RESUMO
Mechanical load is one of the main determinants of cardiac structure and function. Mechanical load is studied in vitro using cardiac preparations together with loading protocols (e.g., auxotonic, isometric). However, such studies are often limited by reductionist models and poorly simulated mechanical load profiles. This hinders the physiological relevance of findings. Living myocardial slices have been used to study load in vitro. Living myocardial slices (LMS) are 300-µm-thick intact organotypic preparations obtained from explanted animal or human hearts. They have preserved cellular populations and the functional, structural, metabolic and molecular profile of the tissue from which they are prepared. Using a three-element Windkessel (3EWK) model we previously showed that LMSs can be cultured while performing cardiac work loops with different preload and afterload. Under such conditions, LMSs remodel as a function of the mechanical load applied to them (physiological load, pressure or volume overload). These studies were conducted in commercially available length actuators that had to be extensively modified for culture experiments. In this paper, we demonstrate the design, development and validation of a novel device, MyoLoop. MyoLoop is a bioreactor that can pace, thermoregulate, acquire and process data, and chronically load LMSs and other cardiac tissues in vitro. In MyoLoop, load is parametrised using a 3EWK model, which can be used to recreate physiological and pathological work loops and the remodelling response to these. We believe MyoLoop is the next frontier in basic cardiovascular research enabling reductionist but physiologically relevant in vitro mechanical studies.
Assuntos
Reatores Biológicos , Coração , Animais , Humanos , Miocárdio , Projetos de PesquisaRESUMO
A retrospective cohort study of patients undergoing laparoscopic inguinal hernia repair compared short- and long-term outcomes between individuals with or without history of previous abdominopelvic surgery, aiming to determine the feasibility of totally extraperitoneal (TEP) repair within this population. All patients who underwent elective TEP inguinal hernia repair by one consultant surgeon across three London hospitals from January 2017 to May 2023 were retrospectively analysed to assess perioperative outcomes. Two hundred sixty-two patients were identified, of whom two hundred forty-three (93%) underwent laparoscopic TEP repair. The most frequent complications were haematoma (6.2%) and seroma (4.1%). Recurrence occurred in four cases (1.6% of operations, 1.1% of hernias). One hundred eighty-four patients (76%) underwent day-case surgery. There were no mesh infections or explanations, vascular or visceral injuries, port-site hernias, damage to testicle, or persisting numbness. There were no requirements for blood transfusion, returns to theatre, or readmissions within 30 days. There was one conversion to open and one death within 60 days of surgery. Eighty-three (34%) had a history of previous AP surgery. There was no significant difference in perioperative outcomes between the AP and non-AP arms. This finding carried true for subgroup analysis of 44 patients whose AP surgical history did not include previous inguinal hernia repair and for those undergoing repair of recurrent hernia. In expert hands, laparoscopic TEP repair is associated with excellent outcomes and low rates of long-term complications, and thus should be considered as standard for patients regardless of a history of AP surgery.
RESUMO
Congenital heart disease (CHD) is the most prevalent hereditary disorder, affecting approximately 1% of all live births. A reduction in morbidity and mortality has been achieved with advancements in surgical intervention, yet challenges in managing complications, extracardiac abnormalities, and comorbidities still exist. To address these, a more comprehensive understanding of the genetic basis underlying CHD is required to establish how certain variants are associated with the clinical outcomes. This will enable clinicians to provide personalized treatments by predicting the risk and prognosis, which might improve the therapeutic results and the patient's quality of life. We review how advancements in genome sequencing are changing our understanding of the genetic basis of CHD, discuss experimental approaches to determine the significance of novel variants, and identify barriers to use this knowledge in the clinics. Next-generation sequencing technologies are unravelling the role of oligogenic inheritance, epigenetic modification, genetic mosaicism, and noncoding variants in controlling the expression of candidate CHD-associated genes. However, clinical risk prediction based on these factors remains challenging. Therefore, studies involving human-induced pluripotent stem cells and single-cell sequencing help create preclinical frameworks for determining the significance of novel genetic variants. Clinicians should be aware of the benefits and implications of the responsible use of genomics. To facilitate and accelerate the clinical integration of these novel technologies, clinicians should actively engage in the latest scientific and technical developments to provide better, more personalized management plans for patients.
La cardiopathie congénitale (CC) est l'affection héréditaire la plus commune, soit environ 1 naissance vivante sur 100. Grâce aux progrès réalisés en chirurgie cardiaque, il a été possible de réduire la morbidité et la mortalité associées à la CC, mais les complications, les anomalies extracardiaques et les affections concomitantes demeurent préoccupantes. Dans ce contexte, il est nécessaire de mieux comprendre les fondements génétiques de la CC pour déterminer les variants qui sont à l'origine des complications cliniques. Les cliniciens pourront ainsi proposer des traitements personnalisés en tenant compte du risque et du pronostic dans l'espoir d'améliorer les résultats thérapeutiques et la qualité de vie des patients. Nous revenons ici sur les avancées réalisées dans le séquençage du génome et sur la façon dont elles ont changé notre compréhension des fondements génétiques de la CC. Nous décrivons les techniques expérimentales utilisées pour mettre au jour de nouveaux variants d'intérêt et présentons les obstacles qui empêchent d'utiliser ces connaissances en clinique. Les techniques de séquençage de nouvelle génération permettent de lever le voile sur le rôle de la transmission oligogénique, de la modification épigénétique, de la mosaïque génétique et des variants non codants dans la régulation de l'expression des gènes candidats associés à la CC. La prédiction du risque clinique en fonction de ces facteurs demeure toutefois hasardeuse. Les études sur les cellules souches pluripotentes induites et le séquençage unicellulaire aident à établir le cadre préclinique nécessaire pour déterminer l'importance des nouveaux variants génétiques. Les cliniciens doivent être conscients des bienfaits et de la portée que peut avoir la génomique lorsqu'elle est utilisée de façon responsable. Pour faciliter et accélérer l'intégration clinique de ces nouvelles technologies, les cliniciens doivent s'intéresser de près aux derniers développements scientifiques et techniques s'ils veulent un jour proposer à leurs patients un plan de traitement plus pertinent et plus personnalisé.