Inhibition of endothelial histone deacetylase 2 shifts endothelial-mesenchymal transitions in cerebral arteriovenous malformation models.

Cerebral arteriovenous malformations (AVMs) are the most common vascular malformations worldwide and the leading cause of hemorrhagic strokes that may result in crippling neurological deficits. Here, using newly generated mouse models, we uncovered that cerebral endothelial cells (ECs) acquired mesenchymal markers and caused vascular malformations. Interestingly, we found that limiting endothelial histone deacetylase 2 (HDAC2) prevented cerebral ECs from undergoing mesenchymal differentiation and reduced cerebral AVMs. We found that endothelial expression of HDAC2 and enhancer of zeste homolog 1 (EZH1) was altered in cerebral AVMs. These alterations changed the abundance of H4K8ac and H3K27me in the genes regulating endothelial and mesenchymal differentiation, which caused the ECs to acquire mesenchymal characteristics and form AVMs. Together, this investigation demonstrated that the induction of HDAC2 altered specific histone modifications, which resulted in mesenchymal characteristics in the ECs and cerebral AVMs. The results provided insight into the epigenetic impact on AVMs.

Erector spinae plane block level does not impact analgesic efficacy in enhanced recovery for lumbar spine surgery.

BACKGROUND CONTEXT: Postoperative pain control following spine surgery can be difficult. The Enhanced Recovery After Surgery (ERAS) programs use multimodal approaches to manage postoperative pain. While an erector spinae plane block (ESPB) is commonly utilized, the ideal distance for injection from the incision, referred to as the ES (ESPB to mid-surgical level) distance, remains undetermined. PURPOSE: We evaluated the impact of varying ES distances for ESPB on Numerical Rating Scale (NRS) measures of postoperative pain within the ERAS protocol. STUDY DESIGN/SETTING: Retrospective observational study. PATIENT SAMPLE: Adult patients who underwent elective lumbar spine fusion surgery. OUTCOME MEASURES: Primary outcome measures include the comparative postoperative NRS scores across groups at immediate (T1), 24 (T2), 48 (T3), and 72 (T4) hours postsurgery. For secondary outcomes, a propensity matching analysis compared these outcomes between the ERAS and non-ERAS groups, with opioid-related recovery metrics also assessed. METHODS: All included patients were assigned to one of three ERAS groups according to the ES distance: Group 1 (G1, ES > 3 segments), Group 2 (G2, ES = 2-3 segments), and Group 3 (G3, ES<2 segments). Each patient underwent a bilateral ultrasound-guided ESPB with 60 mL of diluted ropivacaine or bupivacaine. RESULTS: Patients within the ERAS cohort reported mild pain (NRS < 3), with no significant NRS variation across G1 to G3 at any time. Sixty-five patients were matched across ERAS and non-ERAS groups. The ERAS group exhibited significantly lower NRS scores from T1 to T3 than the non-ERAS group. Total morphine consumption during hospitalization was 26.7 mg for ERAS and 41.5 mg for non-ERAS patients. The ERAS group resumed water and food intake sooner and had less postoperative nausea and vomiting. CONCLUSIONS: ESPBs can be effectively administered at or near the mid-surgical level to the low thoracic region for lumbar spine surgeries. Given challenges with sonovisualization, a lumbar ESPB may be preferred to minimize the risk of inadvertent pleural injury.

CDK1 inhibition reduces osteogenesis in endothelial cells in vascular calcification.

Vascular calcification is a severe complication of cardiovascular diseases. Previous studies demonstrated that endothelial lineage cells transitioned into osteoblast-like cells and contributed to vascular calcification. Here, we found that inhibition of cyclin-dependent kinase (CDK) prevented endothelial lineage cells from transitioning to osteoblast-like cells and reduced vascular calcification. We identified a robust induction of CDK1 in endothelial cells (ECs) in calcified arteries and showed that EC-specific gene deletion of CDK1 decreased the calcification. We found that limiting CDK1 induced E-twenty-six specific sequence variant 2 (ETV2), which was responsible for blocking endothelial lineage cells from undergoing osteoblast differentiation. We also found that inhibition of CDK1 reduced vascular calcification in a diabetic mouse model. Together, the results highlight the importance of CDK1 suppression and suggest CDK1 inhibition as a potential option for treating vascular calcification.

MRI-based lesion quality score assessing ossification of the posterior longitudinal ligament of the cervical spine.

BACKGROUND CONTEXT: No method currently exists for MRI-based determination of ossification of the posterior longitudinal ligament (OPLL) of the cervical spine using objective criteria. PURPOSE: The purpose of this study was to develop an MRI-based score to determine whether a lesion represents a cervical OPLL lesion and to establish the objective diagnostic value. STUDY DESIGN: Retrospective cohort in a single medical institution. PATIENT SAMPLE: Thirty-five patients undergoing surgery for OPLL (Group A) and 99 patients undergoing cervical disc arthroplasty for soft disc herniation (Group B) between 2011 and 2020 were retrospectively included. All OPLL lesions on unenhanced MRI scan were correlated with a corresponding CT scan. Demographics were comparable between the two groups. OUTCOME MEASURES (PHYSIOLOGIC MEASURES): Using unenhanced magnetic resonance imaging (MRI), the T1- and T2- lesion quality (LQ) scores were calculated. Receiver operating characteristic (ROC) analysis was performed to calculate the area-under-the-curve (AUC) of both LQ scores as a predictor of the presence of OPLL. Computed tomography- (CT-) based Hounsfield unit (HU) values of OPLL lesions were obtained and compared with both LQ scores. The LQ scores for MRI scanners from different manufacturers were compared using Student's t test to confirm the validity of the LQ score by scanner type. METHODS: The regions of interest for signal intensity (SI) were defined as the darkest site of the lesion and the cerebrospinal fluid (CSF) at the cerebellomedullary cistern. The T1 and T2 LQ scores were measured as the ratio of the SI at the darkest site of the lesion divided by the SI of the CSF. RESULTS: The T1 and T2 LQ scores in Group A were significantly lower than those in Group B (p < 0.001). ROC analysis determined that T1 and T2 LQ scores of 0.46 and 0.07, respectively, could distinguish the presence of OPLL with an accuracy of 0.93 and 0.89, respectively (p<.001). When the T1 LQ score of the lesion is <0.46, a diagnosis of OPLL may be suspected with 100% sensitivity and 92.3% specificity. The HU of the lesion had a moderate negative correlation with the T1 LQ score (r=-0.665, p<.0001). Both LQ scores were unaffected by manufacturer type. CONCLUSIONS: This study found a correlation between the MRI-based T1 LQ scores and CT-based HU value for identifying OPLL lesions. Additional studies will be needed to validate that the T1 LQ score from the unenhanced MRI scan can identify cervical OPLL.

Two-step regulation by matrix Gla protein in brown adipose cell differentiation.

OBJECTIVE: Bone morphogenetic protein (BMP) signaling is intricately involved in adipose tissue development. BMP7 together with BMP4 have been implicated in brown adipocyte differentiation but their roles during development remains poorly specified. Matrix Gla protein (MGP) inhibits BMP4 and BMP7 and is expressed in endothelial and progenitor cells. The objective was to determine the role of MGP in brown adipose tissue (BAT) development. METHODS: The approach included global and cell-specific Mgp gene deletion in combination with RNA analysis, immunostaining, thermogenic activity, and in vitro studies. RESULTS: The results revealed that MGP directs brown adipogenesis at two essential steps. Endothelial-derived MGP limits triggering of white adipogenic differentiation in the perivascular region, whereas MGP derived from adipose cells supports the transition of CD142-expressing progenitor cells to brown adipogenic maturity. Both steps were important to optimize the thermogenic function of BAT. Furthermore, MGP derived from both sources impacted vascular growth. Reduction of MGP in either endothelial or adipose cells expanded the endothelial cell population, suggesting that MGP is a factor in overall plasticity of adipose tissue. CONCLUSION: MGP displays a dual and cell-specific function in BAT, essentially creating a "cellular shuttle" that coordinates brown adipogenic differentiation with vascular growth during development.

High-resolution liquid level sensor utilizing a microwave photonics interrogated multicore fiber interferometer.

We propose and experimentally demonstrate a high-resolution, high-sensitivity liquid level sensor based on a multicore fiber (MCF) Michelson interferometer (MI), where the sensing fiber is securely affixed to a cantilever beam, such that liquid level variations will change the beam's curvature, meanwhile leading to a substantial phase difference between the two interfering arms of the MI, and the sensor is interrogated using a microwave photonics filter (MPF) system, which can provide greatly enhanced measurement resolution compared to the traditional optical wavelength demodulation methods. The angular position of the MCF is precisely calibrated to ensure optimal sensitivity of the MI sensor. As a result, within a measurement range of up to ±14 cm, the proposed liquid level sensor achieves a sensitivity of 10.35 MHz/cm and an impressive resolution of 0.04835 cm. The proposed sensor has unique advantages of high sensitivity, superior resolution, long-term stability, etc.

Aurora Kinase A Regulates Cell Transitions in Glucocorticoid-Induced Bone Loss.

Glucocorticoid-induced bone loss is a severe and toxic effect of long-term therapy with glucocorticoids, which are currently prescribed for millions of people worldwide. Previous studies have uncovered that glucocorticoids reciprocally converted osteoblast lineage cells into endothelial-like cells to cause bone loss and showed that the modulations of Foxc2 and Osterix were the causative factors that drove this harmful transition of osteoblast lineage cells. Here, we find that the inhibition of aurora kinase A halts this transition and prevents glucocorticoid-induced bone loss. We find that aurora A interacts with the glucocorticoid receptor and show that this interaction is required for glucocorticoids to modulate Foxc2 and Osterix. Together, we identify a new potential approach to counteracting unwanted transitions of osteoblast lineage cells in glucocorticoid treatment and may provide a novel strategy for ameliorating glucocorticoid-induced bone loss.

Preoperative planning of compact zone trajectory is necessary in treating osteoporotic vertebral compression fracture with endplate involvement: A prospective randomized controlled study.

BACKGROUND: This prospective randomized controlled study compares the clinical and radiological outcomes between reduction methods with or without compact trabecular bone during percutaneous kyphoplasty in osteoporotic vertebral fractures. METHODS: The cohort of 100 patients who underwent percutaneous kyphoplasty was randomly divided into group A (guide pin and balloon introduced directly into fracture site) and group B (guide pin and balloon inserted away fracture site). The surgery duration, clinical and radiological outcomes postoperatively and at follow-up, and complications of cement leakage and adjacent fracture were recorded. Patients were followed up for an average of 20.18 months. The clinical outcomes were assessed using the Oswestry Disability Index and visual analog scale. RESULTS: The two groups had similar patient demographics, surgery times, and volume of cement injected. The method using elevation of the collapsed endplate indirectly had no significant influence on radiological outcomes but significantly decreased the occurrence of intradiscal cement leakage and improved 1- and 12-month postoperative functional outcomes. CONCLUSION: Elevating and reinforcing the collapsed endplate rather than just filling the defect during percutaneous kyphoplasty is safe and effective. This technique decreased pain and improved function with lower rates of further collapse of the osteoporotic vertebrae compared to defect-filling alone.

Pilot Study on Percutaneous Delivery of Recombinant Human Bone Morphongenetic Protein-2 Augments Fusion in a Nicotine-impaired Rabbit Fusion Model.

STUDY DESIGN: A nicotine-impaired spinal fusion rabbit model. OBJECTIVE: To examine whether controlled delivery of morselized absorbable collagen sponge recombinant human bone morphogenetic protein-2 (rhBMP2) in a delayed manner postsurgery would allow for improved bone healing. SUMMARY OF BACKGROUND DATA: The current delivery method of rhBMP-2 during surgery causes a burst of rhBMP-2, which is not sustained. Given that bone morphogenetic protein 2 (BMP-2) expression peaks later in the fusion process, there may be the benefit of delivery of rhBMP-2 later in the healing process. METHODS: Sixteen male 1-year-old rabbits underwent a posterolateral spinal fusion with iliac crest bone graft at L5-L6 while being given nicotine to prevent spinal fusion as previously published. Eight were controls, whereas 8 had morselized rhBMP-2 (4.2 mg) injected at the fusion site at 4 weeks postoperatively. Histologic, radiologic, and palpation examinations were performed at 12 weeks to determine fusion status and the volume of bone formed. Hematoxylin and eosin stains were used for histology. A Student t test was used to compare the computed tomography scan measured volume of bone created between the control cohort (CC) and rhBMP-2 delayed delivery cohort (BMP-DDC). RESULTS: Of the total, 7/8 rabbits in the BMP-DDC and 5/8 rabbits in the CC formed definitive fusion with a positive palpation examination, bridging bone between transverse processes on computed tomography scan, and an x-ray showing fusion. Histologic analysis revealed newly remodeled bone within the BMP-DDC. There was an increased average volume of bone formed within the BMP-DDC versus the CC (22.6 ± 13.1 vs 11.1 ± 3.6 cm 3 , P = 0.04). CONCLUSION: Our study shows that injectable morselized absorbable collagen sponge/rhBMP-2 can create twice as much bone within a nicotine-impaired rabbit spine fusion model when delivered 4 weeks out from the time of surgery.

Reducing surgical site infections after spine surgery: the optimal amount of normal saline for intra-wound irrigation.

BACKGROUND CONTEXT: Surgical site infection (SSI) following lumbar surgery can increase healthcare costs and lead to poor clinical outcome. Irrigation of wounds with saline solution is widely accepted globally and safe for nearly all kinds of surgery. However, the efficacy of different volumes of wound irrigation has not been addressed in elective spine surgery. The role and the optimal amount of intraoperative wound saline irrigation in preventing SSI in clean spinal surgery remain unclear. PURPOSE: We aimed to investigate if insufficient intraoperative irrigation may be a risk factor for postoperative SSI. Additionally, we investigated the optimal amount of normal saline (NS) for irrigation to prevent postoperative SSI. STUDY DESIGN: This is a retrospective study of patients with degenerative spinal stenosis who were treated surgically. Patients were grouped according to the amount of intra-wound irrigation during surgery. PATIENT SAMPLE: We included 444 patients with degenerative lumbar spinal conditions who had undergone one to five level open spinal fusion surgeries from January 2015 through April 2020. OUTCOME MEASURES: The definition of superficial or deep SSI in this study was based on the Centers for Disease Control and Prevention criteria for SSI. The fusion status accessed was based on the Bridwell grading system at the final follow-up. Self-reported and clinical outcome measures include visual analog scale and Oswestry Disability Index. METHODS: A total of 193 patients underwent irrigation with a bulb syringe with manual method (B group) with 2,000 mL NS; 251 patients underwent interpulse battery-powered device irrigation (P group) with >6,000 mL NS. Based on our protocolized departmental guidelines, all patients received the same preoperative preparation and standard surgical steps and postoperative care plan. Patients' demographic and surgical parameters were recorded. The main outcome measures included superficial wound infection, deep infection and overall infection. RESULTS: The incidence of overall SSI was 4.66% in the B group and 1.59% in the P group. The univariate analysis revealed a significant correlation with DM and irrigation amount per hour during surgery but not age, BMI, smoking, operative duration, fusion level, or blood loss. We determined the optimal irrigation amount during surgery as 1,400 mL per hour based on the receiver operating characteristic (ROC) curve (sensitivity, 92.3%; specificity, 44.1%). This was statistically significant (p=.033) with an odds ratio of 9.284 (95% confidence interval 1.2-72.0). In the analysis of surgical factors, the infection group had a significantly lower irrigation amount during surgery. To summarize, patients with diabetes and those receiving less than 1,400 mL of NS/hour had a higher likelihood of developing SSI. CONCLUSIONS: We observed that diabetes and lower volume of intraoperative irrigation were both risk factors for postoperative SSI following degenerative lumbar spine surgery. To reduce SSI in lumbar spine surgery, intra-wound irrigation with more than 1,400 mL/h of NS was recommended.

Cell Transitions Contribute to Glucocorticoid-Induced Bone Loss.

Glucocorticoid-induced bone loss is a toxic effect of long-term therapy with glucocorticoids resulting in a significant increase in the risk of fracture. Here, we find that glucocorticoids reciprocally convert osteoblast-lineage cells into endothelial-like cells. This is confirmed by lineage tracing showing the induction of endothelial markers in osteoblast-lineage cells following glucocorticoid treatment. Functional studies show that osteoblast-lineage cells isolated from glucocorticoid-treated mice lose their capacity for bone formation but simultaneously improve vascular repair. We find that the glucocorticoid receptor directly targets Foxc2 and Osterix, and the modulations of Foxc2 and Osterix drive the transition of osteoblast-lineage cells to endothelial-like cells. Together, the results suggest that glucocorticoids suppress osteogenic capacity and cause bone loss at least in part through previously unrecognized osteoblast-endothelial transitions.

COVID-19 Infection May Drive EC-like Myofibroblasts towards Myofibroblasts to Contribute to Pulmonary Fibrosis.

COVID-19 has an extensive impact on Homo sapiens globally. Patients with COVID-19 are at an increased risk of developing pulmonary fibrosis. A previous study identified that myofibroblasts could be derived from pulmonary endothelial lineage cells as an important cell source that contributes to pulmonary fibrosis. Here, we analyzed publicly available data and showed that COVID-19 infection drove endothelial lineage cells towards myofibroblasts in pulmonary fibrosis of patients with COVID-19. We also discovered a similar differentiation trajectory in mouse lungs after viral infection. The results suggest that COVID-19 infection leads to the development of pulmonary fibrosis partly through the activation of endothelial cell (EC)-like myofibroblasts.

GSK3ß Inhibition Ameliorates Atherosclerotic Calcification.

Endothelial-mesenchymal transition (EndMT) drives endothelium to contribute to atherosclerotic calcification. In a previous study, we showed that glycogen synthase kinase-3ß (GSK3ß) inhibition induced ß-catenin and reduced mothers against DPP homolog 1 (SMAD1) in order to redirect osteoblast-like cells towards endothelial lineage, thereby reducing vascular calcification in Matrix Gla Protein (Mgp) deficiency and diabetic Ins2Akita/wt mice. Here, we report that GSK3ß inhibition or endothelial-specific deletion of GSK3ß reduces atherosclerotic calcification. We also find that alterations in ß-catenin and SMAD1 induced by GSK3ß inhibition in the aortas of Apoe-/- mice are similar to Mgp-/- mice. Together, our results suggest that GSK3ß inhibition reduces vascular calcification in atherosclerotic lesions through a similar mechanism to that in Mgp-/- mice.

Distributed twist sensing using frequency-scanning φ-OTDR in a spun fiber.

In this paper, a novel distributed twist sensor based on frequency-scanning phase-sensitive optical time-domain reflectometry (φ-OTDR) in a spun fiber is proposed and demonstrated. Owing to the unique helical structure of the stress rods in the spun fiber, fiber twist gives rise to the variation of the effective refractive index of the transmitting light, which can be quantitatively retrieved through frequency shift using frequency-scanning φ-OTDR. The feasibility of distributed twist sensing has been verified by both simulation and experiment. For proof of concept, distributed twist sensing over a 136 m spun fiber with a 1 m spatial resolution is demonstrated, and the measured frequency shift shows a quadratic fitting dependence on the twist angle. In addition, the responses of both clockwise and counterclockwise twist directions have also been explored and the experiment result indicates that the twist direction can be discriminated since the frequency shift directions are opposite in the correlation spectrum. The proposed twist sensor possesses some outstanding advantages, including high sensitivity, distributed twist measurement and twist direction recognition capability, etc., which is very promising for specific applications in industry, e.g., structural health monitoring, bionic robots, etc.

Advances in Multicore Fiber Interferometric Sensors.

In this paper, a review of multicore fiber interferometric sensors is given. Due to the specificity of fiber structure, i.e., multiple cores integrated into only one fiber cladding, multicore fiber (MCF) interferometric sensors exhibit many desirable characteristics compared with traditional fiber interferometric sensors based on single-core fibers, such as structural and functional diversity, high integration, space-division multiplexing capacity, etc. Thanks to the unique advantages, e.g., simple fabrication, compact size, and good robustness, MCF interferometric sensors have been developed to measure various physical and chemical parameters such as temperature, strain, curvature, refractive index, vibration, flow, torsion, etc., among which the extraordinary vector-bending sensing has also been extensively studied by making use of the differential responses between different cores of MCFs. In this paper, different types of MCF interferometric sensors and recent developments are comprehensively reviewed. The basic configurations and operating principles are introduced for each interferometric structure, and, eventually, the performances of various MCF interferometric sensors for different applications are compared, including curvature sensing, vibration sensing, temperature sensing, and refractive index sensing.

The Impact of Cage and End plate-Related Factors on Cage Subsidence in Oblique Lateral Interbody Fusion.

OBJECTIVES: To identify cage and end plate factors of cage subsidence (CS) in patients who underwent oblique lateral interbody fusion (OLIF) and their association with patient-reported outcomes. METHODS: Sixty-one patients (43 women and 18 men), with a total of 69 segments (138 end plates) which underwent OLIF at a single academic institution between November 2018 and November 2020, were included. All the end plates were separated into CS and nonsubsidence groups. Cage-related parameters (cage height, cage width, cage insertion level, and cage position) and end plate-related parameters (position of end plate, Hounsfield unit value of the vertebra, end plate concave angle [ECA], end plate injury, and angular mismatch measured with cage/end plate angle [C/EA]) were compared and analyzed using logistic regression to predict CS. Receiver operating characteristic curve analysis was used to determine the cutoff points of the parameters. RESULTS: Postoperative CS was identified in 50 of the 138 end plates (36.2%). The CS group had significantly lower mean Hounsfield unit values of the vertebra, higher rate of end plate injury, lower ECA, and higher C/EA than the nonsubsidence group. ECA and C/EA were identified as independent risk factors for developing CS. The optimal cutoff points for ECA and C/EA were 176.9° and 5.4°, respectively. CONCLUSIONS: An ECA greater than 176.9° and a cage/end plate angular mismatch greater than 5.4° were found to be independent risk factors of postoperative CS after the OLIF procedure. These findings aid in preoperative decision-making and intraoperative technical guidance.

GSK3ß Inhibition Reduced Vascular Calcification in Ins2Akita/+ Mice.

Endothelial-mesenchymal transition (EndMT) drives the endothelium to contribute to vascular calcification in diabetes mellitus. In our previous study, we showed that glycogen synthase kinase-3ß (GSK3ß) inhibition induces ß-catenin and reduces mothers against DPP homolog 1 (SMAD1) to direct osteoblast-like cells toward endothelial lineage, thereby reducing vascular calcification in Matrix Gla Protein (Mgp) deficiency. Here, we report that GSK3ß inhibition reduces vascular calcification in diabetic Ins2Akita/wt mice. Cell lineage tracing reveals that GSK3ß inhibition redirects endothelial cell (EC)-derived osteoblast-like cells back to endothelial lineage in the diabetic endothelium of Ins2Akita/wt mice. We also find that the alterations in ß-catenin and SMAD1 by GSK3ß inhibition in the aortic endothelium of diabetic Ins2Akita/wt mice are similar to Mgp-/- mice. Together, our results suggest that GSK3ß inhibition reduces vascular calcification in diabetic arteries through a similar mechanism to that in Mgp-/- mice.

Shorter screw lengths in dynamic Dynesys fixation have less screw loosening: From clinical investigation to finite-element analysis.

BACKGROUND: The dynamic Dynesys Stabilization System preserves lumbar mobility at instrumented levels. This study investigated the effect of screw length on screw loosening (SL) after dynamic Dynesys fixation and screw displacement during lumbar motion, using clinical investigation and finite-element (FE) analysis. METHODS: Clinical data of 50 patients with degenerative spondylolisthesis treated with decompression and Dynesys fixation in 2011 were analyzed retrospectively. Horizontal sliding displacement and vertical displacement of screw tips at L4 were analyzed postoperatively using displacement-controlled FE analysis at the L4-L5 level with screw lengths 45 (long screw), 36 (median screw), and 27 (short screw), and 6.4 mm in diameter, under flexion, extension, lateral bending, and rotation. RESULTS: In 13 patients (13/50, 26%), 40 screws (40/266, 15%) were loose at mean follow-up of 101.3 ± 4.4 months. Radiographic SL at 35, 40, 45, and 50 mm were 7.7%, 10.7%, 12.1%, and 37.5%, respectively, regardless of the fixation level ( p = 0.009). FE analysis revealed that the long screw model with corresponding longer lever arm had maximal horizontal sliding displacement under all directions and maximal vertical displacement, except for lateral bending. CONCLUSION: Shorter screws in Dynesys fixation may help avoid dynamic SL. Clinically, 50 mm screws showed the greatest SL and median screw screws demonstrated the least displacement biomechanically.