Deep-learning reconstructed lumbar spine 3D MRI for surgical planning: pedicle screw placement and geometric measurements compared to CT.

PURPOSE: To test equivalency of deep-learning 3D lumbar spine MRI with "CT-like" contrast to CT for virtual pedicle screw planning and geometric measurements in robotic-navigated spinal surgery. METHODS: Between December 2021 and June 2022, 16 patients referred for spinal fusion and decompression surgery with pre-operative CT and 3D MRI were retrospectively assessed. Pedicle screws were virtually placed on lumbar (L1-L5) and sacral (S1) vertebrae by three spine surgeons, and metrics (lateral deviation, axial/sagittal angles) were collected. Vertebral body length/width (VL/VW) and pedicle height/width (PH/PW) were measured at L1-L5 by three radiologists. Analysis included equivalency testing using the 95% confidence interval (CI), a margin of ± 1 mm (± 2.08° for angles), and intra-class correlation coefficients (ICCs). RESULTS: Across all vertebral levels, both combined and separately, equivalency between CT and MRI was proven for all pedicle screw metrics and geometric measurements, except for VL at L1 (mean difference: - 0.64 mm; [95%CI - 1.05, - 0.24]), L2 (- 0.65 mm; [95%CI - 1.11, - 0.20]), and L4 (- 0.78 mm; [95%CI - 1.11, - 0.46]). Inter- and intra-rater ICC for screw metrics across all vertebral levels combined ranged from 0.68 to 0.91 and 0.89-0.98 for CT, and from 0.62 to 0.92 and 0.81-0.97 for MRI, respectively. Inter- and intra-rater ICC for geometric measurements ranged from 0.60 to 0.95 and 0.84-0.97 for CT, and 0.61-0.95 and 0.93-0.98 for MRI, respectively. CONCLUSION: Deep-learning 3D MRI facilitates equivalent virtual pedicle screw placements and geometric assessments for most lumbar vertebrae, with the exception of vertebral body length at L1, L2, and L4, compared to CT for pre-operative planning in patients considered for robotic-navigated spine surgery.

Does image-guided biopsy of discitis-osteomyelitis provide meaningful information to impact clinical management?

OBJECTIVE: The aims of this study are to assess the diagnostic yield of image-guided biopsy for discitis-osteomyelitis (DO), identify factors associated with biopsy yield (laboratory, pre-defined MRI findings, and biopsy technique), and impact of biopsy on management of patients appropriately selected according to the Infectious Disease Society of America guidelines (IDSA). MATERIALS AND METHODS: This is a retrospective review of patients who underwent biopsy for suspected DO from 2011 to 2019. Reference standards to establish diagnosis of DO in order were histopathology/microbiology from biopsy or subsequent surgical sampling, positive blood culture or serology, and imaging/clinical follow-up. Laboratory markers, pre-biopsy antibiotics and MRI features, procedural-related variables, and impact of biopsy on management were assessed. Multivariable logistic regression was also performed. RESULTS: Out of 97 included patients, 78 were diagnosed with DO. Overall sensitivity of biopsy for detecting DO was 41.0% (32/78), including 10 patients with positive histopathology only, 14 with positive biopsy culture only, and 8 with both. Elevated ESR (p < 0.001) and epidural collection on MRI (p = 0.008) were associated with higher biopsy yield (63.6% and 68.6%, respectively) in a multivariable model. Procedural variables were not associated with yield. Biopsy results impacted the management in 19/77 (24.7%) patients, of whom 15/19 (78.9%) had treatment de-escalation and 4/19 (21.0%) had treatment escalation including starting new anti-tuberculous and anti-fungal regimens. CONCLUSION: Sensitivity of biopsy for detecting DO was 41.0%. When IDSA guidelines are followed, biopsy provided impactful information that changed the management in 24.7% of patients. Evaluation for elevated ESR and epidural collection can help improve yield and patient selection for biopsy.

Intravenous Immunoglobulin (IVIG) Attenuates TNF-Induced Pathologic Bone Resorption and Suppresses Osteoclastogenesis by Inducing A20 Expression.

Investigations on the therapeutic effects of intravenous immunoglobulin (IVIG) have focused on the suppression of autoantibody and immune complex-mediated inflammatory pathogenesis. Inflammatory diseases such as rheumatoid arthritis are often accompanied by excessive bone erosion but the effect of IVIG on osteoclasts, bone-resorbing cells, has not been studied. Here, we investigate whether IVIG directly regulates osteoclast differentiation and has therapeutic potential for suppressing osteoclast-mediated pathologic bone resorption. IVIG or cross-linking of Fcγ receptors with plate-bound IgG suppressed receptor activator of nuclear factor-κ B ligand (RANKL)-induced osteoclastogenesis and expression of osteoclast-related genes such as integrin ß3 and cathepsin K in a dose-dependent manner. Mechanistically, IVIG or plate-bound IgG suppressed osteoclastogenesis by downregulating RANKL-induced expression of NFATC1, the master regulator of osteoclastogenesis. IVIG suppressed NFATC1 expression by attenuating RANKL-induced NF-κB signaling, explained in part by induction of the inflammatory signaling inhibitor A20. IVIG administration attenuated in vivo osteoclastogenesis and suppressed bone resorption in the tumor necrosis factor (TNF)-induced calvarial osteolysis model. Our findings show that, in addition to suppressing inflammation, IVIG directly inhibits osteoclastogenesis through a mechanism involving suppression of RANK signaling. Direct suppression of osteoclast differentiation may provide beneficial effects on preserving bone mass when IVIG is used to treat rheumatic disorders.

Effects of local vanadium delivery on diabetic fracture healing.

This study evaluated the effect of local vanadyl acetylacetonate (VAC), an insulin mimetic agent, upon the early and late parameters of fracture healing in rats using a standard femur fracture model. Mechanical testing, and radiographic scoring were performed, as well as histomorphometry, including percent bone, percent cartilage, and osteoclast numbers. Fractures treated with local 1.5 mg/kg VAC possessed significantly increased mechanical properties compared to controls at 6 weeks post-fracture, including increased torque to failure (15%; p = 0.046), shear modulus (89%; p = 0.043), and shear stress (81%; p = 0.009). The radiographic scoring analysis showed increased cortical bridging at 4 weeks and 6 weeks (119%; p = 0.036 and 209%; p = 0.002) in 1.5 mg/kg VAC treated groups. Histomorphometry of the fracture callus at days 10 and 14 showed increased percent cartilage (121%; p = 0.009 and 45%; p = 0.035) and percent mineralized tissue (66%; p = 0.035 and 58%; p = 0.006) with local VAC treated groups compared to control. Additionally, fewer osteoclasts were observed in the local VAC treated animals as compared to controls at day 14 (0.45% ± 0.29% vs. 0.83% ± 0.36% of callus area; p = 0.032). The results suggest local administration of VAC acts to modulate osteoclast activity and increase percentage of early callus cartilage, ultimately enhancing mechanical properties comparably to non-diabetic animals treated with local VAC. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2174-2180, 2017.

Local manganese chloride treatment accelerates fracture healing in a rat model.

This study investigated the effects of local delivery of manganese chloride (MnCl2), an insulin-mimetic compound, upon fracture healing using a rat femoral fracture model. Mechanical testing, histomorphometry, and immunohistochemistry were performed to assess early and late parameters of fracture healing. At 4 weeks post-fracture, maximum torque to failure was 70% higher (P<0.05) and maximum torsional rigidity increased 133% (P<0.05) in animals treated with 0.125 mg/kg MnCl2 compared to saline controls. Histological analysis of the fracture callus revealed percent new mineralized tissue was 17% higher (P<0.05) at day 10. Immunohistochemical analysis of the 0.125 mg/kg MnCl2 treated group, compared to saline controls, showed a 379% increase in the density of VEGF-C+ cells. In addition, compared to saline controls, the 0.125 mg/kg MnCl2 treated group showed a 233% and 150% increase in blood vessel density in the subperiosteal region at day 10 post-fracture as assessed by detection of PECAM and smooth muscle α actin, respectively. The results suggest that local MnCl2 treatment accelerates fracture healing by increasing mechanical parameters via a potential mechanism of amplified early angiogenesis leading to increased osteogenesis. Therefore, local administration of MnCl2 is a potential therapeutic adjunct for fracture healing.

Inhibition of osteoclastogenesis and inflammatory bone resorption by targeting BET proteins and epigenetic regulation.

Emerging evidence suggests that RANKL-induced changes in chromatin state are important for osteoclastogenesis, but these epigenetic mechanisms are not well understood and have not been therapeutically targeted. In this study, we find that the small molecule I-BET151 that targets bromo and extra-terminal (BET) proteins that 'read' chromatin states by binding to acetylated histones strongly suppresses osteoclastogenesis. I-BET151 suppresses pathologic bone loss in TNF-induced inflammatory osteolysis, inflammatory arthritis and post-ovariectomy models. Transcriptome analysis identifies a MYC-NFAT axis important for osteoclastogenesis. Mechanistically, I-BET151 inhibits expression of the master osteoclast regulator NFATC1 by suppressing expression and recruitment of its newly identified upstream regulator MYC. MYC is elevated in rheumatoid arthritis macrophages and its induction by RANKL is important for osteoclastogenesis and TNF-induced bone resorption. These findings highlight the importance of an I-BET151-inhibited MYC-NFAT axis in osteoclastogenesis, and suggest targeting epigenetic chromatin regulators holds promise for treatment of inflammatory and oestrogen deficiency-mediated pathologic bone resorption.

Genetic analysis of mlh3 mutations reveals interactions between crossover promoting factors during meiosis in baker's yeast.

Crossing over between homologous chromosomes occurs during the prophase of meiosis I and is critical for chromosome segregation. In baker's yeast, two heterodimeric complexes, Msh4-Msh5 and Mlh1-Mlh3, act in meiosis to promote interference-dependent crossing over. Mlh1-Mlh3 also plays a role in DNA mismatch repair (MMR) by interacting with Msh2-Msh3 to repair insertion and deletion mutations. Mlh3 contains an ATP-binding domain that is highly conserved among MLH proteins. To explore roles for Mlh3 in meiosis and MMR, we performed a structure-function analysis of eight mlh3 ATPase mutants. In contrast to previous work, our data suggest that ATP hydrolysis by both Mlh1 and Mlh3 is important for both meiotic and MMR functions. In meiotic assays, these mutants showed a roughly linear relationship between spore viability and genetic map distance. To further understand the relationship between crossing over and meiotic viability, we analyzed crossing over on four chromosomes of varying lengths in mlh3Δ mms4Δ strains and observed strong decreases (6- to 17-fold) in crossing over in all intervals. Curiously, mlh3Δ mms4Δ double mutants displayed spore viability levels that were greater than observed in mms4Δ strains that show modest defects in crossing over. The viability in double mutants also appeared greater than would be expected for strains that show such severe defects in crossing over. Together, these observations provide insights for how Mlh1-Mlh3 acts in crossover resolution and MMR and for how chromosome segregation in Meiosis I can occur in the absence of crossing over.

Negative regulation of osteoclast precursor differentiation by CD11b and ß2 integrin-B-cell lymphoma 6 signaling.

Negative regulation of osteoclastogenesis is important for bone homeostasis and prevention of excessive bone resorption in inflammatory and other diseases. Mechanisms that directly suppress osteoclastogenesis are not well understood. In this study we investigated regulation of osteoclast differentiation by the ß2 integrin CD11b/CD18 that is expressed on myeloid lineage osteoclast precursors. CD11b-deficient mice exhibited decreased bone mass that was associated with increased osteoclast numbers and decreased bone formation. Accordingly, CD11b and ß2 integrin signaling suppressed osteoclast differentiation by preventing receptor activator of NF-κB ligand (RANKL)-induced induction of the master regulator of osteoclastogenesis nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) and of downstream osteoclast-related NFATc1 target genes. CD11b suppressed induction of NFATc1 by the complementary mechanisms of downregulation of RANK expression and induction of recruitment of the transcriptional repressor B-cell lymphoma 6 (BCL6) to the NFATC1 gene. These findings identify CD11b as a negative regulator of the earliest stages of osteoclast differentiation, and provide an inducible mechanism by which environmental cues suppress osteoclastogenesis by activating a transcriptional repressor that makes genes refractory to osteoclastogenic signaling.