The protection of ischemic myocardium: applications in human medicine and experimental prospects

Acute myocardial infarction (AMI) is a serious condition, associated with a high mortality rate in western countries. The emergence of revascularisation techniques for occluded arteries has improved the prognosis considerably, but the time to revascularisation remains critical. New cardioprotective strategies were therefore needed to further improve myocardial salvage. These strategies were for a long time based on meeting the myocardium’s demand in oxygen. In recent years however, new substances were developed to oppose directly the cell disorders associated with ischemia-reperfusion, or to induce an endogenous adaptation of the myocardium through preconditioning. Another approach includes reducing the body temperature during the ischemic process to delay infarct extension.L'infarctus du myocarde est une affection grave, à l'origine d'une mortalité élevée dans les pays occidentaux. L'émergence des techniques de revascularisation des artères occluses a permis d'améliorer considérablement le pronostic de cette affection mais les délais de revascularisation restent incompressibles. Le développement de stratégies cardioprotectrices additionnelles était donc nécessaire. Ces stratégies ont pendant longtemps reposé sur la nécessité de satisfaire les besoins en oxygène du myocarde. Plus récemment, des substances ont été développées dans le but de s'opposer directement aux désordres cellulaires liés à l'ischémie-reperfusion ou d'induire une adaptation endogène du myocarde par préconditionnement. Une autre approche consiste à réduire la température de l'organisme au cours du processus ischémique en vue de retarder l'extension de l'infarctus

Head and thorax elevation prevents the rise of intracranial pressure during extracorporeal resuscitation in swine

Aim: Head and thorax elevation during cardiopulmonary resuscitation improves cerebral hemodynamics and ultimate neurological outcome after cardiac arrest. Its effect during extracorporeal cardiopulmonary resuscitation (E-CPR) is unknown. We tested whether this procedure could improve hemodynamics in swine treated by E-CPR. Methods and Results: Pigs were anesthetized and submitted to 15 minutes of untreated ventricular fibrillation followed by E-CPR. Animals randomly remained in flat position (flat group) or underwent head and thorax elevation since E-CPR institution (head-up group). Electric shocks were delivered after 30 minutes until the return of spontaneous circulation (ROSC). They were followed during 120 minutes after ROSC. After 30 minutes of E-CPR, ROSC was achieved in all animals, with no difference regarding blood pressure, heart rate, and extracorporeal membrane of oxygenation flow among groups. The head-up group had an attenuated increase in ICP as compared with the flat group after cardiac arrest (13 ± 1 vs. 26 ± 2 mm Hg at the end of the follow-up, respectively). Cerebral perfusion pressure tended to be higher in the head-up versus flat group despite not achieving statistical difference (66 ± 1 vs 46 ± 1 mm Hg at the end of the follow-up). Carotid blood flow and cerebral oxygen saturation were not significantly different among groups. Conclusion: During E-CPR, head and thorax elevation prevents ICP increase. Whether it could improve the ultimate neurological outcome in this situation deserves further investigation.The study was supported by grants LIVE-RESP and AREG-SHOCK from Agence Nationale pour la Recherche. Y. Levy was supported by ADEREMVeterinari

Mitral valve endocardiosis in Cavalier King Charles spaniels in France: epidemiological, clinical and echo-Doppler study of 451 cases

A retrospective study was performed in the Cardiology Unit of Alfort in 451 Cavalier King Charles (CKC) spaniels. A left apical systolic murmur was detected in 183 of them (40.6 %). The prevalence of the murmur increased with age (18.8 % for CKC 11 years old). Mitral valve endocardiosis represented 93.3 % of the ultrasound anomalies. There was a positive correlation between age and several echo-Doppler parameters (P<0.01): atrium/aorta ratio, diastolic left ventricular diameter, thickness of the mitral valve leaflets, and mitral regurgitant mapping area. A positive correlation was also noted between the intensity of the murmur and these echo- Doppler parameters (P<0.0001). In conclusion, mitral valve endocardiosis is a frequent valvulopathy which occurs at an early age in CKC spaniels in France. Several clinical and echo-Doppler parameters have a predictive value for the severity of the disease.Une étude rétrospective a été menée dans l'Unité de Cardiologie d'Alfort chez 451 Cavaliers King Charles (CKC). Un souffle systolique apexien gauche a été détecté chez 183 d'entre eux (40,6 %). La prévalence de ce souffle augmentait avec l'âge (18,8 % pour les CKC 11 ans). L'endocardiose valvulaire mitrale a représenté 93,3 % des anomalies diagnostiquées à l'échocardiographie. Une corrélation positive a été observée entre l'âge et différents paramètres échographiques (P<0,01): le rapport atrium/aorte, le diamètre diastolique ventriculaire gauche, l'épaisseur des feuillets mitraux et la surface colorimétrique du reflux mitral. Une corrélation positive a aussi été observée entre l'intensité du souffle et ces paramètres échographiques (P<0,0001). En conclusion, l'endocardiose mitrale est une valvulopathie à la fois précoce et fréquente chez le CKC en France. Certains paramètres cliniques et écho-Doppler ont une valeur prédictive de la gravité de la maladie

Evaluation of lung recovery after static administration of three different perfluorocarbons in pigs.

International audienceBackground: The respiratory properties of perfluorocarbons (PFC) have been widely studied for liquid ventilation inhumans and animals. Several PFC were tested but their tolerance may depend on the species. Here, the effects of asingle administration of liquid PFC into pig lungs were assessed and compared. Three different PFC having distinctevaporative and spreading coefficient properties were evaluated (Perfluorooctyl bromide [PFOB], perfluorodecalin[PFD] and perfluoro-N-octane [PFOC]).Methods: Pigs were anesthetized and submitted to mechanical ventilation. They randomly received an intra-trachealadministration of 15 ml/kg of either PFOB, PFD or PFOC with 12 h of mechanical ventilation before awakening andweaning from ventilation. A Control group was submitted to mechanical ventilation with no PFC administration. Allanimals were followed during 4 days after the initial PFC administration to investigate gas exchanges and clinicalrecovery. They were ultimately euthanized for histological analyses and assessment of PFC residual concentrationswithin the lungs using dual nuclei fluorine and hydrogen Magnetic Resonance Imaging (MRI). Sixteen animals wereincluded (4/group).Results: In the PFD group, animals tended to be hypoxemic after awakening. In PFOB and PFOC groups, blood gaseswere not significantly different from the Control group after awakening. The poor tolerance of PFD was likely related toa large amount of residual PFC, as observed using MRI in all lung samples (≈10% of lung volume). This percentage waslower in the PFOB group (≈1%) but remained significantly greater than in the Control group. In the PFOC group, thepercentage of residual PFC was not significantly different from that of the Control group (≈0.1%). Histologically, themost striking feature was an alveolar infiltration with foam macrophages, especially in the groups treated by PFD orPFOB.Conclusions: Of the three tested perfluorocarbons, PFOC offered the best tolerance in terms of lung function, gasexchanges and residuum in the lung. PFOC was rapidly cleared from the lungs and virtually disappeared after 4 dayswhereas PFOB persisted at significant levels and led to foam macrophage infiltration. PFOC could be relevant for shortterm total liquid ventilation with a rapid weaning

Outcomes and potential impact of a virtual hands-on training program on MRI staging confidence and performance in rectal cancer

Objectives: To explore the potential impact of a dedicated virtual training course on MRI staging confidence and performance in rectal cancer. // Methods: Forty-two radiologists completed a stepwise virtual training course on rectal cancer MRI staging composed of a pre-course (baseline) test with 7 test cases (5 staging, 2 restaging), a 1-day online workshop, 1 month of individual case readings (n = 70 cases with online feedback), a live online feedback session supervised by two expert faculty members, and a post-course test. The ESGAR structured reporting templates for (re)staging were used throughout the course. Results of the pre-course and post-course test were compared in terms of group interobserver agreement (Krippendorf’s alpha), staging confidence (perceived staging difficulty), and diagnostic accuracy (using an expert reference standard). // Results: Though results were largely not statistically significant, the majority of staging variables showed a mild increase in diagnostic accuracy after the course, ranging between + 2% and + 17%. A similar trend was observed for IOA which improved for nearly all variables when comparing the pre- and post-course. There was a significant decrease in the perceived difficulty level (p = 0.03), indicating an improved diagnostic confidence after completion of the course. // Conclusions: Though exploratory in nature, our study results suggest that use of a dedicated virtual training course and web platform has potential to enhance staging performance, confidence, and interobserver agreement to assess rectal cancer on MRI virtual training and could thus be a good alternative (or addition) to in-person training. // Clinical relevance statement: Rectal cancer MRI reporting quality is highly dependent on radiologists’ expertise, stressing the need for dedicated training/teaching. This study shows promising results for a virtual web-based training program, which could be a good alternative (or addition) to in-person training. // Key Points: • Rectal cancer MRI reporting quality is highly dependent on radiologists’ expertise, stressing the need for dedicated training and teaching. • Using a dedicated virtual training course and web-based platform, encouraging first results were achieved to improve staging accuracy, diagnostic confidence, and interobserver agreement. • These exploratory results suggest that virtual training could thus be a good alternative (or addition) to in-person training

Genome-wide analysis in multiple-case families: Assessing the relationship between triglyceride and methylation

The main goal of this paper is to estimate the effect of triglyceride levels on methylation of cytosine-phosphate-guanine (CpG) sites in multiple-case families. These families are selected because they have 2 or more cases of metabolic syndrome (primary phenotype). The methylations at the CpG sites are the secondary phenotypes. Ascertainment corrections are needed when there is an association between the primary and secondary phenotype. We will apply the newly developed secondary phenotype analysis for multiple-case family studies to identify CpG sites where methylations are influenced by triglyceride levels. Our second goal is to compare the performance of the naïve approach, which ignores the sampling of the families, SOLAR (Sequential Oligogenic Linkage Analysis Routines), which adjusts for ascertainment via probands, and the secondary phenotype approach. The analysis of possible CpG sites associated with triglyceride levels shows results consistent with the literature when using the secondary phenotype approach. Overall, the secondary phenotype approach performed well, but the comparison of the different approaches does not show significant differences between them. However, for genome-wide applications, we recommend using the secondary phenotype approach when there is an association between primary and secondary phenotypes, and to use the naïve approach otherwise

Perflubron Distribution During Transition From Gas to Total Liquid Ventilation

Total liquid ventilation (TLV) using perfluorocarbons has shown promising results for the management of neonatal respiratory distress. However, one important safety consideration for TLV is a better understanding of the early events during the transition to TLV, especially regarding the fate of residual air in the non-dependent-lung regions. Our objective was to assess perflubron distribution during transition to TLV using electrical impedance tomography, complemented by fluoroscopy, in a neonatal lamb model of induced surfactant deficiency. Eight lambs were anesthetized and ventilated in supine position. Surfactant deficit was induced by saline lung lavage. After deflation, lungs were filled with 25 ml/kg perflubron over 18 s, and TLV was initiated. Electrical impedance tomography data was recorded from electrodes placed around the chest, during the first 10 and at 120 min of TLV. Lung perfusion was also assessed using hypertonic saline injection during apnea. In addition, fluoroscopic sequences were recorded during initial lung filling with perfluorocarbons, then at 10 and 60 min of TLV. Twelve lambs were used as controls for histological comparisons. Transition to TLV involved a short period of increased total lung volume (p = 0.01) secondary to recruitment of the dependent lung regions. Histological analysis shows that TLV was protective of these same regions when compared to gas-ventilated lambs (p = 0.03). The non-dependent lung regions filled with perflubron over at least 10 min, without showing signs of overdistention. Tidal volume distribution was more homogenous in TLV than during the preceding gas ventilation. Perflubron filling was associated with a non-significant increase in the anterior distribution of the blood perfusion signal, from 46 ± 17% to 53 ± 6% (p = 0.4). However, combined to the effects on ventilation, TLV had an instantaneous effect on ventilation-perfusion relationship (p = 0.03), suggesting better coupling. Conclusion: transition to TLV requires at least 10 min, and involves air evacuation or dissolution in perflubron, dependent lung recruitment and rapid ventilation-perfusion coupling modifications. During that time interval, the total lung volume transiently increases. Considering the potential deleterious effect of high lung volumes, one must manage this transition phase with care and, we suggest using a real-time monitoring system such as electrical impedance tomography

Improving stability of prediction models based on correlated omics data by using network approaches

Building prediction models based on complex omics datasets such as transcriptomics, proteomics, metabolomics remains a challenge in bioinformatics and biostatistics. Regularized regression techniques are typically used to deal with the high dimensionality of these datasets. However, due to the presence of correlation in the datasets, it is difficult to select the best model and application of these methods yields unstable results. We propose a novel strategy for model selection where the obtained models also perform well in terms of overall predictability. Several three step approaches are considered, where the steps are 1) network construction, 2) clustering to empirically derive modules or pathways, and 3) building a prediction model incorporating the information on the modules. For the first step, we use weighted correlation networks and Gaussian graphical modelling. Identification of groups of features is performed by hierarchical clustering. The grouping information is included in the prediction model by using group-based variable selection or group-specific penalization. We compare the performance of our new approaches with standard regularized regression via simulations. Based on these results we provide recommendations for selecting a strategy for building a prediction model given the specific goal of the analysis and the sizes of the datasets. Finally we illustrate the advantages of our approach by application of the methodology to two problems, namely prediction of body mass index in the DIetary, Lifestyle, and Genetic determinants of Obesity and Metabolic syndrome study (DILGOM) and prediction of response of each breast cancer cell line to treatment with specific drugs using a breast cancer cell lines pharmacogenomics dataset

Application thérapeutique potentielle de l’hypothermie par ventilation liquide

Therapeutic applications of hypothermic liquid ventilation. Therapeutic hypothermia is the intentional reduction of body core temperature of patients in order to increase the resistance to ischemic disorders, such as cardiac arrest. The benefit depends on the precocity of cooling following the onset of the ischemic episode. In order to elicit ultra-fast cooling, the lung can be used as a heat exchanger through the administration of liquid perfluorocarbons, which are able to support both gas and thermal exchanges. Experimental prototypes allow reducing the whole-body temperature to 32-34° C within only 15-20 min in rabbits, pigs or sheep. Such cooling does not depend upon body mass and generates potent neuro-and cardioprotective effects in animal models of global or focal ischemia. The development of such devices could allow testing the efficiency of this therapeutic approach in both human and veterinary medicine.L’hypothermie thérapeutique est la réduction de la température des patients afin d’augmenter leur résistance à une agression ischémique, notamment après un arrêt cardiaque. Le bénéfice dépend de la rapidité d’induction de l’hypothermie. Afin de déclencher un refroidissement rapide, il est possible d’utiliser expérimentalement le poumon comme échangeur thermique en lui administrant des liquides perfluorocarbones capables d’assurer les échanges gazeux tout en entrainant des échanges thermiques. Des prototypes expérimentaux permettent de réduire la température de l’ensemble de l’organisme jusqu’à 32-34° C en seulement 15 à 20 min chez des lapins, des porcs ou des brebis. Le refroidissement présente l’avantage de ne pas dépendre de la masse corporelle. Il engendre de puissants effets neuro-et cardio-protecteurs dans les modèles animaux d’arrêt cardiaque ou d’ischémie régionale. Le développement de tels dispositifs en clinique pourrait permettre de tester cette approche thérapeutique dans les situations critiques de réanimation en médecine humaine et vétérinaire.Tissier Renaud. Application thérapeutique potentielle de l’hypothermie par ventilation liquide. In: Bulletin de l'Académie Vétérinaire de France tome 169 n°3, 2016. pp. 201-207