PrP is cleaved from the surface of mast cells by ADAM10 and proteases released during degranulation.

While several functions of the endogenous prion protein (PrP) have been studied, the homeostatic function of PrP is still debated. Notably, PrP is highly expressed on mast cells, granular immune cells that regulate inflammation. When activated, mast cells shed PrP though the mechanism and consequences of this are not yet understood. First, we tested several mast cell lines and found that, while PrP was almost always present, the total amount differed greatly. Activation of mast cells induced a cleavage of the N-terminal region of PrP, and this was reduced by protease inhibitors. Exogenous mast cell proteases caused a similar loss of the PrP N-terminus. Additionally, mast cells shed PrP in an ADAM10-dependent fashion even in the absence of activation. Our results suggest that PrP is cleaved from resting mast cells by ADAM10 and from activated mast cells by mast cell proteases. PrP also appears to affect mast cell function, as Prnp-/- BMMC showed lower levels of degranulation and cytokine release, as well as lower levels of both FcεRI and CD117. Finally, we sought to provide clinical relevance by measuring the levels of PrP in bodily fluids of asthmatic patients, a disease that involves the activation of mast cells. We found an N-terminal fragment of PrP could be detected in human sputum and serum and the amount of this PrP fragment was decreased in the serum of patients with asthma.

Comparison of No Tap (two-step) and tapping robotic assisted cortical bone trajectory screw insertion.

Workflow for cortical bone trajectory (CBT) screws includes tapping line-to-line or under tapping by 1 mm. We describe a non-tapping, two-step workflow for CBT screw placement, and compare the safety profile and time savings to the Tap (three-step) workflow. Patients undergoing robotic assisted 1-3 level posterior fusion with CBT screws for degenerative conditions were identified and separated into either a No-Tap or Tap workflow. Number of total screws, screw-related complications, estimated blood loss, operative time, robotic time, and return to the operating room were collected and analyzed. There were 91 cases (458 screws) in the No-Tap and 88 cases (466 screws) in the Tap groups, with no difference in demographics, revision status, ASA grade, approach, number of levels fused or diagnosis between cohorts. Total robotic time was lower in the No-Tap (26.7 min) versus the Tap group (30.3 min, p = 0.053). There was no difference in the number of malpositioned screws identified intraoperatively (10 vs 6, p = 0.427), screws converted to freehand (3 vs 3, p = 0.699), or screws abandoned (3 vs 2, p = 1.000). No pedicle/pars fracture or fixation failure was seen in the No-Tap cohort and one in the Tap cohort (p = 1.00). No patients in either cohort were returned to OR for malpositioned screws. This study showed that the No-Tap screw insertion workflow for robot-assisted CBT reduces robotic time without increasing complications.

Identifying and Minimizing Incentives for Competing Interests in Sports Medicine Publications.

Academics in sports medicine as well as other medical fields are generally expected to publish research and opinions in peer-reviewed journals. The peer-review process is intended to protect against the publication of flawed research and unsubstantiated claims. However, both financial and non-financial competing interests may result in sub-optimal results by affecting investigators, editors, peer reviewers, academic institutions, and publishers. In this article, we focus on the non-financial competing interests created in our current academic system. Because these competing interests are embedded in our current scholastic framework, the potential biases are difficult to quantify. To minimize the effect of these competing interests, we review and highlight some underlying incentives for each stakeholder and some potential solutions to mitigate their effects.

Intra-Operative Hypotension is an Important Modifiable Risk Factor for Major Complications in Spinal Fusion Surgery.

STUDY DESIGN: Retrospective observational cohort. OBJECTIVES: This study explores the impact of Intraoperative hypotension (IOH)on post-op complications for major thoracolumbar spine fusion procedures. SUMMARY OF BACKGROUND DATA: IOH with mean arterial pressure (MAP) < 65 mmHg is associated with post-op acute kidney injury (AKI) in general surgery. In spinal deformity surgery, IOH is a contributing factor to MEP changes and spinal cord dysfunction with deformity correction. METHODS: 539 thoracolumbar fusion cases, > 6 surgical levels and > 3 hours duration were identified. Anesthetic/surgical data included OR time, fluid volume, blood loss, blood product replacement and use of vasopressors. Arterial-line based MAP data was collected at 1 min intervals. Cummulative duration of MAP < 65 mmHg was recorded. IOH within the first hour of surgery vs. the entire case was determined. Post-op course and complications including SSI, GI complications, pulmonary complications, MI, DVT, PE, AKI and encephalopathy were noted. Cumulative complications were grouped as none, 1-2 complications, or >3 complications. RESULTS: There was a significant association between occurrence of complications and duration of IOH within the first hour of surgery (8.2 vs. 5.6 min, P<0.001) and across the entire procedure (28.1 vs. 19.3 min, P=0.008). This association persisted for individual major complications including SSI, acute respiratory failure, PE, ileus requiring NGT and post-operative cognitive dysfunction. Comparison of patients with 0 vs. 1-2 vs. 3 or more complications demonstrated that patients with 3 or more complications had a longer duration of IOH in the first hour of the surgery and that patients who had no complications received less vasopressor than patients who had 1-2 or 3 or more complications. CONCLUSION: This study identifies duration of IOH during the first hour of surgery as a previously unrecognized modifiable risk associated with major complications for multi-level lumbar fusion surgery.

Treatment of Refractory Bipolar Depression With Stereotactic Radiosurgery Targeting the Subgenual Cingulate Cortex.

Background The subgenual cingulate cortex (SGC) has been identified as a key structure within multiple neural circuits whose dysfunction is implicated in the neurobiology of depression. Deep brain stimulation in the SGC is thought to reduce and normalize local metabolism, causing normalization of circuit behavior and an improvement in depressive symptoms. We hypothesized that nonablative stereotactic radiosurgery (SRS) to the SGC would reduce local metabolism and reduce the severity of depression in patients with treatment-resistant bipolar depression. Methods Under the FDA's Humanitarian Device Exemption program, patients were screened for inclusion and exclusion criteria. Three volunteers meeting the criteria provided informed consent. Bilateral SGC targets were irradiated to a maximum dose of 75 Gy in one fraction. Subjects were followed for one year following the procedure with mood assessments (Hamilton Depression Rating Scale (HDRS), Clinical Global Impression-Improvement, Clinical Global Impression-Severity, and Young Mania Rating Scale), neurocognitive testing (Delis-Kaplan Executive Function System, Wechsler Adult Intelligence Scale III digit span, and California Verbal Learning Test II), and imaging. Further imaging was completed approximately two years after the procedure. Clinical improvement was defined as a ≥50% reduction in HDRS. Results Two of the three subjects showed clinical improvement in depressive symptoms during the follow-up period, while one subject showed no change in symptom severity. One of three subjects was hospitalized for the emergence of an episode of psychotic mania after discontinuing antipsychotic medications against medical advice but promptly recovered with the reinstitution of an antipsychotic. Sequential assessments did not reveal impairment in any cognitive domain assessed. For one of the three subjects, MRI imaging showed evidence of edema at 12 months post-SRS, which resolved at 22 months post-procedure. In a second of three patients, there was evidence of local edema at the target site at long-term follow-up. All imaging changes were asymptomatic. Conclusion Radiosurgical targeting of the SGC may be a noninvasive strategy for the reduction of severe depression in treatment-resistant bipolar disorder. Two out of three patients showed clinical improvement. While these results are promising, further study, including improvements in target selection and dosing considerations, is needed.

CyberKnife stereotactic radiosurgery for extramedullary plasmacytoma in the external auditory canal: illustrative case.

BACKGROUND: Plasmacytoma, a rare plasma cell disorder, often presents as a solitary or multiple tumors within the bone marrow or soft tissues, typically associated with multiple myeloma. Extramedullary plasmacytomas (EMPs), particularly those located in the external auditory canal (EAC), are exceedingly rare and pose significant treatment challenges given their location, anatomical complexity, and high risk of recurrence. OBSERVATIONS: The authors report the case of a 72-year-old male with a history of multiple myeloma, presenting with recurrent left EAC plasmacytoma. After initial conventional radiotherapy for the lesion, a recurrence was documented in 7 years. The patient subsequently underwent stereotactic radiosurgery, which proved successful, leading to complete resolution of the lesion without any long-term adverse effects or radiation-related complications over a 45-month period. LESSONS: This case is a unique instance of utilizing stereotactic radiosurgery for recurrent EMP in the EAC, highlighting its potential as an effective approach in managing complex plasmacytomas.

Fragmented Readmissions From a Nursing Facility in Medicare Beneficiaries.

Over one-third of Medicare beneficiaries discharged to nursing facilities require readmission. When those readmissions are to a different hospital than the original admission, or "fragmented readmissions," they carry increased risks of mortality and subsequent readmissions. This study examines whether Medicare beneficiaries readmitted from a nursing facility are more likely to have a fragmented readmission than beneficiaries readmitted from home among a 2018 cohort of Medicare beneficiaries, and examined whether this association was affected by a diagnosis of Alzheimer's Disease (AD). In fully adjusted models, readmissions from a nursing facility were 19% more likely to be fragmented (AOR 1.19, 95% CI 1.16, 1.22); this association was not affected by a diagnosis of AD. These results suggest that readmission from nursing facilities may contribute to care fragmentation for older adults, underscoring it as a potentially modifiable pre-hospital risk factor for fragmented readmissions.

Proximal Junctional Degeneration and Failure Modes: A Novel Classification and Clinical Implications.

STUDY DESIGN: Case-control study. OBJECTIVE: To introduce a classification system that will include the major types of degenerative changes and failures related to the proximal junction, and to determine the clinical course and characteristics for the different types of proximal junctional degeneration (PJD). SUMMARY OF BACKGROUND DATA: Proximal junctional kyphosis (PJK) and failures are well recognized after adult spinal fusion, however, a standardized classification is lacking. METHODS: The proposed system identified four different patterns of PJD: Type 1 (multi-level symmetrical collapse), Type 2 (Single adjacent level collapse), Type 3 (fracture) and Type 4 (spondylolisthesis). A single center database was reviewed from 2018 to 2021. Patients ≥18 years of age, who underwent posterior spinal fusion of ≥3 levels with an upper instrumented vertebral level between T8-L2, and a follow-up of ≥2 years were included. Radiographic measurements, revision surgery and time to revision were the primary outcomes. RESULTS: 150 patients were included with a mean age of 65.1 (±9.8) years and a mean follow-up of 3.2 (±1) years. 69 patients (46%) developed significant degenerative changes in the proximal junction, and were classified accordingly. 20 (13%) were Type 1, 17 (11%) were Type 2, 22 (15%) were Type 3 and 10 (7%) were Type 4. Type 3 had a significantly shorter time to revision with a mean of 0.9 (±0.9) years. Types 3 and 4 had greater preoperative sagittal vertical axis, and Types 1 and 3 had greater final follow-up lumbar lordosis. Bone density measured by Hounsfield units showed lower measurements for Type 3. Types 1 and 4 had lower rates of developing PJK. Type 1 had the lowest revision rate with 40% (types 2, 3 and 4 were 77%, 73% and 80%, respectively, P=0.045). CONCLUSION: This novel classification system defines different modes of degeneration and failures at the proximal junction, and future studies with larger sample sizes are needed for validation. LEVEL OF EVIDENCE: 3.

Obesity and overweight are associated with worse survival in early-onset colorectal cancer.

BACKGROUND: Obesity and its associated lifestyle are known risk factors for early-onset colorectal cancer and are associated with poor postoperative and survival outcomes in older patients. We aimed to investigate the impact of obesity on the outcomes of early-onset colorectal cancers. METHODS: Retrospective review of all patients undergoing primary resection of colon or rectal adenocarcinoma at our institution between 2015-2022. Patients who had palliative resections, resections performed at another institution, appendiceal tumors, and were underweight were excluded. The primary endpoint was survival according to the patient's body mass index: normal weight (18-24.9 kg/m2), overweight (25-29.9 kg/m2), and obesity (≥30 kg/m2). Patient and tumor characteristics and survival were compared between the three groups. RESULTS: A total of 279 patients aged <50 years with colorectal cancer were treated at our hospital; 120 were excluded from the analysis for the following reasons: main treatment or primary resection performed at another hospital (n = 97), no resection/palliative resection (n = 23), or body mass index <18 kg/m2 (n = 2). Of these, 157 patients were included in the analysis; 61 (38.9%) were overweight and 45 (28.7%) had obesity. Except for a higher frequency of hypertension in the overweight (P = .062) and obese (P = .001) groups, no differences in patient or tumor characteristics were observed. Mean overall survival was 89 months with normal weight, 92 months with overweight, and 65 months with obesity (P = .032). Mean cancer-specific survival was 95 months with normal weight, 94 months with overweight, and 68 months with obesity (P = .018). No statistically significant difference in disease-free survival (75 vs 70 vs 59 months, P = .844) was seen. CONCLUSION: Individuals with early-onset colorectal cancer who are overweight or obese present with similar tumor characteristics and postoperative morbidity to patients with normal weight. However, obesity may have a detrimental impact on their survival. Addressing obesity as a modifiable risk factor might improve early-onset colorectal cancer prognosis.

Lower extremity woven and non-woven venous stent morphology and luminal changes.

OBJECTIVE: Venous stents are a common treatment modality for obstructive venous disease. Venous stents differentiate themselves by either a woven or braided structure, open or closed cell arrangement or based on material composition (elgiloy vs. nitinol). Changes in the morphology of venous stents over time may contribute to restenosis or thrombosis. Woven elgiloy stents are prone to proximal and distal edge deformation compared to dedicated venous stents which offer increased radial force at stent edges. The objective of this study is to describe luminal morphological changes among various venous stents and between woven to non-woven venous stent configuration, over time. METHODS: A retrospective review at a single institution between January 2014-June 2021 identified patients treated with venous stents. Patients with iliac and/or femoral venous stents with intraoperative intravascular ultrasound (IVUS) and a post-operative computed tomography (CT) scan were included in the study. Cross-sectional diameters measurements were taken at proximal, middle, and distal portions of each stent from intravascular ultrasound (IVUS) at the time of initial stenting and compared to the cross-sectional diameter measurements taken from CT imaging at follow-up. A paired t-test was used to compare the luminal change with a D'Agostino-Pearson test used for normality. RESULTS: Fifty-four stents distributed amongst thirty-eight patients were identified. Mean time to follow-up was 17.5 months. Stents were placed in the common iliac vein (n=37, 68.5%), external iliac vein (n=14, 25.9%), and common femoral vein (n=3, 5.6%). Implanted stents included the Boston Scientific Wallstent (n=23, 42.6%), Bard Venovo (n=3, 5.6%), Boston Scientific Vici (n=23, 42.6%), and Medtronic Abre (n=5, 9.3%). The mean luminal loss was measured at 2.12 mm proximally (95% confidence interval (CI), 1.64-2.60; p<0.001), 1.29 mm at the mid-stent (95% CI, 0.83-1.74, p<0.001) and 1.56 mm distally (95% CI, 0.99-2.12; p<0.001). There was no significant difference in luminal changes between woven and non-woven stents at proximal (p=0.374), middle (p=0.179), and distal (p=0.609) stent measurements. CONCLUSION: This study reports morphological changes within venous stents and between woven and non-woven venous stents. Our findings demonstrate that the edge-stent luminal reduction traditionally attributed to woven configurations also occurs with the newer non-woven stents. Additional factors such as anatomic location, pelvic curvature or other external forces may be accountable for this change rather than geometrical configuration of the stent.

Effects of Photobiomodulation on Pain and Return to Play of Injured Athletes: A Systematic Review and Meta-analysis.

ABSTRACT: Morgan, RM, Wheeler, TD, Poolman, MA, Haugen, ENJ, LeMire, SD, and Fitzgerald, JS. Effects of photobiomodulation on pain and return to play of injured athletes: A systematic review and meta-analysis. J Strength Cond Res 38(6): e310-e319, 2024-The aims of this systematic review and meta-analysis were to evaluate the effect of photobiomodulation (PBM) on musculoskeletal pain in injured athletes and to determine if the effects of PBM allowed injured athletes to return to play faster. Electronic databases (MEDLINE Complete, CINAHL, and SPORTDiscus, PubMed, Web of Science, and Embase) were systematically searched (up to and including November 7, 2023) for peer-reviewed randomized controlled trials (RCTs) meeting criteria. Six RCTs, representing 205 competitive and recreational athletes with a mean age of 24 years, were included in the analysis. There were 6 intervention groups using standard physical therapy (n = 1), placebo PBM (n = 4), and aloe gel (n = 1) lasting between 10 minutes and 8 weeks in duration. The level of significance set for the study was p < 0.05. Overall, the use of PBM indicated a positive effect on pain reduction for PBM vs. control groups, standardized mean differences = 1.03, SE = 0.22, 95% confidence intervals = [0.43-1.63], p = 0.0089, but the 2 RCTs found evaluating the effect of PBM on time to return to play after injury in athletes do not support a benefit. Allied healthcare professionals may use PBM to reduce pain, thus allowing an athlete to return to their normal biomechanical movement faster; however, limited evidence suggests that PBM does not reduce time to return to play after an injury.

Oncologic outcomes following transanal total mesorectal excision: the United States experience.

AIM: The benefits and short-term outcomes of transanal total mesorectal excision (taTME) for rectal cancer have been demonstrated previously, but questions remain regarding the oncologic outcomes following this challenging procedure. The purpose of this study was to analyze the oncologic outcomes following taTME at high-volume centers in the USA. METHODS: This was a multicenter, retrospective observational study of 8 tertiary care centers. All consecutive taTME cases for primary rectal cancer performed between 2011 and 2020 were included. Clinical, histopathologic, and oncologic data were analyzed. Primary endpoints were rate of local recurrence, distal recurrence, 3-year disease recurrence, and 3-year overall survival. Secondary endpoints included perioperative complications and TME specimen quality. RESULTS: A total of 391 patients were included in the study. The median age was 57 years (IQR: 49, 66), 68% of patients were male, and the median BMI was 27.4 (IQR: 24.1, 31.0). TME specimen was complete or near complete in 94.5% of cases and the rates of positive circumferential radial margin and distal resection margin were 2.0% and 0.3%, respectively. Median follow-up time was 30.7 months as calculated using reverse-KM estimator (CI 28.1-33.8) and there were 9 cases (2.5%) of local recurrence not accounting for competing risk. The 3-year estimated rate of disease recurrence was 19% (CI 15-25%) and the 3-year estimated overall survival was 90% (CI 87-94%). CONCLUSION: This large multicenter study confirms the oncologic safety and perioperative benefits of taTME for rectal cancer when performed by experienced surgeons at experienced referral centers.

Immediate Postoperative Change in the Upper Instrumented Screw-Vertebra Angle Is a Predictor for Proximal Junctional Kyphosis and Failure.

STUDY DESIGN: Retrospective review. OBJECTIVES: To determine if change in position of upper instrumented vertebral (UIV) screw between intraoperative prone and immediate postoperative standing radiographs is a predictor for proximal junctional kyphosis or failure (PJK/PJF). SUMMARY OF BACKGROUND DATA: Cranially directed UIV screws on post-operative radiographs have been found to be associated with PJK. Change in the screw position between intraoperative and immediate postoperative radiographs has not been studied. METHODS: Patients with posterior fusion ≥3 levels and UIV at or distal to T8, and minimum 2-year follow-up were identified from a single center database. Primary outcomes were radiographic PJK/PJF or revision for PJK/PJF. Demographic, surgical and radiographic variables, including intraoperative screw-vertebra (S-V) angle, change in S-V angle, direction of UIV screw (cranial-neutral-caudal) and rod-vertebra (R-V) angle were collected. RESULTS: 143 cases from 110 patients were included with a mean age of 62.9 years and a follow-up of 3.5 years. 54 (38%) cases developed PJK/PJF, of whom 30 required a revision. Mean S-V angle was -0.9°±5.5° intraoperative and -2.8°±5.5° postoperative. The group with PJK/PJF had a mean S-V angle change of -2.5°±2.4 while the rest had a change of -1.0°±1.6 (P=0.010). When the change in S-V angle was <5°, 33% developed PJK, this increased to 80% when it was ≥5° (P=0.001). Revision for PJK/PJF increased from 16% to 60% when S-V angle changed ≥5° (P=0.001). Regression analysis showed S-V angle change as a significant risk factor for PJK/PJF (P=0.047, OR=1.58) and for revision due to PJK/PJF (P=0.009, OR=2.21). CONCLUSIONS: Change in the S-V angle from intraop prone to immediate postop standing radiograph is a strong predictor for PJK/PJF and for revision. For each degree of S-V angle change, odds of revision for PJK/PJF increases by 2.2x. A change of 5° should alert the surgeon to the likely development of PJK/PJF requiring revision.

Stereotactic Radiosurgery for Ependymoma in Pediatric and Adult Patients: A Single-Institution Experience.

BACKGROUND AND OBJECTIVES: Ependymoma is commonly classified as World Health Organization grade 2 with the anaplastic variant categorized as grade 3. Incomplete resection or anaplastic features can result in unfavorable outcomes. Stereotactic radiosurgery (SRS) provides a minimally invasive approach for recurrent ependymomas. Our study investigates the efficacy and safety of SRS for grade 2 and 3 ependymomas in pediatric and adult populations. METHODS: We conducted a retrospective analysis on 34 patients with 75 ependymomas after CyberKnife SRS between 1998 and 2023. Fourteen were pediatric (3-18 years), and 20 were adult (19-75 years) patients. The median age was 21 years, and the median tumor volume was 0.64 cc. The median single-fraction equivalent dose was 16.6 Gy, with SRS administered at 77% of the median isodose line. RESULTS: After a median follow-up of 42.7 months (range: 3.8-438.3), 22.7% of ependymomas progressed. The 5-year local tumor control rate was 78.1%, varying between 59.6% and 90.2% for children and adults, with grade 2 at 85.9% compared with 58.5% for grade 3 tumors. The 5-year overall survival rate was 73.6%, notably higher in adults (94.7%) than in children (41%), and 100% for grade 2 but decreased to 35.9% for grade 3 patients. The 5-year progression-free survival rate was 68.5%, with 78.3% and 49.2% for adults and children, respectively, and a favorable 88.8% for grade 2, contrasting with 32.6% for grade 3 patients. Symptom improvement was observed in 85.3% of patients. Adverse radiation effects occurred in 21.4% of pediatric patients. CONCLUSION: Our study supports SRS as a viable modality for pediatric and adult patients with grade 2 and 3 ependymomas. Despite lower local tumor control in pediatric and grade 3 cases, integrating SRS holds promise for improved outcomes. Emphasizing careful patient selection, personalized treatment planning, and long-term follow-up is crucial for optimal neurosurgical outcomes.

Protocol for affinity purification-mass spectrometry interactome profiling in larvae of Drosophila melanogaster.

Many techniques exist for the identification of protein interaction networks. We present a protocol that relies on an affinity purification-mass spectrometry (AP-MS) approach to detect proteins that co-purify with a tagged bait of interest from Drosophila melanogaster larval muscles using the GAL4/upstream activating sequence (UAS) expression system. We also describe steps for the isolation and identification of protein complexes, followed by streamlined bioinformatics analysis for rapid and reproducible results. This protocol can be extended to investigate protein interactions in other tissues. For complete details on the use and execution of this protocol, please refer to Guo et al.1.

Novel anti-inflammatory effects of the IL-1 receptor in kidney myeloid cells following ischemic AKI.

Introduction: Acute kidney injury (AKI) is one of the most common causes of organ failure in critically ill patients. Following AKI, the canonical pro-inflammatory cytokine interleukin-1ß (IL-1ß) is released predominantly from activated myeloid cells and binds to the interleukin-1 receptor R1 (IL-1R1) on leukocytes and kidney parenchymal cells. IL-1R1 on kidney tubular cells is known to amplify the immune response and exacerbate AKI. However, the specific role of IL-1R1 on myeloid cells during AKI is poorly understood. The objective of the present study was to elucidate the function of myeloid cell IL-1R1 during AKI. As IL-1R1 is known to signal through the pro-inflammatory Toll-like receptor (TLR)/MyD88 pathway, we hypothesized that myeloid cells expressing IL-1R1 would exacerbate AKI. Methods: IL-1R1 was selectively depleted in CD11c+-expressing myeloid cells with CD11cCre + /IL-1R1 fl/fl (Myel KO) mice. Myel KO and littermate controls (CD11cCre - /IL-1R1 fl/fl-Myel WT) were subjected to kidney ischemia/reperfusion (I/R) injury. Kidney injury was assessed by blood urea nitrogen (BUN), serum creatinine and injury marker neutrophil gelatinase-associated lipocalin (NGAL) protein expression. Renal tubular cells (RTC) were co-cultured with CD11c+ bone marrow-derived dendritic cells (BMDC) from Myel KO and Myel WT mice. Results: Surprisingly, compared to Myel WT mice, Myel KO mice displayed exaggerated I/R-induced kidney injury, as measured by elevated levels of serum creatinine and BUN, and kidney NGAL protein expression. In support of these findings, in vitro co-culture studies showed that RTC co-cultured with Myel KO BMDC (in the presence of IL-1ß) exhibited higher mRNA levels of the kidney injury marker NGAL than those co-cultured with Myel WT BMDC. In addition, we observed that IL-1R1 on Myel WT BMDC preferentially augmented the expression of anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1ra/Il1rn), effects that were largely abrogated in Myel KO BMDC. Furthermore, recombinant IL-1Ra could rescue IL-1ß-induced tubular cell injury. Discussion: Our findings suggest a novel function of IL-1R1 is to serve as a critical negative feedback regulator of IL-1 signaling in CD11c+ myeloid cells to dampen inflammation to limit AKI. Our results lend further support for cell-specific, as opposed to global, targeting of immunomodulatory agents.