Evaluation of bone excision effects on a human skull model - I: Mechanical testing and digital image correlation.

The mechanisms of skull impact loading may change following surgical interventions such as the removal of bone lesions, but little is known about the consequences in the event of subsequent head trauma. We, therefore, prepared acrylonitrile butadiene styrene human skull models based on clinical computed tomography skull data using a three-dimensional printer. Six replicate physical skull models were tested, three with bone excisions and three without. A drop tower was used to simulate the impact sustained by falling backwards onto the occipital lobe region. The impacts were recorded with a high-speed camera, and the occipital strain response was determined by digital image correlation. Although the hole affected neither the magnitude nor the sequence of the fracture pattern, the digital image correlation analysis highlighted an increase in strain around the excised area (0.45%–16.4% of the principal strain). Our approach provides a novel method that could improve the quality of life for patients on many fronts, including protection against trauma, surgical advice, post-operative care, advice in litigation cases, as well as facilitating general biomechanical research in the area of trauma injuries

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Influence de l'acide eicosapentaénoïque sur l'activité cardiaque et sa modulation par le stress oxydant - Perspectives pour l'obésité et l'endocardite aigüe humaines

Cardiovascular disease is the leading cause of death in the world. Many situations trigger heart failure which is usually associated with mitochondrial dysfunction. Oxidative stress is a major contributor to these dysfunctions. Polyunsaturated fatty acids of the 3 family, in particular EPA, have often been associated with cardioprotective effects, but in some cases their impact is deleterious. The hypothesis behind this thesis is that EPA becomes harmful in situations in which the oxidative stress is too high: an appropriate combination with an antioxidant would maintain the cardio-protective properties. Several models of pathological situations characterized by a low or severe and chronic oxidative stress were studied. EPA displays beneficial effects on the heart by modulating collagen, coronary reactivity, mitochondrial function, oxidative status, inflammation, energy metabolism, calcium homeostasis and lipid profile. However, in case of a high and chronic oxidative stress triggered by diabetes mellitus and an obesogenic diet, EPA results in a dramatic increase in animal mortality. This effect is countered by enriching the diet with green tea extract thanks to the antioxidant and lipid-lowering properties of this last. The combination of EPA with an antioxidant adapted to the situation and administered in adequate doses is essential when the oxidative stress is severe enough to induce lipid peroxidation. The beneficial impact of EPA is related to mitochondrial actors such as SOD2, UCP3 and Sirt3. The findings obtained in these animal studies need to be verified in humans to determine whether the cardioprotective effect of EPA combined with an antioxidant is maintained. This thesis also describes a reliable method allowing the extraction of human cardiac mitochondria from atrial rejection obtained during extracorporeal circulation. Omic studies on the plasma would also allow the discovery of new biomarkers of mitochondrial function permitting clinicians to highlight possible dysfunctions prior to onset of the heart failure and to adapt a precocious treatment to the particular patient situation.Les maladies cardiovasculaires constituent la première cause de mortalité dans le monde. De nombreuses situations conduisent à une insuffisance cardiaque généralement associée à une altération mitochondriale. Le stress oxydant est un acteur majeur favorisant ces dysfonctionnements. Les acides gras polyinsaturés de la famille 3 et, en particulier l’EPA, ont été souvent associés à des effets cardio-protecteurs. Cependant, dans certains cas, l’impact engendré était délétère. L’hypothèse qui a porté cette thèse soutient que l’EPA devient nocif dans les situations où le stress oxydant est trop intense : l’association avec un agent antioxydant adapté permettrait de maintenir les propriétés cardioprotectrices. Divers modèles de situations pathologiques, d’un stress oxydant faible vers une situation où il est sévère et chronique, ont été étudiés. L’EPA a montré des effets bénéfiques pour le cœur en modulant le collagène, la réactivité coronaire, la fonction mitochondriale, le statut oxydant, l’inflammation, le métabolisme énergétique, l’homéostasie calcique et le profil lipidique. Cependant, dans le cas d’un stress oxydant intense et chronique modélisé par un diabète sucré associé à un régime obésogène, l’EPA a entraîné un accroissement radical de la mortalité. Cet effet a été contrecarré par un enrichissement en extrait de thé vert grâce aux propriétés anti oxydantes et hypolipémiantes de ce dernier. L’association de l’EPA à un agent antioxydant adapté à la situation et administré à doses adéquates est indispensable dans les situations où le stress oxydant est suffisamment sévère pour induire une peroxydation lipidique. L’impact bénéfique de l’EPA est lié à des acteurs mitochondriaux tels que la SOD2, l’UCP3 et la Sirt3. Les observations récoltées au cours de ces travaux nous incitent à étudier la fonction mitochondriale chez l’Homme afin de déterminer si l’effet cardioprotecteur de l’EPA combiné à un antioxydant est maintenu. Cette thèse décrit également une méthode fiable pour extraire des mitochondries cardiaques humaines à partir de rejections atriales obtenues lors de circulations extracorporelles. Des analyses omiques sur le plasma permettraient également de découvrir des biomarqueurs du fonctionnement mitochondrial permettant la mise en lumière d’altérations éventuelles survenant en amont du développement de l’insuffisance cardiaque et l’adaptation précoce d’un traitement adéquat

Influence of eicosapentaenoic acid on cardiac activity and its modulation by oxidative stress - Prospects for obesity and acute endocarditis in human

Les maladies cardiovasculaires constituent la première cause de mortalité dans le monde. De nombreuses situations conduisent à une insuffisance cardiaque généralement associée à une altération mitochondriale. Le stress oxydant est un acteur majeur favorisant ces dysfonctionnements. Les acides gras polyinsaturés de la famille 3 et, en particulier l’EPA, ont été souvent associés à des effets cardio-protecteurs. Cependant, dans certains cas, l’impact engendré était délétère. L’hypothèse qui a porté cette thèse soutient que l’EPA devient nocif dans les situations où le stress oxydant est trop intense : l’association avec un agent antioxydant adapté permettrait de maintenir les propriétés cardioprotectrices. Divers modèles de situations pathologiques, d’un stress oxydant faible vers une situation où il est sévère et chronique, ont été étudiés. L’EPA a montré des effets bénéfiques pour le cœur en modulant le collagène, la réactivité coronaire, la fonction mitochondriale, le statut oxydant, l’inflammation, le métabolisme énergétique, l’homéostasie calcique et le profil lipidique. Cependant, dans le cas d’un stress oxydant intense et chronique modélisé par un diabète sucré associé à un régime obésogène, l’EPA a entraîné un accroissement radical de la mortalité. Cet effet a été contrecarré par un enrichissement en extrait de thé vert grâce aux propriétés anti oxydantes et hypolipémiantes de ce dernier. L’association de l’EPA à un agent antioxydant adapté à la situation et administré à doses adéquates est indispensable dans les situations où le stress oxydant est suffisamment sévère pour induire une peroxydation lipidique. L’impact bénéfique de l’EPA est lié à des acteurs mitochondriaux tels que la SOD2, l’UCP3 et la Sirt3. Les observations récoltées au cours de ces travaux nous incitent à étudier la fonction mitochondriale chez l’Homme afin de déterminer si l’effet cardioprotecteur de l’EPA combiné à un antioxydant est maintenu. Cette thèse décrit également une méthode fiable pour extraire des mitochondries cardiaques humaines à partir de rejections atriales obtenues lors de circulations extracorporelles. Des analyses omiques sur le plasma permettraient également de découvrir des biomarqueurs du fonctionnement mitochondrial permettant la mise en lumière d’altérations éventuelles survenant en amont du développement de l’insuffisance cardiaque et l’adaptation précoce d’un traitement adéquat.Cardiovascular disease is the leading cause of death in the world. Many situations trigger heart failure which is usually associated with mitochondrial dysfunction. Oxidative stress is a major contributor to these dysfunctions. Polyunsaturated fatty acids of the 3 family, in particular EPA, have often been associated with cardioprotective effects, but in some cases their impact is deleterious. The hypothesis behind this thesis is that EPA becomes harmful in situations in which the oxidative stress is too high: an appropriate combination with an antioxidant would maintain the cardio-protective properties. Several models of pathological situations characterized by a low or severe and chronic oxidative stress were studied. EPA displays beneficial effects on the heart by modulating collagen, coronary reactivity, mitochondrial function, oxidative status, inflammation, energy metabolism, calcium homeostasis and lipid profile. However, in case of a high and chronic oxidative stress triggered by diabetes mellitus and an obesogenic diet, EPA results in a dramatic increase in animal mortality. This effect is countered by enriching the diet with green tea extract thanks to the antioxidant and lipid-lowering properties of this last. The combination of EPA with an antioxidant adapted to the situation and administered in adequate doses is essential when the oxidative stress is severe enough to induce lipid peroxidation. The beneficial impact of EPA is related to mitochondrial actors such as SOD2, UCP3 and Sirt3. The findings obtained in these animal studies need to be verified in humans to determine whether the cardioprotective effect of EPA combined with an antioxidant is maintained. This thesis also describes a reliable method allowing the extraction of human cardiac mitochondria from atrial rejection obtained during extracorporeal circulation. Omic studies on the plasma would also allow the discovery of new biomarkers of mitochondrial function permitting clinicians to highlight possible dysfunctions prior to onset of the heart failure and to adapt a precocious treatment to the particular patient situation

Effets d'un extrait de thé vert alimentaire sur les fonctions cardiaque et mitochondriale chez le rat rendu diabétique par injection de streptozotocine et par un régime riche en graisses

Matériel et méthodes: Des rats mâles ont été subdivisés en 3 groupes de 10 animaux. Chaque groupe a été nourri avec un régime alimentaire spécifique: le groupe contrôle (GC) a reçu un régime conventionnel (A04, Safe) et les deux groupes diabétiques ont été nourris avec un régime riche en graisses (32% de beurre anhydre + 3% d'huile de soja). Le groupe diabétique (GD) n'a reçu aucun complément alimentaire et le groupe diabétique + thé (GDT) a été supplémenté avec un extrait de thé vert (0,5%). Après 3 semaines, les groupes diabétiques ont été traités avec de la streptozotocine (STZ, 33 mg/kg). Le poids et la composition corporels ainsi que la glycémie ont été évalués régulièrement pendant les 6 semaines qui ont suivi la STZ. A la fin de cette période, les coeurs ont été perfusés pour évaluer l'activité mécanique du myocarde et la fonction des micro-vaisseaux coronaires (vasodilatations endothéliale- et non endothéliale-dépendantes: VED et VNED). Les mitochondries cardiaques ont été extraites et leurs capacités oxydatives ont été déterminées. Les teneurs en lipides plasmatiques et la composition en acides gras des phospholipides cardiaques ont également été évaluées.Résultats et Analyse statistique : Avant la STZ, les RRG ont accru le gain de masse corporelle. Ceci s'est expliqué par une augmentation considérable de la masse grasse. Dès le 3ème jour après la STZ, la glycémie a été augmentée de facon durable à une valeur avoisinnant 4 g/l (1 g/l dans le GC). L'hyperglycémie s'est traduite par une baisse importante des masses corporelles (totale, grasse et maigre). La baisse de masse grasse s'est avérée plus ample dans le GDT par rapport au GD. Au moment du sacrifice, le diabète a fortement augmenté la triglycéridémie et le thé vert a complètement corrigé cette augmentation. L'activité contractile du myocarde n'a pas été modifiée significativement. En revanche, les VED et VNED ont été diminuées par le diabète. Le thé vert a partiellement corrigé la VED. Du point de vue mitochondrial, le diabète a réduit les état 3 respiratoires du glutamate/malate et du succinate/roténone sans que le thé vert n'améliore la situation. Il a également accru l'index de contrôle respiratoire du palmitoylcarnitine/malate, ce que le thé vert a encore amplifié. Enfin, la composition en acides gras des phospholipides cardiaques a montré que l'acide docosahexaénoique a été réduit dans les groupes diabétiques par rapport au GC.Conclusion: Nos résultats montrent que le diabète altère la fonction des micro-vaisseaux coronaires sans modifier significativement l'activité mécanique du coeur. Pourtant, il dégrade certains paramètres de l'activité mitochondriale. Malgré ses propriétés antioxydantes, l'extrait de thé vert ne parvient pas à améliorer de façon significative les divers paramètres des activités cardiaque et mitochondriale. Il réduit néanmois les triglycérides circulants de façon considérable et ceci pourrait protéger l'organisme vis-à-vis de l’athérosclérose

Impact sur les fonctions mécanique et mitochondriale cardiaques de l’acide eicosapentaénoïque alimentaire en situation de sepsis précoce

Impact sur les fonctions mécanique et mitochondriale cardiaques de l’acide eicosapentaénoïque alimentaire en situation de sepsis précoce. Journée Scientifique du CRNH Auvergn

Hepatitis C virus infection with peripheral neuropathy is not always associated with cryoglobulinaemia

OBJECTIVES—To describe cases of peripheral neuropathy associated with chronic hepatitis C virus infection without mixed cryoglobulinaemia.
METHODS—Four cases of peripheral neuropathy associated with chronic hepatitis C virus infection with persistent negativity of mixed cryoglobulinaemia were found.
RESULTS—All patients had small increases of transaminase levels and a positive viraemia. Liver biopsy showed chronic active hepatitis in all but one case (Knodell 4-9, Metavir A0F0-A3F3). Neuromuscular biopsy showed axonal neuropathy associated with lymphoid infiltrates around small vessels in two cases. Rheumatoid factor was always negative and C4 complement level was always normal. In three patients, neuropathy improved with interferon α, interferon α + ursodesoxycholic acid, or steroids + plasma exchange.
CONCLUSION—Peripheral neuropathy may be associated with hepatitis C virus infection without mixed cryoglobulinaemia.


Cardiac MRI assessment of the effects of dietary Eicosapentaenoic acid (EPA) on the adverse consequences of sepsis

SynopsisSevere sepsis is one of the leading cause of death in the intensive care units (ICU) or in short time after discharge from ICU. Developing a rat model of early sepsis involving caecal ligation and puncture, we undertaken this cardiac MRI study to quantitatively assess myocardial function and the protective effect of dietary EPA. Our results showed that, in the exception of the rate of contraction, cardiac functions are less impacted in the early hyperdynamic phase of sepsis with no/or milder modulation of dietary EPA.IntroductionSevere sepsis is a serious syndrome requiring adequate medical care. It results in multi-organ damage with a significant toxicity: during the early phase of sepsis, cardiac mechanical activity is increased, but it progressively declines until cardiac failure. In the Western societies, the consumption of omega6 (w6) polyunsaturated fatty acids (PUFA) is too high whereas that of omega3 (w3) PUFA is too low. Yet the consequences of sepsis could be altered by dietary PUFA which modulate the inflammatory process. The aim of this study was to determine the effects of dietary eicosapentaenoic acid (EPA or C20:5 w3) on the adverse cardiac consequences of sepsis.MaterialsFemale Wistar rats (n = 32) were fed with a diet deficient in w3 PUFA (n=16) or with a regime enriched with EPA (n=16) (187 mg/day) for 14 days. Each group was then submitted (n=8) or not to sepsis by caecal ligation and puncture (n=8). 48h after the surgical intervention, the animals were anaesthetized with isofurane for cardiac MR imaging.MethodsHigh resolution cine MR imaging was carried out at 11.7T (500MHz) with a 72-mm inner diameter volume coil. Ten to 12 contiguous 1-mm slices were acquired to cover the heart from the base to the apex using short-axis left ventricular (LV) bright blood cine imaging protocol based on the navigator self-gated FLASH sequence (repetition time (TR) / echo time (TE) 6/2.5 ms, flip angle (FA) 8 degrees, field of view (FOV) 5x5 cm, matrix 256x256, slice thickness 1 mm, oversampling 400). 16 movie frames were reconstructed per slice. After imaging session, rats were euthanized and the heart removed for analysis of mitochondrial function. Image analysis was performed using software Segment [1]. Semi-automatic segmentation of the LV was performed as described in [2] to obtain morphological and functional parameters, e.g., end diastolic volume (EDV), end systolic volume (ESV), ejection fraction (EF), heart rate (HR) and cardiac output (CO), along with the contraction and relaxation rates, which were derived from the time evolution of EDV.ResultsFigure 1 show an example of segmentation results allowing the determination of the rates of contraction and relaxation. Sepsis did not alter significantly the EDV, ESV, EF, HR and CO. The rate of relaxation was not modified by the pathologic event either (Figure 2). However, the speed of contraction tended to be increased (p = 0.085) with the sample size used in the present study. Dietary EPA had no noticeable influence on the parameters of cardiac morphology and function. In omega-3 deficient animals, early sepsis induced an alteration of mitochondrial function in sepsis compared with control rats: i) drop in mitochondrial respiration (p <0.001); ii) decline in ATP production (p <0.05); iii) increased release of ROS (p <0.05). This difference according to the operation undergone is not found in EPA animals.Discussion and conclusionThat sepsis tended to increase the rate of contraction indicates that the pathology was in its early hyperdynamic phase with an activation of cardiac function. Since in omega-3 deficient animals, early sepsis induced drop in mitochondrial respiration (p <0.001) in sepsis compared to control rats, with no difference observed in EPA animals, the absence of difference in MRI global cardiac functions may attributed either the anesthesia or to the early state of sepsis not perceptible in MRI

Evaluation of tire tread particle toxicity to fish using rainbow trout cell lines

Tire and road wear particles (TRWP) resulting from tire abrasion while driving raise concerns due to their potential contribution to aquatic toxicity. Our study aimed to assess cryogenically milled tire tread (CMTT) particle toxicity, used as a proxy for TRWP, and associated chemicals to fish using two Rainbow Trout (Oncorhynchus mykiss) cell lines representing the gill (RTgill-W1) and the intestinal (RTgutGC) epithelium. CMTT toxicity was evaluated through several exposure pathways, including direct contact, leaching, and digestion, while also assessing the impact of particle aging. Following OECD TG249, cell viability was assessed after 24 h acute exposure using a multiple-endpoint assay indicative of cell metabolic activity, membrane integrity and lysosome integrity. In vitro EC50 values for the fish cell lines exceeded river TRWP concentrations (2.02 g/L and 4.65 g/L for RTgill-W1 and RTgutGC cell lines, respectively), and were similar to in vivo LC50 values estimated at 6 g/L. Although toxicity was mainly driven by the leaching of tire-associated chemicals, the presence of the particles contributed to the overall toxicity by inducing a continuous leaching, highlighting the importance of considering combined exposure scenarios. Aging and digestion conditions were also found to mediate CMTT toxicity. Thermooxidation resulted in a decreased chemical leaching and toxicity, while in vitro digestion under mimicked gastrointestinal conditions increased leaching and toxicity. Specific chemicals, especially Zn, 2-mercaptobenzothiazole, 1,3-diphenylguanidine, and N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD) were identified as contributors to the overall toxicity. Although 6PPD-quinone was detected in CMTT digestate, cytotoxicity assays with RTgill-W1 and RTgutGC cell lines showed no toxicity up to 6 mg/L, supporting the notion of a specific mode of action of this chemical. This study provides insights into the toxicological mechanisms induced by tire particles and their associated chemicals and can help in the evaluation of potential risks to aquatic life associated with TRWP.ISSN:0048-9697ISSN:1879-102