Fat Embolism Does Not Alter Cardiac Structure or Induce Pathological Changes in a Rat Model.

INTRODUCTION: Fat embolism (FE) encompasses conditions in which fatty substance becomes embedded in a tissue/organ. Fat emboli most commonly affect the lungs in a trauma setting. This can lead to both significant pathology locally and systemically including changes in structure, inflammatory response, activation of the renin-angiotensin system, and subsequent hypoxia. In fact, changes in skin, brain, lungs, and kidneys have been noted in FE syndrome. Because there is an extensive record of pathology reports on this condition without evidence of direct cardiac involvement, as well as our studies showing apparent complete recovery after the acute embolism, we hypothesized that structural changes similar to the lung and at the same time course would not be observed in the heart. METHODS: We used a rat model of FE previously described by our group where we have documented significant lung pathology. In this study, we analyzed both pulmonary and cardiac structure, histology, and gene expression at 48 h and 10 wks post fat injection to mimic FE. RESULTS: Despite severe inflammatory evidence and structural changes to the lung and vasculature up to 10 wks after FE, we found no significant alterations to cardiovascular morphometry including lumen patency ratio, adventitia/media ratio, fibrosis content, and heart chamber/wall dimensions in stained histological sections. Additionally, genetic markers of cardiac pathological hypertrophy were not significantly elevated 48 h or 10 wks after fat treatment. Oil Red O staining showed increased fat droplet content within lung and aorta tissue, but not in the myocardium. CONCLUSIONS: Our study suggests that, in contrast to the lungs, the heart is more resistant to the inflammatory and remodeling responses that result from FE, possibly due to the organ-specific differences in fat retention.

Hypercalcemia Secondary to Antibiotic-Eluting Calcium Sulfate Beads.

The use of calcium sulfate beads (CSBs) as a carrier for local delivery of antibiotics is increasingly reported for the treatment of localized infections. They are used most commonly in bone and joint infections, post-trauma infections, diabetes-related foot wounds, and vascular grafts. Hypercalcemia is rarely reported with CSB use but is an important safety concern, and patients at higher risk should be identified prospectively and followed carefully postoperatively. This case report details an 85-year-old male who developed severe, symptomatic postoperative hypercalcemia after antibiotic bead placement in the right knee. He presented with confusion, weakness, and lethargy, and was subsequently treated with fluids, calcitonin, and alendronate. The patient quickly returned to normal mental status, and calcium levels normalized, leading to discharge. The case report and review of the literature describe an incident of severe hypercalcemia attributed to the use of antibiotic-eluting CSBs and describe the risk factors and time course that may be expected.

Fibroblast growth factor 23 (FGF23) induces ventricular arrhythmias and prolongs QTc interval in mice in an FGF receptor 4-dependent manner.

Fibroblast growth factor 23 (FGF23) is a phosphate regulating protein hormone released by osteocytes. FGF23 becomes markedly elevated in chronic kidney disease (CKD), for which the leading cause of death is cardiovascular disease, particularly sudden cardiac death. Previously, we found that FGF23 increases intracellular Ca2+ in cardiomyocytes and alters contractility in mouse ventricles ex vivo via FGF receptor 4 (FGFR4). In the present study, we demonstrate that FGF23 induces cardiac arrhythmias and prolongs QTc interval in mice, and we tested whether these effects are mediated through FGFR4. In isolated Langendorff perfused hearts, FGF23 perfusion increased mechanical arrhythmias in the form of premature ventricular beats (PVBs), and induced runs of ventricular tachycardia in 6 of 11 animals, which were attenuated with pretreatment of an anti-FGFR4 blocking antibody. Ex vivo ECG analysis of isolated intact hearts showed increased ventricular arrhythmias and QTc prolongation after FGF23 infusion compared with vehicle. In vivo, injection of FGF23 into the jugular vein led to the emergence of premature ventricular contractions (PVCs) in 5 out of 11 experiments. FGF23 also produced a significant lengthening effect upon QTc interval in vivo. In vivo FGFR4 blockade ameliorated the arrhythmogenic and QTc prolonging effects of FGF23. Finally, FGF23 increased cardiomyocyte Ca2+ levels in intact left ventricular muscle which was inhibited by FGR4 blockade. We conclude that FGF23/FGFR4 signaling in the heart may contribute to ventricular arrhythmogenesis and repolarization disturbances commonly observed in patients with CKD via Ca2+ overload and may be an important therapeutic target to reduce cardiac mortality in CKD.NEW & NOTEWORTHY Here we provide direct evidence that fibroblast growth factor 23 (FGF23), a phosphaturic hormone elevated in chronic kidney disease, is proarrhythmic. FGF23 acutely triggered ventricular arrhythmias and prolonged corrected QT interval (QTc) in isolated mouse hearts and in vivo. FGF23 also increased Ca2+ levels in ventricular muscle tissue. Blockade of the FGF receptor 4 signaling pathway using a monoclonal antibody ameliorated ventricular arrhythmias, QTc prolongation, and elevated ventricular Ca2+ induced by FGF23, and may represent a potential therapeutic target in chronic kidney disease.

Chronic IL-1 Exposed AR+ PCa Cell Lines Show Conserved Loss of IL-1 Sensitivity and Evolve Both Conserved and Unique Differential Gene Expression Profiles.

INTRODUCTION: Inflammation drives prostate cancer (PCa) progression. While inflammation is a cancer hallmark, the underlying mechanisms mediating inflammation-induced PCa are still under investigation. Interleukin-1 (IL-1) is an inflammatory cytokine that promotes cancer progression, including PCa metastasis and castration resistance. We previously found that acute IL-1 exposure represses PCa androgen receptor (AR) expression concomitant with the upregulation of pro-survival proteins, causing de novo accumulation of castration-resistant PCa cells. However, acute inflammation is primarily anti-tumorigenic, while chronic inflammation is pro-tumorigenic. Thus, using the LNCaP PCa cell line as model, we found that PCa cells can evolve insensitivity to chronic IL-1 exposure, restoring AR and AR activity and acquiring castration resistance. In this paper we expanded our chronic IL-1 model to include the MDA-PCa-2b PCa cell line to investigate the response to acute versus chronic IL-1 exposure and to compare the gene expression patterns that evolve in the LNCaP and MDA-PCa-2b cells chronically exposed to IL-1. METHODS: We chronically exposed MDA-PCa-2b cells to IL-1α or IL-1ß for several months to establish sublines. Once established, we determined subline sensitivity to exogenous IL-1 using cell viability assay, RT-qPCR and western blot. RNA sequencing was performed for parental and subline cells and over representation analysis (ORA) for geneset enrichment of biological process/pathway was performed. RESULTS: MDA-PCa-2b cells repress AR and AR activity in response to acute IL-1 exposure and evolve insensitivity to chronic IL-1 exposure. While cell biological and molecular response to acute IL-1 signaling is primarily conserved in LNCaP and MDA-PCa-2b cells, including upregulation of NF-κB signaling and downregulation of cell proliferation, the LNCaP and MDA-PCa-2b cells evolve conserved and unique molecular responses to chronic IL-1 signaling that may promote or support tumor progression. CONCLUSIONS: Our chronic IL-1 subline models can be used to identify underlying molecular mechanisms that mediate IL-1-induced PCa progression.