Zinc finger protein-440 promotes cartilage degenerative mechanisms in human facet and knee osteoarthritis chondrocytes.

OBJECTIVES: To investigate the role of zinc finger protein 440 (ZNF440) in the pathophysiology of cartilage degeneration during facet joint (FJ) and knee osteoarthritis (OA). METHODS: Expression of ZNF440 in FJ and knee cartilage was determined by immunohistochemistry, quantitative (q)PCR, and Western blotting (WB). Human chondrocytes isolated from FJ and knee OA cartilage were cultured and transduced with ZNF440 or control plasmid, or transfected with ZNF440 or control small interfering RNA (siRNA), with/without interleukin (IL)-1ß. Gene and protein levels of catabolic, anabolic and apoptosis markers were determined by qPCR or WB, respectively. In silico analyses were performed to determine compounds with potential to inhibit expression of ZNF440. RESULTS: ZNF440 expression was increased in both FJ and knee OA cartilage compared to control cartilage. In vitro, overexpression of ZNF440 significantly increased expression of MMP13 and PARP p85, and decreased expression of COL2A1. Knockdown of ZNF440 with siRNA partially reversed the catabolic and cell death phenotype of human knee and FJ OA chondrocytes stimulated with IL-1ß. In silico analysis followed by validation assays identified scriptaid as a compound with potential to downregulate the expression of ZNF440. Validation experiments showed that scriptaid reduced the expression of ZNF440 in OA chondrocytes and concomitantly reduced the expression of MMP13 and PARP p85 in human knee OA chondrocytes overexpressing ZNF440. CONCLUSIONS: The expression of ZNF440 is significantly increased in human FJ and knee OA cartilage and may regulate cartilage degenerative mechanisms. Furthermore, scriptaid reduces the expression of ZNF440 and inhibits its destructive effects in OA chondrocytes.

Sequencing identifies a distinct signature of circulating microRNAs in early radiographic knee osteoarthritis.

OBJECTIVE: MicroRNAs act locally and systemically to impact osteoarthritis (OA) pathophysiology, but comprehensive profiling of the circulating miRNome in early vs late stages of OA has yet to be conducted. Sequencing has emerged as the preferred method for microRNA profiling since it offers high sensitivity and specificity. Our objective was to sequence the miRNome in plasma from 91 patients with early [Kellgren-Lawrence (KL) grade 0 or 1 (n = 41)] or late [KL grade 3 or 4 (n = 50)] symptomatic radiographic knee OA to identify unique microRNA signatures in each disease state. DESIGN: MicroRNA libraries were prepared using the QIAseq miRNA Library Kit and sequenced on the Illumina NextSeq 550. Counts were produced for microRNAs captured in miRBase and for novel microRNAs. Statistical, bioinformatics, and computational biology approaches were used to refine and interpret the final list of microRNAs. RESULTS: From 215 differentially expressed microRNAs (FDR < 0.01), 97 microRNAs showed an increase or decrease in expression in ≥85% of samples in the early OA group as compared to the median expression in the late OA group. Increasing this threshold to ≥95%, seven microRNAs were identified: hsa-miR-335-3p, hsa-miR-199a-5p, hsa-miR-671-3p, hsa-miR-1260b, hsa-miR-191-3p, hsa-miR-335-5p, and hsa-miR-543. Four novel microRNAs were present in ≥50% of early OA samples and had 27 predicted gene targets in common with the prioritized set of predicted gene targets from the 97 microRNAs, suggesting common underlying mechanisms. CONCLUSION: Sequencing of well-characterized patient cohorts produced unbiased profiling of the circulating miRNome and identified a unique panel of 11 microRNAs in early radiographic knee OA.

Neuropathic pain in end-stage hip and knee osteoarthritis: differential associations with patient-reported pain at rest and pain on activity.

OBJECTIVE: We investigated whether pain at rest and pain on activity were differentially associated with neuropathic pain scores in individuals with end-stage hip and knee OA. DESIGN: Study participants were 843 patients with hip or knee OA scheduled for total joint arthroplasty. In pre-surgery questionnaires, measures of socio-demographics, health status, medication use, neuropathic pain (painDETECT), pain at rest and pain on activity (WOMAC pain items), depression (HADS) and pain catastrophizing (PCS) were collected. Multivariable linear regression models were estimated for men and women separately to examine the association between neuropathic pain scores (outcome) and study measures, entered in blocks. RESULTS: Sample mean age was 65.1 years (SD: 9.6); 57.1% were women. Mean painDETECT scores were significantly higher (P ≤Ö¹ 0.001) for women (11.2 ± 6.6 out of 38) than men (9.3 ± 7.0), with 35.6% of women and 27.7% of men meeting cut-offs for possible or likely neuropathic pain. In the final regression model for women, the coefficients for both types of pain were statistically significant, although the coefficient for pain at rest was 1.6 times greater than that for pain on activity. For men, only pain at rest was significantly associated with neuropathic pain scores. CONCLUSIONS: Findings support that possible neuropathic pain is experienced by a notable proportion of patients with end-stage hip and knee OA and is more strongly associated with pain at rest than pain on activity, particularly in men. Clinical presentation of pain at rest may warrant more thorough evaluation for potential neuropathic pain and have implications for appropriate pain management.

Virtual fluoroscopy: computer-assisted fluoroscopic navigation.

STUDY DESIGN: In vitro accuracy assessment of a novel virtual fluoroscopy system. OBJECTIVES: To investigate a new technology combining image-guided surgery with C-arm fluoroscopy. SUMMARY OF BACKGROUND DATA: Fluoroscopy is a useful and familiar technology to all musculoskeletal surgeons. Its limitations include radiation exposure to the patient and operating team and the need to reposition the fluoroscope repeatedly to obtain surgical guidance in multiple planes. METHODS: Fluoroscopic images of the lumbar spine of an intact, unembalmed cadaver were obtained, calibrated, and saved to an ). A was used for the sequential insertion of a light-emitting diode-fitted probe into the pedicles of L1-S1 bilaterally. The trajectory of a "virtual tool" corresponding to the tracked tool was overlaid onto the saved fluoroscopic views in real time. Live fluoroscopic images of the inserted pedicle probe were then obtained. Distances between the tips of the virtual and fluoroscopically displayed probes were quantified using the image-guided computer's measurement tool. Trajectory angle differences were measured using a standard goniometer and printed copies of the workstation computer display. The surgeon's radiation exposure was measured using thermolucent dosimeter rings. RESULTS: Excellent correlation between the virtual fluoroscopic images and live fluoroscopy was observed. Mean probe tip error was 0.97 +/- 0.40 mm. Mean trajectory angle difference between the virtual and fluoroscopically displayed probes was 2.7 degrees +/- 0.6 degrees. The thermolucent dosimeter rings measured no detectable radiation exposure for the surgeon. CONCLUSIONS: Virtual fluoroscopy offers several advantages over conventional fluoroscopy while providing acceptable targeting accuracy. It enables a single C-arm to provide real-time, multiplanar procedural guidance. It also dramatically reduces radiation exposure to the patient and surgical team by eliminating the need for repetitive fluoroscopic imaging for tool placement.

Accuracy requirements for image-guided spinal pedicle screw placement.

STUDY DESIGN: Accuracy requirement analysis for image-guided pedicle screw placement. OBJECTIVES: To derive theoretical accuracy requirements for image-guided spinal pedicle screw placement. SUMMARY OF BACKGROUND DATA: Underlying causes of inaccuracy in image-guided surgical systems and methods for quantifying this inaccuracy have been studied. However, accuracy requirements for specific spinal surgical procedures have not been delineated. In particular, the accuracy requirements for image-guided spinal pedicle screw placement have not been previously reported. METHODS: A geometric model was developed relating spinal pedicle anatomy to accuracy requirements for image-guided surgery. This model was used to derive error tolerances for pedicle screw placement when using clinically relevant screw diameters in the cervical (3.5 mm), thoracic (5.0 mm), and thoracolumbar spine (6.5 mm). The error tolerances were represented as the permissible rotational and translational deviations from the ideal screw trajectory that would avoid pedicle wall perforation. The relevant dimensions of the pedicle model were extracted from existing morphometric data. RESULTS: As anticipated, accuracy requirements were greatest at spinal levels where the relevant screw diameter approximated the dimensions of the pedicle. These requirements were highest for T5, followed in descending order by T4, T7, T6, T3, T12, L1, T8, T11, C4, L2, C3, T10, C5, T2, T9, C6, L3, C2, T1, C7, L4, and L5. Maximum permissible translational/rotational error tolerances ranged from 0.0 mm/0.0 degrees at T5 to 3.8 mm/12.7 degrees at L5. CONCLUSIONS: These results, obtained by mathematical analysis, demonstrate that extremely high accuracy is necessary to place pedicle screws at certain levels of the spine without perforating the pedicle wall. These accuracy requirements exceed the accuracy of current image-guided surgical systems, based on clinical utility errors reported in the literature. In actual use, however, these systems have been shown to improve the accuracy of pedicle screw placement. This dichotomy indicates that other factors, such as the surgeon's visual and tactile feedback, may be operative.

Radiation exposure to the spine surgeon during fluoroscopically assisted pedicle screw insertion.

STUDY DESIGN: In vitro study to determine occupational radiation exposure during lumbar fluoroscopy. OBJECTIVES: To assess radiation exposure to the spine surgeon during fluoroscopically assisted thoracolumbar pedicle screw placement. SUMMARY OF BACKGROUND DATA: Occupational radiation exposure during a variety of fluoroscopically assisted musculoskeletal procedures has been previously evaluated. No prior study has assessed fluoroscopy-related radiation exposure to the spine surgeon. METHODS: Bilateral pedicle screw placement (T11-S1) was performed in six cadavers using lateral fluoroscopic imaging. Radiation dose rates to the surgeon's neck, torso, and dominant hand were measured with dosimeter badges and thermolucent dosimeter (TLD) rings. Radiation levels were also quantified at various distances from the dorsal lumbar surface using an ion chamber radiation survey meter. RESULTS: The mean dose rate to the neck was 8.3 mrem/min. The dose rate to the torso was greatest when the surgeon was positioned ipsilateral to the beam source (53.3 mrem/min, compared with 2.2 mrem/min on the contralateral side). The average hand dose rate was 58.2 mrem/min. A significant increase in hand dose rate was associated with placement of screws ipsilateral to the beam source (P = 0.0005) and larger specimens (P = 0.0007). Radiation levels significantly decreased as distance from the beam source and dorsal body surface increased. The greatest levels of radiation were noted on the side where the primary radiograph beam entered the cadaver. CONCLUSION: Fluoroscopically assisted thoracolumbar pedicle screw placement exposes the spine surgeon to significantly greater radiation levels than other, nonspinal musculoskeletal procedures that involve the use of a fluoroscope. In fact, dose rates are up to 10-12 times greater. Spine surgeons performing fluoroscopically assisted thoracolumbar procedures should monitor their annual radiation exposure. Measures to reduce radiation exposure and surgeon awareness of high-exposure body and hand positions are certainly called for.

Anterior cervical plating reverses load transfer through multilevel strut-grafts.

STUDY DESIGN: In vitro biomechanical study using a programmable testing apparatus that replicated physiologic flexion/extension cervical spine motion and loading mechanics. OBJECTIVE: To determine the influence of anterior plating on multilevel cervical strut-graft mechanics in vitro. SUMMARY OF BACKGROUND DATA: The addition of anterior instrumentation does not prevent construct failure in multilevel cervical corpectomy. METHODS: Six fresh human cadaveric cervical spines (C2-T1) were tested in the four following sequential conditions: harvested, C4-C6 corpectomy, strut-grafted, and strut-grafted with an anterior cervical plate. A force-sensing strut-graft was used to measure compression/tension, flexion/extension and lateral bending moments, and axial torsion. Parameters of stiffness, vertebral motion, and strut-graft loads were compared to determine differences between the four spine conditions. RESULTS: Application of the anterior plate significantly increased the global stiffness (P < 0.01) and decreased the local motion (P < or = 0.01) of the instrumented levels (C3-C7). Flexion of the strut-grafted spine loaded the strut-graft, whereas extension unloaded the strut-graft. With the anterior plate, flexion of the plated spine unloaded the strut-graft. Extension significantly loaded the strut-graft more than similar degrees of flexion in the strut-grafted condition (P = 0.01). Strut-graft loading end limits of 225 N were reached with a mean 7.5 degrees extension in the plated spines. CONCLUSIONS: Anterior multilevel cervical plating effectively increases stiffness and decreases local cervical motion after corpectomy. However, anterior cervical plating also reverses graft loads and excessively loads the graft in extension, which may promote pistoning and failure of multilevel constructs.

The in vitro effects of instrumentation on multilevel cervical strut-graft mechanics.

STUDY DESIGN: Biomechanical study using a programmable testing apparatus that replicated physiologic flexion-extension cervical spine motion, and loading mechanics. OBJECTIVES: To determine the influence of anterior, posterior, or combined plating on multilevel cervical strut-graft mechanics in vitro. SUMMARY OF BACKGROUND DATA: The addition of instrumentation does not prevent construct failure in multilevel (more than two levels) cervical corpectomy. METHODS: Six fresh human cadaveric cervical spines (C2-T1) were tested in six sequential conditions that included harvested (H), C4-6 corpectomy, strut grafted, strut grafted with an anterior cervical plate (SGAP), strut grafted with posterior plates (SGPP), and strut grafted with combined anterior and posterior plates (SGAPP). A customized force-sensing strut graft (FSSG) was used to measure axial compression-tension, flexion-extension and lateral bending moments, and axial torsion. Parameters of stiffness, segmental vertebral motion, and strut-graft loads were compared, to determine differences among the spine conditions. RESULTS: Flexion of the strut-grafted spine loaded the FSSG, and extension motion unloaded the FSSG. With the anterior plate, flexion of the SGAP spine significantly unloaded the FSSG; extension loaded the FSSG more than flexion of the unplated spine (P = 0.03). The opposite occurred with the posterior plates (SGPP), where flexion of the spine significantly loaded the FSSG (more than the strut grafted spine) and extension unloaded the FSSG (P < 0.03). The combined construct (SGAPP) counteracted the tension band effect of the individual plates and demonstrated significantly less overall FSSG load change than either plate alone (P = 0.03). CONCLUSIONS: Multilevel cervical instrumentation effectively increases stiffness after corpectomy. However, anterior or posterior plating alone excessively loads the graft with small degrees of motion, which may promote pistoning and failure of multilevel constructs.

Microendoscopic approach to far-lateral lumbar disc herniation.

The purpose of this study was to determine the feasibility of performing far-lateral lumbar discectomy by using the microendoscopic discectomy (MED) technique. The authors studied 11 consecutive patients with unilateral, single-level radiculopathy secondary to far-lateral disc herniation. There were eight men and three women, with an average age of 43 years. In all patients magnetic resonance imaging and/or computerized tomography scanning documented far-lateral disc herniations. Six patients experienced motor deficits, nine patients sensory abnormalities, and five depressed reflexes. All patients complained of radicular pain, which failed to improve with conservative care. After induction of epidural anesthesia, single-level, unilateral percutaneous discectomies were performed using the MED technique. Five discectomies were performed at L3-4 and six at L4-5. There were four contained and seven sequestered disc herniations. All surgeries were performed on an outpatient basis. Follow up ranged from for 12 to 27 months. Improvement was shown in all patients postoperatively. Using modified Macnab criteria to assess results of surgery, there were 10 excellent results and one good result. None of the patients experienced residual motor deficits, four had residual decreased sensation, and one still had some degree of nonradicular pain. There were no complications. Although various open techniques exist for the treatment of far-lateral disc herniation, MED is unique in that far-lateral pathological entities can be directly visualized and removed via a 15-mm paramedian incision. The percutaneous approach avoids larger, potentially denervating and destabilizing procedures. The need for general anesthesia can be avoided, and surgery is performed on an outpatient basis, thereby reducing hospital cost and length of stay.