Invasive devices to monitor the intraspinal perfusion pressure in the hemodynamic management of acute spinal cord injury: A systematic scoping review.

BACKGROUND: Various methods for measuring intrathecal pressure (ITP) after spinal cord injury (SCI) to guide hemodynamic management have been investigated. To synthesize the current literature, this current study conducted a scoping review of the use of intrathecal devices to monitor ITP during acute management of SCI with the aim of understanding the association between ITP monitoring with physiological and clinical outcomes. METHODS: A systematic review of literature following the Cochrane Handbook for Systematic Reviews of Interventions and Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement. All eligible studies were screened for inclusion and exclusion criteria. Data extracted included number of patients included, severity of injury, characteristics of the intervention-intrathecal device used to record the ITP, outcomes -hemodynamic parameters observed, changes in the American Spinal Injury Association (ASIA) Impairment Scale (AIS), total motor scores, association of ITP with other physiological variables. RESULTS: The search yielded a total of 1,698 articles, of which 30 observational studies and 2 randomized clinical trials were deemed eligible based on their use of an intrathecal invasive device to monitor spinal cord perfusion pressure (SCPP) in patients with SCI. Of these, 9 studies used a lumbar drain, 23 a Codman pressure probe and 1 study that used both. These studies underscore the crucial interplay between ITP, the SCPP and physiological variables, with neurological outcome. It is still unclear whether monitoring from a lumbar drain is accurate enough to highlight what is occurring at the site of SCI, which is the main advantage of Codman Probe, however, the latter requires specialized personnel that may not be available in most settings. Minor adverse effects were associated with lumbar drain catheters, while cerebrospinal fluid leak requiring repair (~ 7%) is the main concern with Codman Probes. CONCLUSION: Future investigation of SCPP protocols via lumbar drains and Codman probes ought to involve multi-centered randomized controlled trials and continued translational investigation with animal models.

Obesity accelerates endothelial-to-mesenchymal transition in adipose tissues of mice and humans.

Introduction: Vascular dysfunction and chronic inflammation are characteristics of obesity-induced adipose tissue dysfunction. Proinflammatory cytokines can drive an endothelial-to-mesenchymal transition (EndoMT), where endothelial cells undergo a phenotypic switch to mesenchymal-like cells that are pro-inflammatory and pro-fibrotic. In this study, we sought to determine whether obesity can promote EndoMT in adipose tissue. Methods: Mice in which endothelial cells are lineage-traced with eYFP were fed a high-fat/high-sucrose (HF/HS) or Control diet for 13, 26, and 52 weeks, and EndoMT was assessed in adipose tissue depots as percentage of CD45-CD31-Acta2+ mesenchymal-like cells that were eYFP +. EndoMT was also assessed in human adipose endothelial cells through cell culture assays and by the analysis of single cell RNA sequencing datasets obtained from the visceral adipose tissues of obese individuals. Results: Quantification by flow cytometry showed that mice fed a HF/HS diet display a time-dependent increase in EndoMT over Control diet in subcutaneous adipose tissue (+3.0%, +2.6-fold at 13 weeks; +10.6%, +3.2-fold at 26 weeks; +11.8%, +2.9-fold at 52 weeks) and visceral adipose tissue (+5.5%, +2.3-fold at 13 weeks; +20.7%, +4.3-fold at 26 weeks; +25.7%, +4.8-fold at 52 weeks). Transcriptomic analysis revealed that EndoMT cells in visceral adipose tissue have enriched expression of genes associated with inflammatory and TGFß signaling pathways. Human adipose-derived microvascular endothelial cells cultured with TGF-ß1, IFN-γ, and TNF-α exhibited a similar upregulation of EndoMT markers and induction of inflammatory response pathways. Analysis of single cell RNA sequencing datasets from visceral adipose tissue of obese patients revealed a nascent EndoMT sub-cluster of endothelial cells with reduced PECAM1 and increased ACTA2 expression, which was also enriched for inflammatory signaling genes and other genes associated with EndoMT. Discussion: These experimental and clinical findings show that chronic obesity can accelerate EndoMT in adipose tissue. We speculate that EndoMT is a feature of adipose tissue dysfunction that contributes to local inflammation and the systemic metabolic effects of obesity..

The Cell Surface Receptors Ror1/2 Control Cardiac Myofibroblast Differentiation.

Background A hallmark of heart failure is cardiac fibrosis, which results from the injury-induced differentiation response of resident fibroblasts to myofibroblasts that deposit extracellular matrix. During myofibroblast differentiation, fibroblasts progress through polarization stages of early proinflammation, intermediate proliferation, and late maturation, but the regulators of this progression are poorly understood. Planar cell polarity receptors, receptor tyrosine kinase-like orphan receptor 1 and 2 (Ror1/2), can function to promote cell differentiation and transformation. In this study, we investigated the role of the Ror1/2 in a model of heart failure with emphasis on myofibroblast differentiation. Methods and Results The role of Ror1/2 during cardiac myofibroblast differentiation was studied in cell culture models of primary murine cardiac fibroblast activation and in knockout mouse models that underwent transverse aortic constriction surgery to induce cardiac injury by pressure overload. Expression of Ror1 and Ror2 were robustly and exclusively induced in fibroblasts in hearts after transverse aortic constriction surgery, and both were rapidly upregulated after early activation of primary murine cardiac fibroblasts in culture. Cultured fibroblasts isolated from Ror1/2 knockout mice displayed a proinflammatory phenotype indicative of impaired myofibroblast differentiation. Although the combined ablation of Ror1/2 in mice did not result in a detectable baseline phenotype, transverse aortic constriction surgery led to the death of all mice by day 6 that was associated with myocardial hyperinflammation and vascular leakage. Conclusions Together, these results show that Ror1/2 are essential for the progression of myofibroblast differentiation and for the adaptive remodeling of the heart in response to pressure overload.