Fibronectin-aggrecan complex as a marker for cartilage degradation in non-arthritic hips.

PURPOSE: To report hip synovial fluid cytokine concentrations in hips with and without radiographic arthritis. METHODS: Patients with no arthritis (Tonnis grade 0) and patients with Tonnis grade 2 or greater hip osteoarthritis (OA) were identified from patients undergoing either hip arthroscopy or arthroplasty. Synovial fluid was collected at the time of portal establishment for those undergoing hip arthroscopy and prior to arthrotomy for the arthroplasty group. Analytes included fibronectin-aggrecan complex (FAC) as well as a standard 12 cytokine array. Variables recorded were Tonnis grade, centre-edge angle of Wiberg, as well as labrum and cartilage pathology for the hip arthroscopy cohort. A priori power analysis was conducted, and a Mann-Whitney U test and regression analyses were used with an alpha value of 0.05 set as significant. RESULTS: Thirty-four patients were included (17 arthroplasty, 17 arthroscopy). FAC was the only analyte to show a significant difference between those with and without OA (p < 0.001). FAC had significantly higher concentration in those without radiographic evidence of OA undergoing microfracture versus those not receiving microfracture (p < 0.05). CONCLUSION: There was a significantly higher FAC concentration in patients without radiographic OA. Additionally, those undergoing microfracture had increased levels of FAC. As FAC is a cartilage breakdown product, no significant amounts may be present in those with OA. In contrast, those undergoing microfracture have focal area(s) of cartilage breakdown. These data suggest that FAC may be useful in predicting cartilage pathology in those patients with hip pain but without radiographic evidence of arthritis.

The effect of local anaesthetics on synoviocytes: a possible indirect mechanism of chondrolysis.

PURPOSE: While the effect of local anaesthetics on chondrocyte viability is widely documented, the effect of these medications on synoviocytes is largely unknown. The purpose of this study was to understand the effect of 0.5 % bupivacaine and 0.5 % bupivacaine with epinephrine on synoviocyte viability, cytokine and growth factor release, and breakdown product formation. METHODS: Rabbit fibroblast-like synoviocyte (Type B) cultures were perfused with 0.5 % bupivacaine or 0.5 % bupivacaine with epinephrine (1:200,000) for 24 h. Cell viability was evaluated using a two-colour fluorescence assay. The supernatant was analysed using multiplex inflammatory and matrix metalloproteinase assays. RESULTS: Synoviocytes treated for 24 h with 0.5 % bupivacaine with epinephrine demonstrated a significant decrease in viability (31.3 ± 19.4 % cell death) when compared with synoviocytes cultured in control media (3.8 ± 1.3 % cell death, p = 0.000) and those cultured in 0.5 % bupivacaine alone (12.6 ± 11.1 % cell death, p = 0.003). No significant decrease in cell viability was observed in synoviocytes treated with 0.5 % bupivacaine compared to those in control media (12.6 ± 11.1 % vs 3.8 ± 1.3 % cell death, p = 0.194). Significantly greater amounts of MMP-1 (47.0 ± 9.2 pg/ml) and MMP-3 (250.0 ± 68.8 pg/ml) were observed in 0.5 % bupivacaine cultures compared with controls (14.3 ± 14.3, p = 0.023 and 72.0 ± 84.9, p = 0.045, respectively). CONCLUSIONS: 0.5 % bupivacaine with epinephrine caused a significant increase in cell death of the synoviocytes, while 0.5 % bupivacaine alone produced cell injury and a significant release of matrix metalloproteinases, which may also lead to indirect injury of the surrounding chondrocytes. These results may help explain the onset of chondrolysis observed in patients who have been treated with intra-articular local anaesthetics.

Correlation of intra-articular ankle pathology with cytokine biomarkers and matrix degradation products.

BACKGROUND: Articular cartilage degeneration is mediated by inflammatory cytokines and fragments of structural matrix proteins. Few studies have examined the role of these biomarkers in intra-articular pathology of the ankle. METHODS: Four groups of patients with increasing ankle pathology were enrolled. Group 1 included controls with no pain who underwent unrelated forefoot surgery. Group 2 included patients undergoing arthroscopy with intraoperative mild chondrosis. Group 3 included patients undergoing arthroscopy with moderate/severe chondrosis, osteochondral lesions, impingement, or loose bodies. Group 4 included positive controls with severe arthrosis undergoing ankle arthrodesis/arthroplasty. Ankle fluid was obtained by intra-articular aspiration and was assayed for IL-6, IFN-γ, MCP, MIP-1ß, and fibronectin-aggrecan complex (FAC), a matrix-degradation marker. There were 36 patients total, 21 males and 15 females with a mean age 45 (±16; range 18 to 76) years and a mean VAS for pain of 4.7 (±3.5; range 0 to 9). In groups 1 through 4, there were 11, 6, 15 and 4 patients respectively. RESULTS: The mean values of MCP-1 were 49.8 (±8.0) for minimal pathology and 133.9 (±33.0) for substantial pathology (pg/ml). The mean values of the FAC were 2.83 (±1.16) for minimal pathology and 9.62 (±2.23) for substantial pathology (optical density at 450 nm). The groups differed significantly in age, preoperative VAS, FAC, IL-6, and MCP-1 (p<0.05). CONCLUSION: There are differences in FAC and MCP-1 with increasing grades of severity of intra-articular pathology. CLINICAL RELEVANCE: These tests may play a role in determining the necessity for arthroscopy or intra-articular procedures in equivocal candidates.

Are persistently symptomatic vertebral compression fractures associated with abnormal inflammatory profiles? A prospective study.

STUDY DESIGN: A case-control study with prospectively collected samples for laboratory analysis in a series of patients with spinal fragility fractures and a series of patients without fracture who underwent fusion for LBP. OBJECTIVE: Was an exploratory data analysis for candidate cytokine biomarkers present in the fracture milieu of patients with persistent back pain associated with vertebral compression fracture. SUMMARY OF BACKGROUND DATA: Lumbar and thoracic compression fractures are common. Little is known about the presence of inflammatory mediators within fractured vertebra in the clinical setting. METHODS: Thirty patients diagnosed with a single thoracic or lumbar compression fracture were treated with single level vertebroplasty. At the time of intervention, needle aspiration was carried out at the fractured level. A multiplexed bead assay was used to assess the presence of 27 different cytokines and inflammatory mediators. A control group consisted of needle aspiration samples of 30 lumbar vertebra from 13 patients with chronic pain but no fracture undergoing open instrumented fusion. RESULTS: Thirty patients with 30 fractures consisted of 23 female and 7 male with a mean age of 77.5 years (SD 13.6; range 42 to 97) and a mean of 3.9 weeks of pain (SD 3.1; range 1 to 12). The highest levels of inflammatory mediators were (in order): IL-1 receptor antagonist, PDGF, RANTES, IP-10, IL-8, and eotaxin. These mediators were present at concentrations>200 pg/mL. Compared with controls with chronic pain, significant differences were present for 4 mediators: TNF, MIP-1b, IL-9, and IL-12. The panel of these 4 markers was 93.3% specific and 66.7% sensitive for fracture compared with the control group. CONCLUSIONS: Inflammatory mediators are present in needle aspirates of symptomatic vertebral compression fractures. Some of these mediators show different levels than in patients with chronic pain but no fracture. LEVEL OF EVIDENCE: Diagnostic level of evidence II.

Uncovering transcriptional dark matter via gene annotation independent single-cell RNA sequencing analysis.

Conventional scRNA-seq expression analyses rely on the availability of a high quality genome annotation. Yet, as we show here with scRNA-seq experiments and analyses spanning human, mouse, chicken, mole rat, lemur and sea urchin, genome annotations are often incomplete, in particular for organisms that are not routinely studied. To overcome this hurdle, we created a scRNA-seq analysis routine that recovers biologically relevant transcriptional activity beyond the scope of the best available genome annotation by performing scRNA-seq analysis on any region in the genome for which transcriptional products are detected. Our tool generates a single-cell expression matrix for all transcriptionally active regions (TARs), performs single-cell TAR expression analysis to identify biologically significant TARs, and then annotates TARs using gene homology analysis. This procedure uses single-cell expression analyses as a filter to direct annotation efforts to biologically significant transcripts and thereby uncovers biology to which scRNA-seq would otherwise be in the dark.

Spatiotemporal single-cell RNA sequencing of developing chicken hearts identifies interplay between cellular differentiation and morphogenesis.

Single-cell RNA sequencing is a powerful tool to study developmental biology but does not preserve spatial information about tissue morphology and cellular interactions. Here, we combine single-cell and spatial transcriptomics with algorithms for data integration to study the development of the chicken heart from the early to late four-chambered heart stage. We create a census of the diverse cellular lineages in developing hearts, their spatial organization, and their interactions during development. Spatial mapping of differentiation transitions in cardiac lineages defines transcriptional differences between epithelial and mesenchymal cells within the epicardial lineage. Using spatially resolved expression analysis, we identify anatomically restricted expression programs, including expression of genes implicated in congenital heart disease. Last, we discover a persistent enrichment of the small, secreted peptide, thymosin beta-4, throughout coronary vascular development. Overall, our study identifies an intricate interplay between cellular differentiation and morphogenesis.

Cytokine profiling in acute anterior cruciate ligament injury.

PURPOSE: To evaluate the presence and relative concentrations of cytokines, known to be involved in the inflammatory cascade, in acute anterior cruciate ligament (ACL) injury. METHODS: We evaluated an extensive cytokine profile in synovial fluid from 12 patients with acute ACL injury undergoing arthroscopy compared with 15 control subjects using a BioPlex assay (Bio-Rad Laboratories, Hercules, CA) to measure the concentration of 17 inflammatory cytokines. RESULTS: In patients with acute ACL injury compared with asymptomatic control subjects, the following cytokines were identified at significantly increased concentrations (P < .001, Mann-Whitney U test) compared with control samples: interleukin 6 (105 ± 72 v 0 ± 0 pg/ml), interferon γ (1,544 ± 608 v 9 ± 7.5 pg/ml), macrophage inflammatory protein 1ß (16 ± 3.8 v 0.3 ± 0.2 pg/ml), and monocyte chemotactic protein 1 (35 ± 13 v 0.5 ± 0.4 pg/ml). There was no case of a cytokine exhibiting increased levels in asymptomatic compared with symptomatic knee samples. CONCLUSIONS: This investigation identified 4 specific cytokines (interleukin 6, interferon γ, monocyte chemotactic protein 1, and macrophage inflammatory protein 1ß) out of a panel of 17 inflammatory molecules for which the levels were consistently elevated in the context of ACL injury compared with non-painful, non-acutely injured knees in a volunteer population. LEVEL OF EVIDENCE: Level IV, prognostic case series.

Accelerated degeneration after failed cervical and lumbar nucleoplasty.

STUDY DESIGN: Observational cohort study. SUMMARY OF BACKGROUND DATA: Studies evaluating the treatment of presumed discogenic spine pain using nucleoplasty have reported variable success rates. It has been suggested that these procedures lower the intradiscal pressure, reduce disk protrusion, improve disk hydration, and restore disk height. It is proposed that such structural changes in treated disks correspond to the clinical improvement in patients. Radiographic and clinical evidence showing the efficacy of nucleoplasty remains inadequate. OBJECTIVE: To document the comparative changes in magnetic resonance imaging (MRI) the appearance of disk morphology as reflected by Pfirrmann classification scores before and after the nucleoplasty treatment in patients with continued symptoms. METHODS: Twenty-eight consecutive patients with persistent symptoms after nucleoplasty within 1 year of treatment were evaluated. Prenucleoplasty and postnucleoplasty MRIs were evaluated and Pfirrmann scores of the symptomatic level were determined. RESULTS: In all the treated patients, comparison between the prenucleoplasty and the postnucleoplasty MRI of the targeted disks failed to show increased signal hydration, disk space height improvement, or shrinkage of the preoperative disk bulge at a mean time of 6 months after the procedure. Of the 17 cervical levels treated in 12 patients, 5 seemed to show progressive degeneration at treated levels (42% of the patients). Of the 17 lumbar procedures in 16 patients, 4 seemed to show progressive degeneration (25% of the patients) and 1 developed a new spondylolisthesis (6.3%). Thus, 32% of the patients in our cohort showed progressive degeneration at the treated level. The median Pfirrmann score in both prenucleoplasty and postnucleoplasty was 2, and the mean Pfirrmann classification prenucleoplasty and postnucleoplasty was 1.8 and 2.1, respectively (P<0.05, 2-tailed t test). CONCLUSION: This study failed to detect any morphologic improvement of disk abnormalities by MRI evaluation in patients with persistent pain, who then underwent nucleoplasty. Thirty-two percent showed progressive degeneration in less than 1 year after nucleoplasty, a rate greater than expected by natural progression during the interval of examination.

Does the presence of the fibronectin-aggrecan complex predict outcomes from lumbar discectomy for disc herniation?

BACKGROUND CONTEXT: Protein biomarkers associated with lumbar disc disease have been studied as diagnostic indicators and therapeutic targets. Recently, a cartilage degradation product, the fibronectin-aggrecan complex (FAC) identified in the epidural space, has been shown to predict response to lumbar epidural steroid injection in patients with radiculopathy from herniated nucleus pulposus (HNP). PURPOSE: Determine the ability of FAC to predict response to microdiscectomy for patients with radiculopathy due to lumbar disc herniation STUDY DESIGN/SETTING: Single-center prospective consecutive cohort study. PATIENT SAMPLE: Patients with radiculopathy from HNP with concordant symptoms to MRI who underwent microdiscectomy. OUTCOMES MEASURES: Oswestry disability index (ODI) and visual analog scores (VAS) were noted at baseline and at 3-month follow-up. Primary outcome of clinical improvement was defined as patients with both a decrease in VAS of at least 3 points and ODI >20 points. METHODS: Intraoperative sampling was done via lavage of the excised fragment by ELISA for presence of FAC. Funding for the ELISA was provided by Cytonics, Inc. RESULTS: Seventy-five patients had full complement of data and were included in this analysis. At 3-month follow-up, 57 (76%) patents were "better." There was a statistically significant association of the presence of FAC and clinical improvement (p=.017) with an 85% positive predictive value. Receiver-operating-characteristic (ROC) curve plotting association of FAC and clinical improvement demonstrates an area under the curve (AUC) of 0.66±0.08 (p=.037). Subset analysis of those with weakness on physical examination (n=48) plotting the association of FAC and improvement shows AUC on ROC of 0.81±0.067 (p=.002). CONCLUSIONS: Patients who are "FAC+" are more likely to demonstrate clinical improvement following microdiscectomy. The data suggest that the inflammatory milieu plays a significant role regarding improvement in patients undergoing discectomy for radiculopathy in lumbar HNP, even in those with preoperative weakness. The FAC represents a potential target for treatment in HNP.

Treatment of subacute low back pain with a novel device for continuous passive motion of the spine: a report of three cases.

Patients experiencing subacute low back pain (LBP) represent a challenge for the physical therapist. There have been few studies on the use of continuous passive motion of the lumbar spine for the treatment of LBP. Three patients with symptoms of subacute LBP without radiculopathy were treated using a novel device for continuous passive motion of the lumbar spine. The protocol consisted of 12 sessions of lumbar continuous passive motion at 30 minutes per session two to three times per week for 4 to 5 weeks. Outcomes were assessed at baseline and after 12 sessions at 4 to 5 weeks by Oswestry score and active range of motion measurements by a blinded investigator. Clinically significant improvements in Oswestry score and consistent improvements in range were observed. A supervised protocol using a commercial device can benefit some patients with subacute LBP if supervised by a knowledgeable practitioner.

A critical evaluation of discography in patients with lumbar intervertebral disc disease.

STUDY DESIGN: The study is a prospective observational study of 48 continuous patients with symptomatic lumbar degenerative disk disease. Each patient underwent discography, MRI, and a biochemical analysis of disk lavage fluid. OBJECTIVES: The purpose of this study was to correlate concordant pain on discography with MRI grade and biochemical markers of inflammation in a clinical setting. SUMMARY OF BACKGROUND DATA: The pathophysiology of degenerative disk disease is complex. Discography is used to differentiate symptomatic from asymptomatic levels. MRI is used to image changes in disk water content. Biochemical assays have identified molecular markers of inflammation. To date, no study has correlated concordant pain on discography with MRI findings and biochemical markers. METHODS: Forty-eight (48) continuous patients with symptomatic lumbar degenerative disk disease gave informed consent for study entry. Patient sex, age, insurance, work status and visual analog score (VAS) were recorded. MRI was obtained and Pfirrmann grading was performed by a single spine surgeon. Discography with disc lavage was performed by a single anesthesiologist. Lavage samples were tested for inflammatory markers with high resolution multi-plex bead immunoassays and ELISA with >5 pg/ml resolution. RESULTS: None of demographic variables was significantly related to concordant pain on discogram by chi-squared tests and Mann-Whitney U-test. The Pfirrmann score was significantly different for patients with and without concordant pain at L3-L4 (p<0.001), but was insignificant at other levels after multitest correction. Pfirrmann scores were significantly different at any level in patients with and without concordant pain. VAS scores were not significantly correlated with opening pressures at any level. Despite the presence of serum proteins in the disk lavage fluid, none of the tested inflammatory mediators was identified by multi-plex bead immunoassays and ELISA. CONCLUSIONS: There are only weak correlations between demographic, discogram, and radiographic variables. Response to discogram cannot be predicted by non-invasive means. The disk lavage method was unable to identify the presence of specific inflammatory peptides with multi-plex immunoassays and ELISA.

Naturally Engineered Maturation of Cardiomyocytes.

Ischemic heart disease remains one of the most prominent causes of mortalities worldwide with heart transplantation being the gold-standard treatment option. However, due to the major limitations associated with heart transplants, such as an inadequate supply and heart rejection, there remains a significant clinical need for a viable cardiac regenerative therapy to restore native myocardial function. Over the course of the previous several decades, researchers have made prominent advances in the field of cardiac regeneration with the creation of in vitro human pluripotent stem cell-derived cardiomyocyte tissue engineered constructs. However, these engineered constructs exhibit a functionally immature, disorganized, fetal-like phenotype that is not equivalent physiologically to native adult cardiac tissue. Due to this major limitation, many recent studies have investigated approaches to improve pluripotent stem cell-derived cardiomyocyte maturation to close this large functionality gap between engineered and native cardiac tissue. This review integrates the natural developmental mechanisms of cardiomyocyte structural and functional maturation. The variety of ways researchers have attempted to improve cardiomyocyte maturation in vitro by mimicking natural development, known as natural engineering, is readily discussed. The main focus of this review involves the synergistic role of electrical and mechanical stimulation, extracellular matrix interactions, and non-cardiomyocyte interactions in facilitating cardiomyocyte maturation. Overall, even with these current natural engineering approaches, pluripotent stem cell-derived cardiomyocytes within three-dimensional engineered heart tissue still remain mostly within the early to late fetal stages of cardiomyocyte maturity. Therefore, although the end goal is to achieve adult phenotypic maturity, more emphasis must be placed on elucidating how the in vivo fetal microenvironment drives cardiomyocyte maturation. This information can then be utilized to develop natural engineering approaches that can emulate this fetal microenvironment and thus make prominent progress in pluripotent stem cell-derived maturity toward a more clinically relevant model for cardiac regeneration.

Evaluation of non-lead-based protective radiological material in spinal surgery.

BACKGROUND CONTEXT: Traditionally, lead-based garments are the standard method of intraoperative radiation protection during fluoroscopy. Unfortunately, the lead used is heavy, lacks durability, is difficult to launder, and its disposal is associated with environmental hazards. PURPOSE: An evaluation of the protective radiation efficiency of three commercially available radiation protective garments compared with a standardized lead protective shield. STUDY DESIGN/SETTING: Measured radiation transmission through lead and three commercially available lightweight radiological protective garments (Xenolite, EarthSafe, and Demron) was performed using a standard, calibrated dosimeter. METHODS: Radiation transmission, attenuation, lead equivalencies as well as garment weight comparisons were measured. The tests were repeated through a range of voltage and tube current settings that are common to clinical radiological applications (60-120 keV). RESULTS: All materials tested demonstrated effectiveness at common clinically relevant energy exposures (100 keV). EarthSafe and Xenolite demonstrated 0.5 mm lead equivalency protection at 80 and 100 keV X-ray energies but not at higher energy levels (>100 keV), which is where most radiological procedures are performed utilizing more advanced technological imaging equipment. Demron was best able to effectively shield ionizing radiation at higher energy levels (>100 keV). The lightweight nature of these lead-free materials may result in less fatigue and musculoskeletal complaints by the wearer. CONCLUSIONS: Of the tested lead-free garments, Demron appears to offer equivalent levels of protection to standard lead-based shields within traditional energy zones but with less weight than standard lead-based shields.

α2-Macroglobulin: Autologous Protease Inhibition Technology.

α2-Macroglobulin (A2M) is a plasma glycoprotein best known for its ability to inhibit a broad spectrum of serine, threonine, and metalloproteases as well as inflammatory cytokines by a unique bait-and-trap method. A2M has emerged as a unique potential treatment of cartilage-based pathology and inflammatory arthritides. This article describes the unique method by which A2M not only inhibits the associated inflammatory cascade but also disrupts the catabolic process of cartilage degeneration. Autologous concentrated A2M from plasma is currently in use to successfully treat various painful arthritides. Future directions will focus on recombinant variants that enhance its anti-inflammatory and disease-modifying potential.

Cytokines as a predictor of clinical response following hip arthroscopy: minimum 2-year follow-up.

Hip arthroscopy in patients with osteoarthritis has been shown to have suboptimal outcomes. Elevated cytokine concentrations in hip synovial fluid have previously been shown to be associated with cartilage pathology. The purpose of this study was to determine whether a relationship exists between hip synovial fluid cytokine concentration and clinical outcomes at a minimum of 2 years following hip arthroscopy. Seventeen patients without radiographic evidence of osteoarthritis had synovial fluid aspirated at time of portal establishment during hip arthroscopy. Analytes included fibronectin-aggrecan complex as well as a multiplex cytokine array. Patients completed the modified Harris Hip Score, Western Ontario and McMaster Universities Arthritis Index and the International Hip Outcomes Tool pre-operatively and at a minimum of 2 years following surgery. Pre and post-operative scores were compared with a paired t-test, and the association between cytokine values and clinical outcome scores was performed with Pearson's correlation coefficient with an alpha value of 0.05 set as significant. Sixteen of seventeen patients completed 2-year follow-up questionnaires (94%). There was a significant increase in pre-operative to post-operative score for each clinical outcome measure. No statistically significant correlation was seen between any of the intra-operative cytokine values and either the 2-year follow-up scores or the change from pre-operative to final follow-up outcome values. No statistically significant associations were seen between hip synovial fluid cytokine concentrations and 2-year follow-up clinical outcome assessment scores for those undergoing hip arthroscopy.

Symptomatic cervical disc herniation following a motor vehicle collision: return to work comparative study of workers' compensation versus personal injury insurance status.

BACKGROUND CONTEXT: Patients with approved workers' compensation injuries receive guaranteed compensation for the duration of their injury, whereas patients with personal injury claims are only compensated, if at all, at the time of a successful settlement or trial verdict at a time point distant from their injury. PURPOSE: This study compares the financial impact and loss of work patterns due to a workers' compensation (WC) claim or personal injury in patients with a symptomatic cervical disc herniation resulting from a motor vehicle collision. STUDY DESIGN: A prospective study of patients who were seen by a single spine specialist between 1/2/96 and 9/1/01. PATIENT SAMPLE: A consecutive evaluation of 531 patients who were treated for a cervical pain syndrome caused by a motor vehicle collision. OUTCOME MEASURES: Mechanism of injury and insurance type, ie, workers' compensation or personal injury, was recorded for each patient as well as treatment response and return to work patterns. The data were analyzed using the two-way Z test. METHODS: All patients were managed in a similar manner with noninvasive treatment initially, followed by injections, and finally surgical intervention in those who failed conservative measures. Return to work rates and work disability were determined at either final follow-up or at the last doctor's visit before loss to follow-up. RESULTS: 270 of 531 patients were diagnosed with a symptomatic one or two level disc herniation by a cervical magnetic resonance imaging scan. Fifty-four patients were insured through the workers' compensation board, and 216 reported their crash as a personal injury claim. In the WC group the work disability at 3 months follow-up revealed a cumulative 2,262 total lost days of work (average 37.1 days per person). At the point of maximal medical improvement (MMI) or 2-year follow-up, total days lost from work were 7,107 (average 131.6 days per person.) In the personal injury non-WC group, the 3-month follow-up of lost days of work was 1,093 days (average 5.1 days per person.) At 2 years follow-up, the total lost days of work were 6,206 (average 28.7 days per person.) CONCLUSIONS: Participants compensated through the workers' compensation system demonstrated a significant loss of days of work as compared with injured patients who received compensation by other means. This may be a reflection of the guaranteed method of compensation afforded to WC patients as opposed to patients who receive no form of financial support (i.e., personal injury) during the recuperative process. Further analysis as to injury severity and a stratification of non-workers' compensation reimbursement methods are needed to further improve the validity of this study.

Can We Improve Workflows in the OR? A Comparison of Quality Perceptions and Preoperative Efficiency across Institutions in Spine Surgery.

INTRODUCTION: Cost containment and surgical inefficiencies are major concerns for hospitals in this era of declining resources. The primary aim of this investigation was to understand subjective perceptions of perioperative spine surgical quality across three practice settings and to identify potential factors contributing to these perceptions. Subsequently, we objectively evaluated factors that influence the duration of time in which the patient is in the operating room (OR) prior to the surgical incision and assessed the influence of fluoroscopy technician expertise on radiation dose and imaging efficiency. METHODS: One hundred and eight medical device representatives with at least 1 year of OR experience were surveyed at a national conference. Three distinct healthcare facilities were identified: university, small volume, and large volume private hospitals. Respondents rated facilities on a five-point scale for staff quality; size and consistency of surgical teams; and overall likelihood of recommending the facility. Separately, 140 posterior lumbar procedures from two institutions were retrospectively reviewed. Two time periods were quantified for each surgical case: patient arrival in the OR to induction of anesthesia (T1) and induction to surgical incision (T2). T1 and T2 were compared between university and large private hospital settings using t tests and multivariate analysis. For 44 separate lumbar spine surgical procedures, practice setting, patient BMI, number of vertebral levels requiring imaging, number of localizing fluoroscopy images taken, total fluoroscopy time, total radiation dose, fluoroscopy machine, and whether the fluoroscopist could correctly state his or her role, which was to obtain a lateral lumbar localizing image, were recorded. T-tests were used to compare cases in which the fluoroscopist could and could not correctly state the task. RESULTS: Survey ratings for surgeons were not significantly different across university, large private, and small private hospitals. Fewer circulating nurses were rated as excellent or good in university versus private hospitals (p < 0.001). Small volume private hospital surgical teams were more likely to have worked together before than university teams (p < 0.05), and university teams were larger (p < 0.05). Respondents were more likely to recommend a university or large private hospital for complex instrumentation cases (p < 0.001). On objective measures, university patients were older, less obese, and had higher mean ASA scores (2.5 versus 2.2, p < 0.001). Compared to the university setting, private hospital cases had significantly shorter Time 1 (8 versus 37 min, p < 0.001) and Time 2 (23 versus 30 min, p < 0.001), even after adjusting for ASA score, BMI, and age. Cases in which the fluoroscopist knew the imaging purpose were associated with significantly fewer images (mean 1.8 versus 3.4 images, p < 0.0001) and shorter total exposure times (2.3 versus 4.0 sec, p < 0.001). Operations performed in the university setting were associated with significantly more images (2.7 versus 1.8 images, p < 0.001), longer total exposure times (3.2 versus 2.3 sec, p = 0.0027), and total radiation dose (27.8 versus 53.3 rad, p < 0.001) when compared with those performed in the private setting. The university practice setting was associated with significantly more images (2.7 versus 1.8 images, p < 0.001), longer total exposure times (3.2 versus 2.3 sec, p = 0.003), and total radiation dose (27.8 versus 53.3 rad, p < 0.001) when compared with non-university settings. CONCLUSION: Large private and university hospitals had higher surgeon ratings. The university setting was associated with larger and less consistent surgical teams and lower nurse ratings. Surgical staff awareness of the procedure and attention to preoperative tasks specific to the procedure reduced pre-operative time spent in the OR as well as fluoroscopy radiation. These data suggest that nurses and support staff make substantial contributions to overall quality of care, and that leadership and interpersonal coordination are especially important within large teams at teaching hospitals.

Does a fibronectin and aggrecan complex play a role in painful vertebral disks?

OBJECTIVE: To determine the presence of a fibronectin-aggrecan complex (FAC) in the disk space of persons with chronic low back pain as relates to provocative diskography. DESIGN: A single-center prospective consecutive case series. SETTING: A single private practice setting. PATIENTS: Thirty-seven patients with symptomatic degenerative disk disease of the cervical, thoracic, or lumbar spine undergoing provocative diskography to identify a source of pain. METHODS: Diskographic lavage for analysis was simultaneously performed at each disk level injected during diskography. MAIN OUTCOME MEASURES: Visual analog scale (VAS) pain scores, Pfirrmann magnetic resonance imaging grade, and biochemical analysis of disk material were statistically analyzed. RESULTS: A total of 105 levels in 37 patients had a complete set of data (mean age 43.2 ± 11.9 years; 15 male/22 female). The FAC was present in 43 of 108 levels and in at least one level in 25 of 37 patients. The Pfirrmann magnetic resonance imaging grade did not differ between complex-positive and negative levels (P = .125), nor did the intraoperative VAS (IO-VAS) score for pain by level (P = .206). A significant but loose correlation was found between Pfirrmann grade and IO-VAS (R(2) = 0.4, P < .001), but no significant correlation was found between VAS or IO-VAS and complex concentration (R(2) = 0.08, P = .11 and R(2) = 0.003, P = .5). CONCLUSIONS: The FAC was identified in some painful disks by diskography. There was no significant correlation between the Pfirrmann grade or pre/intraoperative pain scores during diskography and complex concentrations within the disk measured by disk lavage.

Cytokine expression in the epidural space: a model of noncompressive disc herniation-induced inflammation.

STUDY DESIGN: Animal study. OBJECTIVE: Development of an animal model for the study of biochemical changes that occur in the epidural space after intervertebral disc herniation. SUMMARY OF BACKGROUND DATA: Although strong evidence for an inflammatory component exists, the biochemical processes underlying pain after disc herniation remain unknown. METHODS: Epidural lavage was performed in 48 rats after L5 dorsal root ganglion exposure at baseline and 3, 6, or 24 hours after placement of autologous nucleus pulposus (NP) (N = 15), saline (N = 15), or NP + an interferon-γ antibody (anti-IFN-γ; N = 18) directly onto the dorsal root ganglion. Multiplex assays quantifying interleukin (IL)-1α, IL-1ß, IL-2, IL-4, IL-6, IL-10, tumor necrosis factor α (TNF-α), IFN-γ, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were performed. NP (N = 7) was also analyzed for these cytokines by placing NP into saline and measuring the relative concentration. RESULTS: Cytokines measured low at baseline (0-100 pg/mL) in all groups. Compared with saline, NP application caused IL-6 elevation, peaking at T = 3 hours, that was prevented by anti-IFN-γ. NP induced elevation of TNF-α, peaking at T = 24 hours and was prevented by anti-IFN-γ. IFN-γ was elevated after NP at T = 3 hours and T = 24 hours. IL-1α was similar after saline versus NP. The concentrations of IL-1ß and IL-10 were elevated at T = 3 hours, 6 hours, and 24 hours in all groups without between-groups difference. The level of IL-4 peaked at T = 3 hours in the NP group and was different than saline and NP + anti-IFN-γ groups, but the time effect was insignificant. There was no change for GM-CSF. The concentration of cytokines measured in normal NP was less than 2 pg/mL for all cytokines except TNF-α. CONCLUSION: In this model of acute noncompressive disc herniation, NP caused the elevation of epidural IL-6, TNF-α, and IFN-γ--all attenuated by IFN-γ blockade. IL-1ß and IL-10 were both significantly elevated by saline alone and their response was not prevented by IFN-γ blockade. This model may prove useful for the study of the biochemical processes by which NP induces inflammation-induced nerve root irritation and radiculopathic pain.

Platelet-rich plasma increases matrix metalloproteinases in cultures of human synovial fibroblasts.

BACKGROUND: The effect of platelet-rich plasma on chondrocytes has been studied in cell and tissue culture. Less attention has been given to the effect of platelet-rich plasma on nonchondrocytic cell lineages within synovial joints, such as fibroblast-like synoviocytes, which produce cytokines and matrix metalloproteinases (MMPs) that mediate cartilage catabolism. The purpose of the present study was to determine the effect of platelet-rich plasma on cytokines and proteases produced by fibroblast-like synoviocytes. METHODS: Platelet-rich plasma and platelet-poor plasma from harvested autologous blood were prepared with a commercially available system. Fibroblast-like synoviocytes were treated with platelet-rich plasma, platelet-poor plasma, recombinant PDGFßß (platelet-derived growth factor ßß), or phosphate-buffered saline solution and incubated at 37°C for forty-eight hours. The concentrations of IL-1ß (interleukin-1ß), IL-1RA (IL-1 receptor antagonist), IL-6, IFN-γ (interferon-γ), IP-10 (interferon gamma-induced protein 10), MCP-1 (monocyte chemotactic protein-1), MIP-1ß (macrophage inflammatory protein-1ß), PDGFßß, RANTES, TNF-α (tumor necrosis factor-α), VEGF (vascular endothelial growth factor), MMP-1, MMP-3, and MMP-9 in the culture medium were determined by multiplex immunoassay. RESULTS: Platelet-rich plasma cultured in medium contained multiple catabolic mediators in substantial concentrations, including MMP-9 (15.8 ± 2.3 ng/mL) and MMP-1 (2.5 ± 0.8 ng/mL), as well as proinflammatory mediators IL-1ß, IL-6, IFN-γ, IP-10, MCP-1, MIP-1ß, RANTES, and TNF-α in concentrations between 20 pg/mL and 20 ng/mL. Platelet-poor plasma contained significantly lower concentrations of these compounds. Platelet-rich plasma was used to treat human fibroblast-like synoviocytes, and the resulting concentrations of mediators were corrected for the concentrations in the platelet-rich plasma alone. Compared with untreated fibroblast-like synoviocytes, synoviocytes treated with platelet-rich plasma exhibited significantly greater levels of MMP-1 (363 ± 94.0 ng/mL, p = 0.018) and MMP-3 (278 ± 90.0 ng/mL, p = 0.018). In contrast, platelet-poor plasma had little effect on mediators secreted by the synoviocytes. PDGFßß-treated fibroblast-like synoviocytes exhibited a broad proinflammatory cytokine response at four and forty-eight hours. CONCLUSIONS: Platelet-rich plasma was shown to contain a mixture of anabolic and catabolic mediators. Synoviocytes treated with platelet-rich plasma responded with substantial MMP secretion, which may increase cartilage catabolism. Synoviocytes responded to PDGF with a substantial proinflammatory response.