Localized cytokine responses to total knee arthroplasty and total knee revision complications

Background The study of localized immune-related factors has proven beneficial for a variety of conditions, and one area of interest in the field of orthopaedics is the impact of implants and localized infections on immune response. Several cytokines have shown increased systemic concentrations (in serum/plasma) in response to implants and infection, but tissue-level cytokines have not been investigated as thoroughly. Methods This exploratory study investigated tissue-level cytokines in a cohort of patients (N = 17) in response to total knee arthroplasty and total knee revision to better understand the immune response to implants and localized infection (e.g., prosthetic joint infection). The overall goal of this study was to provide insight into the localized cytokine response of tissues and identify tissue-level markers specific to inflammation caused by implants vs. inflammation caused by infection. Tissues were collected across several anatomical locations and assayed with a panel of 20 human inflammatory cytokines to understand spatial differences in cytokine levels. Results In this study, six cytokines were elevated in implanted joints, as compared to native joints: IL-10, IL-12p70, IL-13, IL-17A, IL-4, and TNF-α (p \u3c 0.05). Seven cytokines showed infection-dependent increases in localized tissues: IL-1α, IL-1β, IL-6, IL-8, MCP-1, MIP-1α, and MIP-1β (p \u3c 0.05). Conclusions This study demonstrated that differences exist in tissue-level cytokines in response to presence of implant, and some cytokines were specifically elevated for infection; these responses may be informative of overall tissue health. These results highlight the utility of investigating localized cytokine concentrations to offer novel insights for total knee arthroplasty and total knee revision procedures, as well as their complications. Ultimately, this information could provide additional, quantitative measurements of tissue to aid clinical decision making and patient treatment options

Early detection of soluble CD27, BTLA, and TIM-3 predicts the development of nosocomial infection in pediatric burn patients

Thermal injury induces concurrent inflammatory and immune dysfunction, which is associated with adverse clinical outcomes. However, these effects in the pediatric population are less studied and there is no standard method to identify those at risk for developing infections. Our goal was to better understand immune dysfunction and identify soluble protein markers following pediatric thermal injury. Further we wanted to determine which early inflammatory, soluble, or immune function markers are most predictive of the development of nosocomial infections (NI) after burn injury. We performed a prospective observational study at a single American Burn Association-verified Pediatric Burn Center. A total of 94 pediatric burn subjects were enrolled and twenty-three of those subjects developed a NI with a median time to diagnosis of 8 days. Whole blood samples, collected within the first 72 hours after injury, were used to compare various markers of inflammation, immune function, and soluble proteins between those who recovered without developing an infection and those who developed a NI after burn injury. Within the first three days of burn injury, innate and adaptive immune function markers (ex vivo lipopolysaccharide-induced tumor necrosis factor alpha production capacity, and ex vivo phytohemagglutinin-induced interleukin-10 production capacity, respectively) were decreased for those subjects who developed a subsequent NI. Further analysis of soluble protein targets associated with these pathways displayed significant increases in soluble CD27, BTLA, and TIM-3 for those who developed a NI. Our findings indicate that suppression of both the innate and adaptive immune function occurs concurrently within the first 72 hours following pediatric thermal injury. At the same time, subjects who developed NI have increased soluble protein biomarkers. Soluble CD27, BTLA, and TIM-3 were highly predictive of the development of subsequent infectious complications. This study identifies early soluble protein makers that are predictive of infection in pediatric burn subjects. These findings should inform future immunomodulatory therapeutic studies

Exploring early signaling associated with complex stressors

Humans are constantly exposed to a vast number of stressors in our everyday lives from social interactions to physical activity to chemical exposures, to name a few. These stressors have significant impacts on an individual, from the cellular to whole organismal level. The body contains an intricate communication system that elicits a number of both biological and physiological responses as it attempts to maintain homeostasis. Observing these responses to stressors, can offer insight into a number of outcomes, which can be beneficial (increasing life longevity) or detrimental (leading to a disease state). By measuring specific biological adaptations at particular time points, we can better understand the organismal response to these stressors. While human studies provide a unique opportunity to truly understand the organismal response, there are a number of factors that influence individual responses. Therefore, replicating these stressors in vivo can be exceptionally difficult, especially when the primary focus of many studies is on a single stressor, rather than a more realistic combinatory exposure. The work presented in this dissertation had the ultimate goal of building upon previous research with a focus on the biochemical adaptations that take place to protect and maintain optimal organismal function. Specifically, this dissertation observes both extracellular (cytokine) and intracellular (phosphorylation modifications) responses to social, physical, and occupational stressors. Additionally, this work observes both systemic and localized responses in different biological samples (saliva vs ex vivo tissue) to analyze various biomarkers of stress. The findings from this dissertation reveal the rapid responses of signaling mechanisms related to complex mixtures in both human and animal work