Resident cardiac macrophages mediate adaptive myocardial remodeling.

Cardiac macrophages represent a heterogeneous cell population with distinct origins, dynamics, and functions. Recent studies have revealed that C-C Chemokine Receptor 2 positive (CCR2+) macrophages derived from infiltrating monocytes regulate myocardial inflammation and heart failure pathogenesis. Comparatively little is known about the functions of tissue resident (CCR2-) macrophages. Herein, we identified an essential role for CCR2- macrophages in the chronically failing heart. Depletion of CCR2- macrophages in mice with dilated cardiomyopathy accelerated mortality and impaired ventricular remodeling and coronary angiogenesis, adaptive changes necessary to maintain cardiac output in the setting of reduced cardiac contractility. Mechanistically, CCR2- macrophages interacted with neighboring cardiomyocytes via focal adhesion complexes and were activated in response to mechanical stretch through a transient receptor potential vanilloid 4 (TRPV4)-dependent pathway that controlled growth factor expression. These findings establish a role for tissue-resident macrophages in adaptive cardiac remodeling and implicate mechanical sensing in cardiac macrophage activation.

Assaying three-dimensional cellular architecture using X-ray tomographic and correlated imaging approaches.

Much of our understanding of the spatial organization of and interactions between cellular organelles and macromolecular complexes has been the result of imaging studies utilizing either light- or electron-based microscopic analyses. These classical approaches, while insightful, are nonetheless limited either by restrictions in resolution or by the sheer complexity of generating multidimensional data. Recent advances in the use and application of X-rays to acquire micro- and nanotomographic data sets offer an alternative methodology to visualize cellular architecture at the nanoscale. These new approaches allow for the subcellular analyses of unstained vitrified cells and three-dimensional localization of specific protein targets and have served as an essential tool in bridging light and electron correlative microscopy experiments. Here, we review the theory, instrumentation details, acquisition principles, and applications of both soft X-ray tomography and X-ray microscopy and how the use of these techniques offers a succinct means of analyzing three-dimensional cellular architecture. We discuss some of the recent work that has taken advantage of these approaches and detail how they have become integral in correlative microscopy workflows.

Developing a risk score to inform the use of rhBMP-2 in adult spinal deformity surgery.

BACKGROUND: Recombinant human bone morphogenetic protein-2 (rhBMP-2) has not shown superior benefit overall in cost-effectiveness during adult spinal deformity (ASD) surgery. STUDY DESIGN/SETTING: Retrospective PURPOSE: Generate a risk score for pseudarthrosis to inform the utilization of rhBMP-2, balancing costs against quality of life and complications. METHODS: ASD patients with 3-year data were included. Quality of life gained was calculated from ODI to SF-6D and translated to quality-adjusted life years (QALYs). Cost was calculated using the PearlDiver database and CMS definitions for complications and comorbidities. Established weights were generated for predictive variables via logistic regression to yield a predictive risk score for pseudarthrosis that accounted for frailty, diabetes, depression, ASA grade, thoracolumbar kyphosis and three-column osteotomy use. Risk score categories, established via conditional inference tree (CIT)-derived thresholds were tested for cost-utility of rhBMP-2 usage, controlling for age, prior fusion, and baseline deformity and disability. RESULTS: 64% of ASD patients received rhBMP-2 (308/481). There were 17 (3.5%) patients that developed pseudarthrosis. rhBMP-2 use overall did not lower pseudarthrosis rates (OR: 0.5, [0.2-1.3]). Pseudarthrosis rates for each risk category were: No Risk (NoR) 0%; Low-Risk (LowR) 1.6%; Moderate Risk (ModR) 9.3%; High-Risk (HighR) 24.3%. Patients receiving rhBMP-2 had similar QALYs overall to those that did not (0.163 vs. 0.171, p = .65). rhBMP-2 usage had worse cost-utility in the LowR cohort (p < .001). In ModR patients, rhBMP-2 usage had equivocal cost-utility ($53,398 vs. $61,581, p = .232). In the HighR cohort, the cost-utility was reduced via rhBMP-2 usage ($98,328 vs. $211,091, p < .001). CONCLUSION: Our study shows rhBMP-2 demonstrates effective cost-utility for individuals at high risk for developing pseudarthrosis. The generated score can aid spine surgeons in the assessment of risk and enhance justification for the strategic use of rhBMP-2 in the appropriate clinical contexts. LEVEL OF EVIDENCE: III.

Revision reverse shoulder arthroplasty has similar outcomes to primary reverse shoulder arthroplasty at 5 Year average follow-up.

Background: Shoulder arthroplasty is a successful procedure that provides pain relief and improvements in function and range of motion. Anatomic and reverse shoulder arthroplasty are both effective procedures, and their indications continue to expand. We look at the outcomes of revision reverse total shoulder arthroplasty and compare it to the outcomes of primary reverse and anatomic total shoulder arthroplasty. Methods: We identified patients undergoing total shoulder arthroplasty at our institution between the years of 2010 and 2020. Data was prospectively collected and retrospectively reviewed for post-operative range of motion and strength in patients with revision surgery and compared to controls. Measurements were collected preoperatively and postoperatively including range of motion and strength in the affected and unaffected shoulder. We collected patient reported outcome measures in person and via phone to identify subjective outcomes of total shoulder arthroplasty. Average final follow-up was 5.27 years. Results: Our total patient sample was split between three groups: those with primary anatomic arthroplasty those who underwent primary reverse arthroplasty, and those who were revised to a reverse shoulder arthroplasty. All three groups had significant improvements in abduction and forward elevation from their pre-operative baseline to two years follow-up. Primary reverse had a significant improvement over revision reverse in abduction at one year follow-up. For all other range of motion measurements, there was no statistically significant difference at 2 years between primary and revision reverse shoulder arthroplasty. Patient reported outcomes had a significant increase from pre-op to most recent follow-up in all three groups. Conclusion: Overall, our data suggest there is an improvement in outcomes with both primary and revision surgeries, and that results after revision reverse total shoulder arthroplasty may be comparable to primary reverse total shoulder arthroplasty.

Pancreatic ß-Cell-Specific Deletion of VPS41 Causes Diabetes Due to Defects in Insulin Secretion.

Insulin secretory granules (SGs) mediate the regulated secretion of insulin, which is essential for glucose homeostasis. The basic machinery responsible for this regulated exocytosis consists of specific proteins present both at the plasma membrane and on insulin SGs. The protein composition of insulin SGs thus dictates their release properties, yet the mechanisms controlling insulin SG formation, which determine this molecular composition, remain poorly understood. VPS41, a component of the endolysosomal tethering homotypic fusion and vacuole protein sorting (HOPS) complex, was recently identified as a cytosolic factor involved in the formation of neuroendocrine and neuronal granules. We now find that VPS41 is required for insulin SG biogenesis and regulated insulin secretion. Loss of VPS41 in pancreatic ß-cells leads to a reduction in insulin SG number, changes in their transmembrane protein composition, and defects in granule-regulated exocytosis. Exploring a human point mutation, identified in patients with neurological but no endocrine defects, we show that the effect on SG formation is independent of HOPS complex formation. Finally, we report that mice with a deletion of VPS41 specifically in ß-cells develop diabetes due to severe depletion of insulin SG content and a defect in insulin secretion. In sum, our data demonstrate that VPS41 contributes to glucose homeostasis and metabolism.