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The adult heart is uniquely designed and equipped to provide a continuous supply of energy in the form of ATP to support persistent contractile function. This high-capacity energy transduction system is the result of a remarkable surge in mitochondrial biogenesis and maturation during the fetal-to-adult transition in cardiac development. Substantial evidence indicates that nuclear receptor signaling is integral to dynamic changes in the cardiac mitochondrial phenotype in response to developmental cues, in response to diverse postnatal physiologic conditions, and in disease states such as heart failure. A subset of cardiac-enriched nuclear receptors serve to match mitochondrial fuel preferences and capacity for ATP production with changing energy demands of the heart. In this Review, we describe the role of specific nuclear receptors and their coregulators in the dynamic control of mitochondrial biogenesis and energy metabolism in the normal and diseased heart., Brief overview of cardiac fuel and energy metabolism The adult mammalian heart has immense energy demands in order to support its role as a constantly active pump. Indeed, the human [...]

Intramuscular lipid accumulation is a common manifestation of chronic caloric excess and obesity that is strongly associated with insulin resistance. The mechanistic links between lipid accumulation in myocytes and insulin resistance are not completely understood. In this work, we used a high-throughput chemical biology screen to identify a small-molecule probe, SBI-477, that coordinately inhibited triacylglyceride (TAG) synthesis and enhanced basal glucose uptake in human skeletal myocytes. We then determined that SBI-477 stimulated insulin signaling by deactivating the transcription factor MondoA, leading to reduced expression of the insulin pathway suppressors thioredoxin-interacting protein (TXNIP) and arrestin domain-containing 4 (ARRDC4). Depleting MondoA in myocytes reproduced the effects of SBI-477 on glucose uptake and myocyte lipid accumulation. Furthermore, an analog of SBI-477 suppressed TXNIP expression, reduced muscle and liver TAG levels, enhanced insulin signaling, and improved glucose tolerance in mice fed a high-fat diet. These results identify a key role for MondoA-directed programs in the coordinated control of myocyte lipid balance and insulin signaling and suggest that this pathway may have potential as a therapeutic target for insulin resistance and lipotoxicity., Introduction The rising prevalence of obesity is driving an alarming increase in type 2 diabetes, a global health threat. Comorbidities associated with obesity include insulin resistance and fatty liver disease [...]

Introduction: The inherited hemoglobin disorders constitute a major public health problem. Facilitators (experienced hemoglobin counselors) were trained to deliver knowledge and skills to "frontline" practitioners to enable them to support parents during antenatal screening via a cascade (train-the-trainer) model. Objectives of evaluation were to explore the extent that the cascade model was perceived to be embedded in practice, identify enablers and barriers to effective cascading, assess the feasibility of incorporating e-learning into the model, and obtain the facilitators' perceptions of the change process. Methods: Focus groups and interviews were undertaken with 50 facilitators. Data were analyzed thematically. Results: Cascading was influenced by contextual factors operating in the work environment, especially workload, existing roles and responsibilities and adequate preparation. Facilitators' confidence and perceptions of success varied for individuals in the same workplace exposed to the same opportunities to receive and deliver training. Cascading could by enhanced by carefully selecting potential facilitators, training needs assessment to identify the knowledge and skills required by individuals, and follow-up to offer ongoing support. Discussion: Evaluation demonstrated the importance of contextual and individual factors to successful cascading and the feasibility of combining it with e-learning. Future evaluations should consider the perspectives of all stakeholders, namely managers, recipients of cascading and clients, and cost-effectiveness. (Contains 1 table.)

Mitochondrial homeostasis is critical for tissue health, and mitochondrial dysfunction contributes to numerous diseases, including heart failure. Here, we have shown that the transcription factor Kruppel-like factor 4 (KLF4) governs mitochondrial biogenesis, metabolic function, dynamics, and autophagic clearance. Adult mice with cardiac-specific Klf4 deficiency developed cardiac dysfunction with aging or in response to pressure overload that was characterized by reduced myocardial ATP levels, elevated ROS, and marked alterations in mitochondrial shape, size, ultrastructure, and alignment. Evaluation of mitochondria isolated from KLF4-deficient hearts revealed a reduced respiration rate that is likely due to defects in electron transport chain complex I. Further, cardiac- specific, embryonic Klf4 deletion resulted in postnatal premature mortality, impaired mitochondrial biogenesis, and altered mitochondrial maturation. We determined that KLF4 binds to, cooperates with, and is requisite for optimal function of the estrogen-related receptor/PPARγ coactivator 1 (ERR/PGC-1) transcriptional regulatory module on metabolic and mitochondrial targets. Finally, we found that KLF4 regulates autophagy flux through transcriptional regulation of a broad array of autophagy genes in cardiomyocytes. Collectively, these findings identify KLF4 as a nodal transcriptional regulator of mitochondrial homeostasis., Introduction The heart has an unrelenting need for energy throughout life to sustain contractile function. Despite its high-energy demand, the heart contains relatively low ATP reserves, and thus, a continual [...]

Palliative care patients often present to the emergency department (ED) for various reasons e.g., acute illness, pain, altered mental status, and complications of therapy. Many visits involve less severe etiologies e.g., dyspnea, constipation, fear as patients approach the end of life, which may be more effectively and efficiently managed outside of the ED. The objective of this study is to identify and assess the frequency of presenting complaints, primary diagnosis, triage acuity, need for admission, in an Irish setting. A single-center retrospective, observational study of palliative care patients presenting to a tertiary-care university hospital emergency department in Dublin, Ireland. Study subjects were identified using the palliative care database and cross-referencing with the ED electronic patient record system database. The primary objective to identify potential areas to minimize ED visits and improve patient care and quality of life by elucidating reasons for visits. Outcome measures include presenting complaint, primary diagnosis, triage severity score, admission, discharge, death in hospital. Statistical analysis presented as descriptive statistics. Four-hundred-ninety-nine ED visits, 245 (49%) were male, and 254 (51%) were female with a mean age of 69.3 years-of-age. Most patients, 285 (57.1%) self-referred to the emergency department, with general practitioners and skilled nursing facility referrals 72 (14.4%) and 39 (7.8%), respectively. Primary diagnoses were various cancers, chronic obstructive pulmonary disease, congestive heart failure, and dementia. Major reasons for visits were dyspnea, pain, falls, trauma, fever, and altered mental status. Two-hundred-eighty-nine patients (58%) had an emergency severity index (ESI) score of 1 or 2 demonstrating a higher level of acuity. Three-hundred-fifty-eight (71.7%) were admitted, 141 (28.3%) discharged to home, 64 (12.8%) admitted patients died during their hospital admission. Palliative care patients utilize ED services not uncommonly. Though many of these patients presented with higher acuity triage scores, 42% had lower ESI scores and may be effectively managed outside of the ED. These data suggest developing mechanisms for these patients to be urgently evaluated in their homes or facilities obviating the need for an ED evaluation. [ABSTRACT FROM AUTHOR]

Since the recent observation that immune cells undergo metabolic reprogramming upon activation, there has been immense research in this area to not only understand the basis of such changes, but also to exploit metabolic rewiring for therapeutic benefit. In a resting state, macrophages preferentially utilise oxidative phosphorylation to generate energy; however, in the presence of immune cell activators, glycolytic genes are upregulated, and energy is generated through glycolysis. This facilitates the rapid production of biosynthetic intermediates and a pro-inflammatory macrophage phenotype. While this is essential to mount responses to infectious agents, more evidence is accumulating linking dysregulated metabolism to inappropriate immune responses. Given that certain biomaterials are known to promote an inflammatory macrophage phenotype, this prompted us to investigate if biomaterial particulates can impact on macrophage metabolism. Using micron and nano sized hydroxyapatite (HA), we demonstrate for the first time that these biomaterials can indeed drive changes in metabolism, and that this occurs in a size-dependent manner. We show that micronHA, but not nanoHA, particles upregulate surrogate markets of glycolysis including the glucose transporter (GLUT1), hexokinase 2 (HK2), GAPDH, and PKM2. Furthermore, we demonstrate that micronHA alters mitochondrial morphology and promotes a bioenergetic shift to favour glycolysis. Finally, we demonstrate that glycolytic gene expression is dependent on particle uptake and that targeting glycolysis attenuates the pro-inflammatory profile of micronHA-treated macrophages. These results not only further our understanding of biomaterial-based macrophage activation, but also implicate immunometabolism as a new area for consideration in intelligent biomaterial design and therapeutic targeting. Several recent studies have reported that immune cell activation occurs concurrently with metabolic reprogramming. Furthermore, metabolic reprogramming of innate immune cells plays a prominent role in determining cellular phenotype and function. In this study we demonstrate that hydroxyapatite particle size alters macrophage metabolism, in turn driving their functional phenotype. Specifically, the pro-inflammatory phenotype promoted by micron-sized HA-particles is accompanied by changes in mitochondrial dynamics and a bioenergetic shift favouring glycolysis. This effect is not seen with nano-HA particles and can be attenuated upon inhibition of glycolysis. This study therefore not only identifies immunometabolism as a useful tool for characterising the immune response to biomaterials, but also highlights immunometabolism as a targetable aspect of the host response for therapeutic benefit. [Display omitted] [ABSTRACT FROM AUTHOR]

The meniscus is characterised by an anisotropic collagen fibre network which is integral to its biomechanical functionality. The engineering of structurally organized meniscal grafts that mimic the anisotropy of the native tissue remains a significant challenge. In this study, inkjet bioprinting was used to deposit a cell-laden bioink into additively manufactured scaffolds of differing architectures to engineer fibrocartilage grafts with user defined collagen architectures. Polymeric scaffolds consisting of guiding fibre networks with varying aspect ratios (1:1; 1:4; 1:16) were produced using either fused deposition modelling (FDM) or melt electrowriting (MEW), resulting in scaffolds with different internal architectures and fibre diameters. Scaffold architecture was found to influence the spatial organization of the collagen network laid down by the jetted cells, with higher aspect ratios (1:4 and 1:16) supporting the formation of structurally anisotropic tissues. The MEW scaffolds supported the development of a fibrocartilaginous tissue with compressive mechanical properties similar to that of native meniscus, while the anisotropic tensile properties of these constructs could be tuned by altering the fibre network aspect ratio. This MEW framework was then used to generate scaffolds with spatially distinct fibre patterns, which in turn supported the development of heterogenous tissues consisting of isotropic and anisotropic collagen networks. Such bioprinted tissues could potentially form the basis of new treatment options for damaged and diseased meniscal tissue. This study describes a multiple tool biofabrication strategy which enables the engineering of spatially organized fibrocartilage tissues. The architecture of MEW scaffolds can be tailored to not only modulate the directionality of the collagen fibres laid down by cells, but also to tune the anisotropic tensile mechanical properties of the resulting constructs, thereby enabling the engineering of biomimetic meniscal-like tissues. Furthermore, the inherent flexibility of MEW enables the development of zonally defined and potentially patient-specific implants. [Display omitted] [ABSTRACT FROM AUTHOR]