132 research outputs found

    High-fat diet induces protein kinase A and G-protein receptor kinase phosphorylation of β2 -adrenergic receptor and impairs cardiac adrenergic reserve in animal hearts.

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    Key pointsPatients with diabetes show a blunted cardiac inotropic response to β-adrenergic stimulation despite normal cardiac contractile reserve. Acute insulin stimulation impairs β-adrenergically induced contractile function in isolated cardiomyocytes and Langendorff-perfused hearts. In this study, we aimed to examine the potential effects of hyperinsulinaemia associated with high-fat diet (HFD) feeding on the cardiac β2 -adrenergic receptor signalling and the impacts on cardiac contractile function. We showed that 8 weeks of HFD feeding leads to reductions in cardiac functional reserve in response to β-adrenergic stimulation without significant alteration of cardiac structure and function, which is associated with significant changes in β2 -adrenergic receptor phosphorylation at protein kinase A and G-protein receptor kinase sites in the myocardium. The results suggest that clinical intervention might be applied to subjects in early diabetes without cardiac symptoms to prevent further cardiac complications.AbstractPatients with diabetes display reduced exercise capability and impaired cardiac contractile reserve in response to adrenergic stimulation. We have recently uncovered an insulin receptor and adrenergic receptor signal network in the heart. The aim of this study was to understand the impacts of high-fat diet (HFD) on the insulin-adrenergic receptor signal network in hearts. After 8 weeks of HFD feeding, mice exhibited diabetes, with elevated insulin and glucose concentrations associated with body weight gain. Mice fed an HFD had normal cardiac structure and function. However, the HFD-fed mice displayed a significant elevation of phosphorylation of the β2 -adrenergic receptor (β2 AR) at both the protein kinase A site serine 261/262 and the G-protein-coupled receptor kinase site serine 355/356 and impaired adrenergic reserve when compared with mice fed on normal chow. Isolated myocytes from HFD-fed mice also displayed a reduced contractile response to adrenergic stimulation when compared with those of control mice fed normal chow. Genetic deletion of the β2 AR led to a normalized adrenergic response and preserved cardiac contractile reserve in HFD-fed mice. Together, these data indicate that HFD promotes phosphorylation of the β2 AR, contributing to impairment of cardiac contractile reserve before cardiac structural and functional remodelling, suggesting that early intervention in the insulin-adrenergic signalling network might be effective in prevention of cardiac complications in diabetes

    DAP12 Signaling Directly Augments Proproliferative Cytokine Stimulation of NK Cells during Viral Infections

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    Abstract NK cells vigorously proliferate during viral infections. During the course of murine CMV infection, this response becomes dominated by the preferential proliferation of NK cells that express the activation receptor Ly49H. The factors driving such selective NK cell proliferation have not been characterized. In this study, we demonstrate that preferential NK cell proliferation is dependent on DAP12-mediated signaling following the binding of Ly49H to its virally encoded ligand, m157. Ly49H signaling through DAP12 appears to directly augment NK cell sensitivity to low concentrations of proproliferative cytokines such as IL-15. The impact of Ly49H-mediated signaling on NK cell proliferation is masked in the presence of high concentrations of proproliferative cytokines that nonselectively drive all NK cells to proliferate

    DRAC: Diabetic Retinopathy Analysis Challenge with Ultra-Wide Optical Coherence Tomography Angiography Images

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    Computer-assisted automatic analysis of diabetic retinopathy (DR) is of great importance in reducing the risks of vision loss and even blindness. Ultra-wide optical coherence tomography angiography (UW-OCTA) is a non-invasive and safe imaging modality in DR diagnosis system, but there is a lack of publicly available benchmarks for model development and evaluation. To promote further research and scientific benchmarking for diabetic retinopathy analysis using UW-OCTA images, we organized a challenge named "DRAC - Diabetic Retinopathy Analysis Challenge" in conjunction with the 25th International Conference on Medical Image Computing and Computer Assisted Intervention (MICCAI 2022). The challenge consists of three tasks: segmentation of DR lesions, image quality assessment and DR grading. The scientific community responded positively to the challenge, with 11, 12, and 13 teams from geographically diverse institutes submitting different solutions in these three tasks, respectively. This paper presents a summary and analysis of the top-performing solutions and results for each task of the challenge. The obtained results from top algorithms indicate the importance of data augmentation, model architecture and ensemble of networks in improving the performance of deep learning models. These findings have the potential to enable new developments in diabetic retinopathy analysis. The challenge remains open for post-challenge registrations and submissions for benchmarking future methodology developments

    Status of Initiating Pattern of Hemodialysis: A Multi-center Study

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    This study was to evaluate the status of initiating pattern of hemodialysis (HD). Five hundred-three patients in 8 University Hospitals were included. Presentation mode (planned vs. unplanned), and access type (central venous catheters [CVC] vs. permanent access) at initiation of HD were evaluated, and the influence of predialysis care on determining the mode of HD and access type was also assessed. Most patients started unplanned HD (81.9%) and the most common initial access type was CVC (86.3%). The main reason for unplanned HD and high rate of CVC use was patient-related factors such as refusal of permanent access creation and failure to attend scheduled clinic appointments. Predialysis care was performed in 57.9% of patients and only 24.1% of these patients started planned HD and 18.9% used permanent accesses initially. Only a minority of patients initiated planned HD with permanent accesses in spite of predialysis care. To overcome this, efforts to improve the quality of predialysis care are needed

    Effect of shared decision-making education on physicians’ perceptions and practices of end-of-life care in Korea

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    Background Evidence of the ethical appropriateness and clinical benefits of shared decision-making (SDM) are accumulating. This study aimed to not only identify physicians’ perspectives on SDM, and practices related to end-of-life care in particular, but also to gauge the effect of SDM education on physicians in Korea. Methods A 14-item questionnaire survey using a modified Delphi process was delivered to nephrologists and internal medicine trainees at 17 university hospitals. Results A total of 309 physicians completed the survey. Although respondents reported that 69.9% of their practical decisions were made using SDM, 59.9% reported that it is not being applied appropriately. Only 12.3% of respondents had received education on SDM as part of their training. The main obstacles to appropriate SDM were identified as lack of time (46.0%), educational materials and tools (29.4%), and education on SDM (24.3%). Although only a few respondents had received training on SDM, the proportion of those who thought they were using SDM appropriately in actual practice was high; the proportion of those who chose lack of time and education as factors that hindered the proper application of SDM was low. Conclusion The majority of respondents believed that SDM was not being implemented properly in Korea, despite its use in actual practice. To improve the effectiveness of SDM in the Korean medical system, appropriate training programs and supplemental policies that guarantee sufficient application time are required

    A connectome and analysis of the adult Drosophila central brain.

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    The neural circuits responsible for animal behavior remain largely unknown. We summarize new methods and present the circuitry of a large fraction of the brain of the fruit fly Drosophila melanogaster. Improved methods include new procedures to prepare, image, align, segment, find synapses in, and proofread such large data sets. We define cell types, refine computational compartments, and provide an exhaustive atlas of cell examples and types, many of them novel. We provide detailed circuits consisting of neurons and their chemical synapses for most of the central brain. We make the data public and simplify access, reducing the effort needed to answer circuit questions, and provide procedures linking the neurons defined by our analysis with genetic reagents. Biologically, we examine distributions of connection strengths, neural motifs on different scales, electrical consequences of compartmentalization, and evidence that maximizing packing density is an important criterion in the evolution of the fly's brain

    Escape of Mutant Double-Stranded DNA Virus from Innate Immune Control

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    As innate immune system components, natural killer (NK) cells respond rapidly to infections and effectively control replication of pathogens, including murine cytomegalovirus (MCMV), a double-stranded DNA beta-herpesvirus. In the absence of NK cell control, MCMV infection results in early mortality due to uncontrolled viral replication. However, here we show that even in the face of initial NK cell control, there is late recrudescence of disease and mortality in immunodeficient mice due to the outgrowth of MCMV mutants that escape recognition by innate NK cells. These data suggest that viral infections in certain clinical settings also may be due to viral escape from innate immunity
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