David F. Schneider

Innate Lymphocyte Subsets and Their Immunoregulatory Roles in Burn Injury and Sepsis

The vast majority of clinical and basic science research on the immune consequences of burn injury and sepsis conducted during the last three decades has focused mainly on the roles of macrophages, neutrophils and, to a lesser extent, conventional T lymphocytes. During recent years, however, it has become increasingly clear that minor subsets of innate immune cells, innate regulatory lymphocytes in particular, are central to processes involved in both protective immunity and immunopathology. Recent reports by our laboratory and others have just begun to shed light on the critical roles of innate lymphocyte subsets, including natural killer T cells, natural killer cells, gamma-delta T cells, and naturally occurring CD4+CD25+ regulatory T cells during the immune response to burn injury and sepsis. Given their emerging importance and documented upstream regulatory capacities over macrophage, dendritic cell, and T lymphocyte functions, innate regulatory lymphocytes represent attractive new targets for therapeutic intervention for the overall immune paralysis that occurs with injury and sepsis. Here, we provide an overview of the current state of knowledge of these particular cell subsets in the immune response to burn injury and sepsis.

Prevention of NKT Cell Activation Accelerates Cutaneous Wound Closure and Alters Local Inflammatory Signals

We previously reported that in the absence of NKT cells, wound closure was accelerated in a murine excisional punch wound model. Here, we explored whether purposefully inhibiting NKT cell activation had similar effects on wound closure and the dermal inflammatory response to injury. We found that prevention of NKT cell activation accelerated wound closure in a dose-responsive manner. If anti-CD1d was administered before wounding, NKT cell infiltration into cutaneous wounds was diminished without quantitative changes in cellular infiltrates. Furthermore, prevention of NKT cell activation transiently enhanced the local production of a subset of chemokines, including MIP-2, MCP-1, MIP-1α, and MIP-1β, and altered the relative expression of CD69 and CXCR2 on the surface of both circulating and wound NKT cells. Taken together, these findings suggest that wounding activates NKT cells via CD1d presentation of glycolipid antigen and help further define a role for NKT cells in the regulation of wound inflammation and closure. Many soluble factors have been targeted as potential wound healing therapies, but their clinical success has been limited. Given our findings, the NKT cell may be an attractive target for wound healing therapies.

Predicting acute kidney injury among burn patients in the 21st century: a classification and regression tree analysis.

Historically, acute kidney injury (AKI) carried a deadly prognosis in the burn population. The aim of this study is to provide a modern description of AKI in the burn population and to develop a prediction tool for identifying patients at risk for late AKI. A large multi-institutional database, the Glue Grants Trauma-Related Database, was used to characterize AKI in a cohort of critically ill burn patients. The authors defined AKI according to the RIFLE criteria and categorized AKI as early, late, or progressive. They then used Classification and Regression Tree (CART) analysis to create a decision tree with data obtained from the first 48 hours of admission to predict which subset of patients would develop late AKI. The accuracy of this decision tree was tested in a separate, single-institution cohort of burn patients who met the same criteria for entry into the Glue Grant study. Of the 220 total patients analyzed from the Glue Grant cohort, 49 (22.2%) developed early AKI, 39 (17.7%) developed late AKI, and 16 (7.2%) developed progressive AKI. The group with progressive AKI was statistically older, with more comorbidities and with the worst survival when compared with those with early or late AKI. Using CART analysis, a decision tree was developed with an overall accuracy of 80% for the development of late AKI for the Glue Grant dataset. The authors then tested this decision tree on a smaller dataset from our own institution to validate this tool and found it to be 73% accurate. AKI is common in severe burns with notable differences between early, late, and progressive AKI. In addition, CART analysis provided a predictive model for early identification of patients at highest risk for developing late AKI with proven clinical accuracy.

An improved cell isolation method for flow cytometric and functional analyses of cutaneous wound leukocytes

Isolation of leukocytes from full-thickness excisional wounds has proven to be a difficult process that results in poor cell yield and holds significant limitations for functional assays. Given the increased interest in the isolation, characterization and functional measurements of wound-derived cell populations, herein we describe a method for preparing wound cell suspensions with an improved yield that enables both phenotypic and functional assessments.

Calcium-lowering medications in patients with primary hyperparathyroidism: intraoperative findings and postoperative hypocalcemia

BACKGROUND We analyzed how calcium-lowering medications (CLMs) influenced surgical findings in patients with primary hyperparathyroidism. METHODS A retrospective review was conducted of 281 patients undergoing surgery for primary hyperparathyroidism. Logistic regression evaluated the relationship between CLM and surgical findings. A mixed-effects model determined the influence of CLMs on these curves. RESULTS We found that CLM (P = .018) and a higher serum calcium level (P = .018) were variables making 4-gland hyperplasia less likely. Analysis of intraoperative parathyroid hormone (IOPTH) plots revealed that CLMs altered the kinetics (P = .043). However, the 2 groups did not differ in the number of measurements necessary for a 50% decrease in IOPTH levels. Multivariate logistic regression also revealed that patients taking more than one CLM had an increased association with postoperative hypocalcemia (P = .018). CONCLUSIONS Although CLM contributed to differences in IOPTH curves, their use does not require changing standard IOPTH protocol but should alert the surgeon to the risk of postoperative hypocalcemia.