Faculty Bibliography

BACKGROUND/UNASSIGNED:This study compares outcomes and complications of patients with Bado II Monteggia fracture-dislocations that required radial head fixation or replacement based upon approach to the radial head. METHODS/UNASSIGNED:A retrospective review was performed of 159 consecutive patients with proximal ulna fractures and a radial head dislocation or fracture (Monteggia Variant). Injuries were classified by Bado type. Forty-one patients with Bado II Monteggia injuries treated with either a radial head replacement or fixation with complete follow up were included. Demographics, injury information, surgical details, and follow up information including elbow range of motion (ROM) and complications were collected. A trans-osseous posterior (TOP) approach working through the ulna fracture to address the radial head first was used in 19 patients, while 22 patients had their radial head treated via a separate lateral (Kocher) interval after ulnar fixation. Ulnar plate fixation was performed for all patients. Comparisons were made using independent t-tests. RESULTS/UNASSIGNED:Forty-one Monteggia lesions treated through TOP (19, 46 %) or Kocher (22, 64 %) approaches underwent a radial head replacement (33, 80.5 %) or fracture repair (8, 19.5 %) with a mean final follow-up of 15.3 months. At all post-operative visits, groups displayed similar rates of functional elbow ROM. At latest follow-up rates of patient-reported pain, ultimate elbow ROM, time to radiographic healing were equivalent. No significant differences were observed in ulna non-union, joint malalignment, post-operative nerve injury, post-operative infection, heterotopic ossification, incidence of hardware failure, patient-reported pain, and rate of removal of symptomatic hardware. Sub-analysis of radial head replacement versus fixation revealed equivalent percentage of patients with full ROM at each post-operative time point. CONCLUSION/UNASSIGNED:For Bado II Monteggia fracture-dislocations, the surgical approach to the radial head-TOP versus Kocher-does not influence ultimate patient outcomes or complication rates. Radial head replacement and fixation provide comparable results. LEVEL OF EVIDENCE/UNASSIGNED:III.

BACKGROUND & AIM/UNASSIGNED:Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing health issue. Identifying factors that prevent hepatic lipid accumulation could inform new MASLD prevention or treatment strategies. We previously demonstrated that adipocyte microsomal triglyceride transfer protein (MTP) regulates intracellular lipolysis by inhibiting adipose triglyceride lipase activity. The aim of this study was to investigate the impact of adipose MTP deficiency on MASLD. METHODS/UNASSIGNED: RESULTS/UNASSIGNED: CONCLUSION/UNASSIGNED:These findings highlight the importance of regulated FA flux from adipose tissue to the liver and the liver's adaptive capacity to utilize adipose-derived FAs in maintaining hepatic health. Modulation of adipocyte FA release may represent a therapeutic strategy to reduce hepatic steatosis. IMPACT AND IMPLICATIONS/UNASSIGNED:This study provides significant insights into the role of adipose-specific microsomal triglyceride transfer protein in regulating hepatic lipid metabolism and its potential implications for treating metabolic dysfunction-associated steatotic liver disease. By demonstrating that microsomal triglyceride transfer protein deficiency in adipose tissue leads to increased fatty acid oxidation and reduced hepatic steatosis through enhanced PPARα activation, the research underscores the importance of adipose-liver crosstalk in maintaining liver health. These findings suggest that targeting adipocyte fatty acid release could be a promising therapeutic strategy to mitigate hepatic lipid accumulation and combat metabolic dysfunction-associated steatotic liver disease, offering a novel approach to addressing this growing health issue.

Phosphorylation of hundreds of protein extracellular domains is mediated by two kinase families but the functional role of these kinases is underexplored. We find that the presynaptic release of the tyrosine-directed ectokinase, vertebrate lonesome kinase (VLK/Pkdcc), is necessary and sufficient for the direct extracellular interaction between EphB2 and GluN1 at synapses for phosphorylation of the ectodomain of EphB2 and mediation of injury-induced pain. Pkdcc is an essential gene in the nervous system, and VLK is enriched at synapses and released from neurons in an activity- and soluble N-ethylmaleimide-sensitive factor activating protein receptor (SNARE)-dependent manner to drive extracellular interactions. Our results show that presynaptic sensory neuron-specific VLK knockout attenuates postsurgical pain in mice without changing sensorimotor performance, suggesting that VLK critically regulates synaptic protein-protein interactions and acute pain in response to injury.

Under osmotic stress, bacteria express a heterotetrameric protein complex, KdpFABC, which functions as an ATP-dependent K⁺ pump to maintain intracellular potassium levels. The subunit KdpA belongs to the superfamily of K⁺ transporters and adopts pseudo fourfold symmetry with a membrane-embedded selectivity filter as seen in K⁺ channels. KdpB belongs to the superfamily of P-type ATPases with a conserved binding site for ions within the membrane domain and three cytoplasmic domains that orchestrate ATP hydrolysis via an aspartyl phosphate intermediate. Previous work hypothesized that K⁺ moves parallel to the membrane plane through a 40 Å long tunnel that connects the selectivity filter of KdpA with a canonical binding site in KdpB. In the current work, we have reconstituted KdpFABC into lipid nanodiscs and used cryo-EM to image the wild-type pump under turnover conditions. We present a 2.1 Å structure of the E1~P·ADP conformation, which reveals new features of the conduction pathway. This map shows strong densities within the selectivity filter and at the canonical binding site, consistent with K⁺ bound at each of these sites in this conformation. Many water molecules occupy a vestibule and the proximal end of the tunnel, which becomes markedly hydrophobic and dewetted at the subunit interface. We go on to use ATPase and ion transport assays to assess effects of numerous mutations along this proposed conduction pathway. The results confirm that K⁺ ions pass through the tunnel and support the existence of a low-affinity site in KdpB for releasing these ions to the cytoplasm. Taken together, these data shed new light on the unique partnership between a transmembrane channel and an ATP-driven pump in maintaining the large electrochemical K⁺ gradient essential for bacterial survival.

Expression of the IgE BCR is associated with increased B cell apoptosis, yet in persistent allergy, sustained production of IgE antibodies in the absence of allergen exposure suggests the existence of long-lived IgE plasma cells (PCs). Here we studied the development and localization of IgE PCs in mouse models of allergy. After immunization, IgE PCs underwent maturation in spleen and lymph nodes, acquiring a stable MHCII^loCD93⁺CD98^hiBCR^lo phenotype. Mature IgE PCs had a distinct transcriptional profile adapted to high protein synthesis, glycosylation, and survival and resisted BCR-crosslinking-induced apoptosis. Immunization induced a burst of short-lived IgE PC formation, followed by a reduced differentiation rate over time, compared with IgG1 PCs. Timestamping of PCs revealed long-lived IgE PCs that localize to the spleen, in addition to the bone marrow (BM). Thus, immune challenge can generate both short-lived and long-lived IgE PCs, with long-lived IgE PCs in spleen and BM contributing to allergy persistence.

Insulin resistance impairs benefits of lipid-lowering treatment as evidenced by higher cardiovascular risk in individuals with type 2 diabetes versus those without. Because platelet activity is higher in insulin-resistant patients and promotes atherosclerosis progression, we questioned whether platelets impair inflammation resolution in plaques during lipid-lowering. In mice with obesity and insulin resistance, we induced advanced plaques, then implemented lipid-lowering to promote atherosclerotic plaque inflammation-resolution. Concurrently, mice were treated with either platelet-depleting or control antibodies for 3 weeks. Platelet activation and insulin resistance were unaffected by lipid-lowering. Both antibody-treated groups showed reduced plaque macrophages, but plaque cellular and structural composition differed. In platelet-depleted mice, scRNA seq revealed dampened inflammatory gene expression in plaque macrophages and an expansion of a subset of Fcgr4+ macrophages having features of inflammation-resolving, phagocytic cells. Necrotic core size was smaller and collagen content greater, resembling stable human plaques. Consistent with the mouse results, clinical data showed that patients with lower platelet counts had decreased pro-inflammatory signaling pathways in circulating non-classical monocytes after lipid-lowering. These findings highlight that platelets hinder inflammation-resolution in atherosclerosis during lipid-lowering treatment. Identifying novel platelet-targeted therapies following lipid-lowering treatment in individuals with insulin resistance may be a promising therapeutic approach to promote atherosclerotic plaque inflammation-resolution.

INTRODUCTION/BACKGROUND:Tibial plateau fractures are some of the most commonly treated injuries around the knee and loss of range of motion has a significant effect on post-operative outcomes, very few studies have demonstrated the impact of flexion contractures. The purpose of this study was to determine the effect that development of a knee flexion contracture has on outcomes following operative repair of tibial plateau fractures. METHODS:Patients operatively treated for tibial plateau fractures (Schatzker II, IV, V, and VI) between 2005-2024 at a multi-center academic urban hospital system were included in this retrospective comparative study. Patients were grouped into 3 cohorts: 1. Full extension (FE), 2. 5-10 degrees of flexion contracture (Mild, ME) and 3. Greater than 10 degrees of flexion (Severe, SE) contracture at 6 months post-operatively. Patients with contracture were matched to patients who regained full extension based on age and Schatzker classification. Statistical analysis was used to evaluate outcomes including patient reported pain levels, Short Musculoskeletal Function Assessment (SMFA) scores, complication rates and reoperation rates. RESULTS:The cohort consisted of 3 groups of 30 patients (14 Schatzker II, 5 Schatzker IV, 3 Schatzker V, and 8 Schatzker VI). The average knee flexion contracture for the mild cohort was 5 degrees and the average knee flexion contracture for the severe cohort was 12.7 degrees. Patients who experienced flexion contracture had poorer SMFA scores at 6 months, and those in the severe cohort had the poorest SMFA scores (112.6) when compared to those with full extension at 6 months (77.7) (p<0.001). Flexion contractures were associated with higher rates of fracture related infection (FRI) (p =0.002). Patients with flexion contracture also had a higher rate of subsequent re-operation, with 36.7% of the ME undergoing re-operation and 40% of SE undergoing re-operation. CONCLUSIONS:Patients who developed a flexion contracture following repair of a tibial plateau fracture experienced worse outcomes, higher rates of complications, increased pain, and poorer function at long term follow up compared to those who achieved full knee extension.

BACKGROUND:Accumulated levels of mutant huntingtin protein (mHTT) and its fragments are considered contributors to the pathogenesis of Huntington's disease (HD). Stimulating autophagy may enhance clearance of mHTT and its aggregates which has been considered as a possible therapeutic strategy. However, the role and competence of the autophagy-lysosomal pathway (ALP) during HD progression in the human disease remains largely unknown. METHODS:Here, we used multiplex confocal and ultrastructural immunocytochemical analyses of ALP functional markers in relation to mHTT aggresome pathology in striatum and the less affected cortex or cerebellum of HD brains staged from Grade HD2 to HD4 by Vonsattel neuropathological criteria compared to controls. RESULTS:Immunolabeling revealed the localization of HTT/mHTT in ALP vesicular compartments labeled by autophagy-related adaptor proteins sequestosome 1 (p62/SQSTM1) and ubiquitin, and cathepsin D (CTSD) as well as HTT-positive inclusions. Although comparatively normal at HD2, neurons at later HD stages exhibited progressive enlargement and clustering of CTSD-immunoreactive autolysosomes/lysosomes and, ultrastructurally, autophagic vacuole/lipofuscin granules accumulated progressively, more prominently in striatum than cortex. These changes were accompanied by rises in levels of HTT/mHTT and p62/SQSTM1, particularly their fragments, in striatum but not in the cortex, and by increases of LAMP1 and LAMP2 RNA and LAMP1 protein. In addition, cargo-loaded autophagosomes and cathepsin-positive autolysosomes were readily observed, implying a lack of significant blockage in autophagosome formation and autophagosome-lysosome fusion. CONCLUSIONS:The findings collectively suggest that upregulated lysosomal biogenesis and preserved proteolysis maintain autophagic clearance in early-stage HD, but the observed progressive HTT build-up and AL accumulation at advanced disease stages may signify a failure in autophagy substrate clearance. These findings support the prospect that ALP stimulation applied at early disease stages, when clearance machinery is fully competent, could lead to therapeutic benefits in HD patients.

INTRODUCTION/BACKGROUND:The purpose of this study was to assess the effect of an acute traumatic meniscus tear that required repair in association with a tibial plateau fracture repair on outcomes. METHODS:Over a 17-year period, 843 patients presented with a tibial plateau fracture and were followed prospectively. 721 patients with Schatzker I-VI fractures were treated operatively via a standardized algorithm. 161 tibial plateau fractures (22.3 %) had an associated meniscus tear that underwent acute repair at the time of bony fixation. These patients were compared to operatively repaired tibial plateau fracture patients with no meniscus injury (NMR). Demographics were collected and outcomes including: radiographic healing, knee range of motion (ROM), and complication rates, were recorded. In addition, re-operation rates were compared and any reoperation for meniscus repair failure identified. All patients had a minimum of 1 year follow up. RESULTS:A total of 524 patients with a mean of 21.4 (range: 12-120) months follow up met inclusion criteria. Patients in the meniscus repair (MR) cohort had poorer knee extension (1.01 degrees, range: 0-30 degrees) compared to the NMR cohort (0.07 degrees, range: 0-10 degrees) (p < 0.001), in addition to poorer knee flexion (123 degrees, range: 0-145 degrees, p = 0.024). Additionally, MR patients reported higher pain scores (mean: 3 and range: 0-8, p = 0.005) at latest follow up. Finally, MR patients had higher rates of infection (8.1 % vs. 3.3 %, p = 0.025) and lateral collapse of the joint (p = 0.032). CONCLUSION/CONCLUSIONS:Patients who had a meniscus repair at the time of tibial plateau fracture repair were found to have poorer knee ROM, more patient reported pain at minimum 12 (mean 24) months post-operation. Additionally, these patients developed more post-operative complications than those patients who did not undergo a meniscus repair.