and expression of markers of apoptosis in human myocardium in vitro. METHODS: Human atrial trabeculae were exposed to hypoxia for 30 min and reoxygenation for 60 min (control group; n = 10). Pravastatin (5, 10, 50, 75 µM; n = 6 in each group) was administered throughout the reoxygenation. In separate groups (n = 6 in each group), pravastatin 50 µM was administered in the presence of 200 µM L-NG-nitroarginine methyl ester, a nitric oxide synthase inhibitor, and 50 µM atractyloside, the mitochondrial permeability transition pore opener. The primary endpoint was the developed force of contraction at the end of reoxygenation, expressed as a percentage of baseline (mean ± SD). Protein expression of BAD, phospho-BAD, caspase 3, Pim-1 kinase, and Bcl-2 were measured using Western immunoblotting. RESULTS: The administration of 10 (77 ± 5% of baseline), 50 (86 ± 6%), and 75 µM (88 ± 13%) pravastatin improved the force of contraction at the end of reoxygenation, compared with that of the control group (49 ± 11%; P < 0.001). These beneficial effects were prevented by L-NG-nitroarginine methyl ester and atractyloside. Compared with control group, the administration of 5 µM pravastatin did not modify the force of contraction. Pravastatin increased the phosphorylation of BAD, activated the expression of Pim-1 kinase and Bcl-2, and maintained the caspase 3 concentration relative to that of the respective untreated controls. CONCLUSIONS: Pravastatin, administered at reoxygenation, protected the human myocardium by preventing the mitochondrial permeability transition pore opening, phosphorylating BAD, activating nitric oxide synthase, Pim-1 kinase, and Bcl-2, and preserving the myocardium against the caspase 3 activation.

Ferritin as a predictive biomarker of severity in Covid-19 / La ferritine comme biomarqueur prédictif des formes sévères de Covid-19

Background: To prevent the crisis-level shortage of beds in hospitals and for a more efficient support, it's necessary to early identify coronavirus disease-19 (Covid-19) patients at risk to develop a severe form of the disease. Objective: The goal of our study was to determine whether biological markers, including the serum ferritin, could predict the severity of the Covid-19. Methods: One hundred and seventy-one patients, who were admitted to Caen University Hospital, were included retrospectively with a positive diagnosis of Covid-19 by RT-PCR. A serum ferritin measurement was performed for all patients. They were further classified either into a non-severe or a severe group based on their hospitalization in intense care unit (ICU) for mechanical ventilation or death. Results: Univariate analysis revealed a significant association between increased serum ferritin and CRP levels, obesity, CT scan lesions, pathological respiratory rate, decreased PaO2/FiO2 ratio, the NEWS-2 score and the severe (n = 59) vs the non-severe (n = 112) outcome of Covid-19 patients. However, in a multivariate analysis, only CRP and obesity were associated with the severe form of Covid-19. Conclusion: While pathological level of serum ferritin at admission is associated with severe form of Covid-19, combination of increased CRP level and obesity would better predict the severity of the disease.

Pour une meilleure prise en charge, il est nécessaire de pouvoir identifier précocement les patients atteints de la Covid-19 susceptibles de développer une forme sévère. L'objectif de notre étude était de déterminer si des marqueurs biologiques, notamment la ferritinémie, peuvent prédire la sévérité de la Covid-19. Nous avons inclus de manière rétrospective 171 patients au CHU de Caen avec un diagnostic de Covid-19. Les patients devaient avoir un bilan biologique incluant la ferritinémie à l'admission et ont été classés en formes sévères (n = 59, hospitalisation et ventilation invasive en soins intensifs ou en réanimation, et/ou décès) et non-sévères (n = 112, tous les autres patients). L'analyse univariée a montré une association entre les formes sévères de Covid-19 avec les niveaux élevés de ferritine et de CRP, l'obésité, les lésions pulmonaires, la fréquence respiratoire élevée, la diminution du ratio PaO2/FiO2 et le score de NEWS-2. Cependant, en analyse multivariée seules la CRP et l'obésité montraient une association avec les formes sévères. En conclusion, alors que la ferritinémie élevée est associée à un risque accru de développer une forme sévère de la Covid-19, la CRP et la présence d'une obésité seraient de meilleurs marqueurs prédictifs.

Tracking the immune response by MRI using biodegradable and ultrasensitive microprobes.

Molecular magnetic resonance imaging (MRI) holds great promise for diagnosis and therapeutic monitoring in a wide range of diseases. However, the low intrinsic sensitivity of MRI to detect exogenous contrast agents and the lack of biodegradable microprobes have prevented its clinical development. Here, we synthetized a contrast agent for molecular MRI based on a previously unknown mechanism of self-assembly of catechol-coated magnetite nanocrystals into microsized matrix-based particles. The resulting biodegradable microprobes (M3P for microsized matrix-based magnetic particles) carry up to 40,000 times higher amounts of superparamagnetic material than classically used nanoparticles while preserving favorable biocompatibility and excellent water dispersibility. After conjugation to monoclonal antibodies, targeted M3P display high sensitivity and specificity to detect inflammation in vivo in the brain, kidneys, and intestinal mucosa. The high payload of superparamagnetic material, excellent toxicity profile, short circulation half-life, and widespread reactivity of the M3P particles provides a promising platform for clinical translation of immuno-MRI.

Serum neuron-specific enolase as predictor of outcome in comatose cardiac-arrest survivors: a prospective cohort study.

BACKGROUND: The prediction of neurological outcome in comatose patients after cardiac arrest has major ethical and socioeconomic implications. The purpose of this study was to assess the capability of serum neuron-specific enolase (NSE), a biomarker of hypoxic brain damage, to predict death or vegetative state in comatose cardiac-arrest survivors. METHODS: We conducted a prospective observational cohort study in one university hospital and one general hospital Intensive Care Unit (ICU). All consecutive patients who suffered cardiac arrest and were subsequently admitted from June 2007 to February 2009 were considered for inclusion in the study. Patients who died or awoke within the first 48 hours of admission were excluded from the analysis. Patients were followed for 3 months or until death after cardiopulmonary resuscitation. The Cerebral Performance Categories scale (CPC) was used as the outcome measure; a CPC of 4-5 was regarded as a poor outcome, and a CPC of 1-3 a good outcome. Measurement of serum NSE was performed at 24 h and at 72 h after the time of cardiac arrest using an enzyme immunoassay. Clinicians were blinded to NSE results. RESULTS: Ninety-seven patients were included. All patients were actively supported during the first days following cardiac arrest. Sixty-five patients (67%) underwent cooling after resuscitation. At 3 months 72 (74%) patients had a poor outcome (CPC 4-5) and 25 (26%) a good outcome (CPC 1-3). The median and Interquartile Range [IQR] levels of NSE at 24 h and at 72 h were significantly higher in patients with poor outcomes: NSE at 24 h: 59.4 ng/mL [37-106] versus 28.8 ng/mL [18-41] (p < 0.0001); and NSE at 72 h: 129.5 ng/mL [40-247] versus 15.7 ng/mL [12-19] (p < 0.0001). The Receiver Operator Characteristics (ROC) curve for poor outcome for the highest observed NSE value for each patient determined a cut-off value for NSE of 97 ng/mL to predict a poor neurological outcome with a specificity of 100% [95% CI = 87-100] and a sensitivity of 49% [95% CI = 37-60]. However, an approach based on a combination of SSEPs, NSE and clinical-EEG tests allowed to increase the number of patients (63/72 (88%)) identified as having a poor outcome and for whom intensive treatment could be regarded as futile. CONCLUSION: NSE levels measured early in the course of patient care for those who remained comatose after cardiac arrest were significantly higher in patients with outcomes of death or vegetative state. In addition, we provide a cut-off value for NSE (> 97 ng/mL) with 100% positive predictive value of poor outcome. Nevertheless, for decisions concerning the continuation of treatment in this setting, we emphasize that an approach based on a combination of SSEPs, NSE and clinical EEG would be more accurate for identifying patients with a poor neurological outcome.

Is plasma concentration of coenzyme Q10 a predictive marker for left ventricular remodelling after revascularization for ST-segment elevation myocardial infarction?

BACKGROUND: Left ventricular remodelling that frequently occurs after acute myocardial infarction is associated with an increased risk of heart failure and cardiovascular death. Although several risk factors have been identified, there is still no marker in clinical use to predict left ventricular remodelling. Plasma concentration of coenzyme Q10, which plays a key role in mitochondrial energy production and as an antioxidant, seems to be negatively correlated with left ventricular function after acute myocardial infarction. OBJECTIVE: The goal of our study was to determine whether the plasma coenzyme Q10 baseline concentrations at time of the ST-elevation myocardial infarction (STEMI) could predict left ventricular remodelling at six months' follow-up. METHODS: Sixty-eight patients who were admitted to hospital for STEMI and successfully revascularized with primary percutaneous coronary intervention were recruited. All patients underwent a 3D-echocardiography examination within the first four days after percutaneous coronary intervention and six months later then divided into two groups based on the presence or not of left ventricular remodelling. Plasma coenzyme Q10 concentration at the time of percutaneous coronary intervention was determined using high-performance liquid chromatography-tandem mass spectrometry. RESULTS: While we found similar plasma coenzyme Q10 concentrations compared with other studies, no association was evidenced between coenzyme Q10 concentrations and left ventricular remodelling (P = 0.89). CONCLUSION: We found no evidence for using plasma coenzyme Q10 concentration as an early prediction marker of left ventricular remodelling after STEMI.

Ability of procalcitonin to distinguish between bacterial and nonbacterial infection in severe acute exacerbation of chronic obstructive pulmonary syndrome in the ICU.

BACKGROUND: To assess the ability of procalcitonin (PCT) to distinguish between bacterial and nonbacterial causes of patients with severe acute exacerbation of COPD (AECOPD) admitted to the ICU, we conducted a retrospective analysis of two prospective studies including 375 patients with severe AECOPD with suspected lower respiratory tract infections. PCT levels were sequentially assessed at the time of inclusion, 6 h after and at day 1, using a sensitive immunoassay. The patients were classified according to the presence of a documented bacterial infection (including bacterial and viral coinfection) (BAC + group), or the absence of a documented bacterial infection (i.e., a documented viral infection alone or absence of a documented pathogen) (BAC- group). The accuracy of PCT levels in predicting bacterial infection (BAC + group) vs no bacterial infection (BAC- group) at different time points was evaluated by receiver operating characteristic (ROC) analysis. RESULTS: Regarding the entire cohort (n = 375), at any time, the PCT levels significantly differed between groups (Kruskal-Wallis test, p < 0.001). A pairwise comparison showed that PCT levels were significantly higher in patients with bacterial infection (n = 94) than in patients without documented pathogens (n = 218) (p < 0.001). No significant difference was observed between patients with bacterial and viral infection (n = 63). For example, the median PCT-H0 levels were 0.64 ng/ml [0.22-0.87] in the bacterial group vs 0.24 ng/ml [0.15-0.37] in the viral group and 0.16 ng/mL [0.11-0.22] in the group without documented pathogens. With a c-index of 0.64 (95% CI; 0.58-0.71) at H0, 0.64 [95% CI 0.57-0.70] at H6 and 0.63 (95% CI; 0.56-0.69) at H24, PCT had a low accuracy for predicting bacterial infection (BAC + group). CONCLUSION: Despite higher PCT levels in severe AECOPD caused by bacterial infection, PCT had a poor accuracy to distinguish between bacterial and nonbacterial infection. Procalcitonin might not be sufficient as a standalone marker for initiating antibiotic treatment in this setting.

Reevaluating the pathogenicity of the variations c.439 G>A and c.2132 C>T in the PLA2G6 gene.

The phospholipase A2 group VI (PLA2G6) gene encodes for a Ca2+-independent PLA2, which is localized in the cytosol, in the endoplasmic reticulum and in the mitochondrial membrane, plays a major role in phospholipid remodelling. Mutations within this gene have been reported to cause different phenotypes: infantile-onset neuroaxonal dystrophy associated with brain iron accumulation and adult-onset parkinsonian syndrome. In the present study, we analysed the PLA2G6 gene sequence in an asymptomatic young woman that was referred to our laboratory by a geneticist for an history of infantile neuroaxonal dystrophy in her little maternal cousin in whom the results of the genetical analysis were not available. We found two variants in the PLA2G6 gene (NM_003560.4, c.439 G>A and c.2132 C>T, p.Ala147Thr and p.Pro711Leu) previously reported as pathogenic. These results prompted us to perform a segregation analysis in the parents of this woman and we only found the presence of both variants in the asymptomatic 56-year-old patient's mother. Our molecular genetic testing clearly indicates that the c.439 G>A and c.2132 C>T variations identified in the PLA2G6 gene are positioned in cis and are not responsible for infantile neuroaxonal dystrophy which is an autosomal recessive disease.

Plasma aldosterone and atrial mitochondrial functions of patients undergoing cardiac surgery.

Aim: Mitochondrial dysfunction (MD) has been associated with poor outcomes after coronary artery bypass graft surgery. Methods: 58 consecutive patients from the ALDO-POAF Study (NCT02814903) were prospectively included. Plasma aldosterone was assessed at the time of the preoperative consultation and mitochondrial functional studies were performed using atrial appendage tissue collected during surgery. Results: Patients with the highest preoperative plasma aldosterone level had a lower mitochondrial respiratory chain functioning and a lower calcium retention capacity. Chronic kidney disease, patient's age and preoperative high-aldosterone were independent predictors of MD in multivariate analysis. Conclusion: These exploratory data support the use of preventive strategies targeting aldosterone and/or mineralocorticoid receptor activation, in order to prevent perioperative MD and associated poor outcomes.