Integrative multi-omics profiling in human decedents receiving pig heart xenografts

Nature Medicine, Journal Year: 2024, Volume and Issue: 30(5), P. 1448 - 1460

Published: May 1, 2024

Language: Английский

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Single-cell transcriptomics of the immune system in ME/CFS at baseline and following symptom provocation

Cell Reports Medicine, Journal Year: 2024, Volume and Issue: 5(1), P. 101373 - 101373

Published: Jan. 1, 2024

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious and poorly understood disease. To understand immune dysregulation in ME/CFS, we use single-cell RNA sequencing (scRNA-seq) to examine cells patient control cohorts. Postexertional malaise (PEM), an exacerbation of symptoms following strenuous exercise, characteristic symptom ME/CFS. detect changes coincident with PEM, applied scRNA-seq on the same cohorts exercise. At baseline, ME/CFS patients display classical monocyte suggestive inappropriate differentiation migration tissue. We identify both diseased more normal monocytes within patients, fraction correlates disease severity. Comparing transcriptome at baseline postexercise challenge, discover patterns indicative improper platelet activation minimal elsewhere system. Taken together, these data immunological defects present additional layer platelets.

Language: Английский

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Improving Outcomes After Post–Cardiac Arrest Brain Injury: A Scientific Statement From the International Liaison Committee on Resuscitation

Circulation, Journal Year: 2024, Volume and Issue: 150(7)

Published: June 27, 2024

This scientific statement presents a conceptual framework for the pathophysiology of post–cardiac arrest brain injury, explores reasons previous failure to translate preclinical data clinical practice, and outlines potential paths forward. Post–cardiac injury is characterized by 4 distinct but overlapping phases: ischemic depolarization, reperfusion repolarization, dysregulation, recovery repair. Previous research has been challenging because limitations laboratory models; heterogeneity in patient populations enrolled; overoptimistic estimation treatment effects leading suboptimal sample sizes; timing route intervention delivery; limited or absent evidence that engaged mechanistic target; postresuscitation care, prognostication, withdrawal life-sustaining treatments. Future trials must tailor their interventions subset patients most likely benefit deliver this at appropriate time, through route, dose. The complexity suggests monotherapies are unlikely be as successful multimodal neuroprotective therapies. Biomarkers should developed identify with targeted mechanism quantify its severity, measure response therapy. Studies need adequately powered detect effect sizes realistic meaningful patients, families, clinicians. Study designs optimized accelerate evaluation promising interventions. Multidisciplinary international collaboration will essential realize goal developing effective therapies injury.

Language: Английский

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A cell-free nutrient-supplemented perfusate allows four-day ex vivo metabolic preservation of human kidneys

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: May 13, 2024

Abstract The growing disparity between the demand for transplants and available donor supply, coupled with an aging population increasing prevalence of chronic diseases, highlights urgent need development platforms enabling reconditioning, repair, regeneration deceased organs. This necessitates ability to preserve metabolically active kidneys ex vivo days. However, current kidney normothermic machine perfusion (NMP) approaches allow metabolic preservation only hours. Here we show that human discarded transplantation can be preserved in a state up 4 days when perfused cell-free perfusate supplemented TCA cycle intermediates at subnormothermia (25 °C). Using spatially resolved isotope tracing demonstrate fluxes microenvironment Day perfusion. Beyond 4, significant changes were observed renal cell populations through spatial lipidomics, increases injury markers such as LDH, NGAL oxidized lipids. Finally, maintain functional parameters 4. Collectively, these findings provide evidence this approach enables over multiple days, establishing solid foundation future clinical investigations.

Language: Английский

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Cellular dynamics in pig-to-human kidney xenotransplantation

Med, Journal Year: 2024, Volume and Issue: 5(8), P. 1016 - 1029.e4

Published: May 21, 2024

Xenotransplantation of genetically engineered porcine organs has the potential to address challenge organ donor shortage. Two cases porcine-to-human kidney xenotransplantation were performed, yet physiological effects on xenografts and recipients' immune responses remain largely uncharacterized.

Language: Английский

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Improving Outcomes After Post–Cardiac Arrest Brain Injury: A Scientific Statement From the International Liaison Committee on Resuscitation

Resuscitation, Journal Year: 2024, Volume and Issue: 201, P. 110196 - 110196

Published: June 27, 2024

Language: Английский

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Metabolic Considerations in Direct Procurement and Perfusion Protocols with DCD Heart Transplantation

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(8), P. 4153 - 4153

Published: April 9, 2024

Heart transplantation with donation after circulatory death (DCD) provides excellent patient outcomes and increases donor heart availability. However, unlike conventional grafts obtained through brain death, DCD cardiac are not only exposed to warm, unprotected ischemia, but also a potentially damaging pre-ischemic phase withdrawal of life-sustaining therapy (WLST). In this review, we aim bring together knowledge about changes in energy metabolism its regulation that occur donors during WLST, arrest, following the onset warm ischemia. Acute metabolic, hemodynamic, biochemical expose hearts high circulating catecholamines, hypoxia, all which can negatively impact heart. Further metabolic cellular damage reperfusion. The altered substrate availability prior organ procurement likely plays an important role graft quality post-ischemic recovery. These aspects should, therefore, be considered clinical protocols, as well pre-clinical models. Notably, interventions limited for ethical reasons donors; thus, it is understand these mechanisms optimize conditions initial reperfusion concert evaluation re-evaluation purpose tailoring adjusting therapies ensuring optimal transplantation.

Language: Английский

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Single-nucleus RNA sequencing revealed the impact of post-mortem interval on the cellular component and gene expression analysis of mouse brains

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Abstract Accurate analysis of cell atlas and gene expression in biological tissues using single-nucleus RNA sequencing (snRNA-seq) is dependent on the quality source material, post-mortem interval (PMI) one major sources variation quality. Although use RNA-degraded transcriptome remains controversial, such samples are sometimes sole means to address specific questions. Current studies impact PMI data limited large-scale RNA-seq, which ignores cellular heterogeneity. Thus, deciphering non-cell- autonomous effects caused by imperative for understanding molecular disruption it elicits. Here, we investigated components snRNA-seq from mouse brain post-mortem. We collected that were allowed decay varying amounts time at 25°C prior snRNA-seq, covering entire range RIN values. The different degradation rate mRNA rRNA within nuclei, presented a more stable state. Multi-channel revealed preferential transient depletion oligodendrocytes OPCs with increasing PMI. In addition, rapid widespread overregulation ribosomal recruitment protein (RP) genes various cells, reached plateau 36h. state neuronal cells was not detected, reported significant upregulation PMI-dependent RP its subpopulations their loss. Moreover, showed greatest differential greater perturbation, speculated aberrant these might be associated death. this study, systematically changes profile tissue induced single-cell resolution, important factors responsible changes. our complemented possible explanation postmortem hypoxia-ischemia, provided reference samples.

Language: Английский

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The Heart Team Approach to Cardiac Arrest

European Heart Journal Supplements, Journal Year: 2025, Volume and Issue: 27(Supplement_4), P. iv31 - iv38

Published: Feb. 4, 2025

Abstract Cardiac arrest is a critical emergency in cardiovascular medicine, requiring rapid, multidisciplinary interventions to enhance patient survival and neurological outcomes. This review explores the unique challenges of managing out-of-hospital (OHCA) in-hospital cardiac (IHCA), with focus on mechanical circulatory support (MCS) extracorporeal cardiopulmonary resuscitation for selected patients. While OHCA management should prioritize rapid transport specialized centres, IHCA may allow immediate, patient-tailored interventions. Post-cardiac syndrome adds complexity, often nuanced MCS escalation weaning. Standardized protocols, ethical considerations, further research are essential refine selection improve outcomes, ultimately advancing care.

Language: Английский

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Advances and Challenges of Thrombolytic Therapy for Donation After Circulatory Death Organs

Clinical Transplantation, Journal Year: 2025, Volume and Issue: 39(2)

Published: Feb. 1, 2025

The demand for organ transplantation has exceeded the global supply of available organs. Donation after circulatory death (DCD) is considered an effective method to solve disparity between and organs, by expanding donor pool. However, DCD organs experience long-term damage caused warm ischemia (WI) microthrombosis diffuse intravascular coagulation. Unfortunately, because concerns about post-transplantation complications, most high-risk are discarded, resulting in wasted medical resources economic losses. thrombolytic therapy before may dissolve improve microcirculation, increase use. Herein, we review current status potential value transplantation, summarize progress according preclinical clinical research, emphasize heterogeneity limitations studies that have some controversies associated with this therapy. Overall, role should not be overlooked. We anticipate combined machine perfusion will provide opportunity inferior-quality grafts, their becoming more widely safer thus solving urgent problem shortage.

Language: Английский

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