Interleukin-8 as a therapeutic target for chronic low back pain: Upregulation in human cerebrospinal fluid and pre-clinical validation with chronic reparixin in the SPARC-null mouse model.

BACKGROUND: Low back pain (LBP) is the leading global cause of disability and is associated with intervertebral disc degeneration (DD) in some individuals. However, many adults have DD without LBP. Understanding why DD is painful in some and not others may unmask novel therapies for chronic LBP. The objectives of this study were to a) identify factors in human cerebrospinal fluid (CSF) associated with chronic LBP and b) examine their therapeutic utility in a proof-of-concept pre-clinical study. METHODS: Pain-free human subjects without DD, pain-free human subjects with DD, and patients with chronic LBP linked to DD were recruited and lumbar MRIs, pain and disability levels were obtained. CSF was collected and analyzed by multiplex cytokine assay. Interleukin-8 (IL-8) expression was confirmed by ELISA in CSF and in intervertebral discs. The SPARC-null mouse model of progressive, age-dependent DD and chronic LBP was used for pre-clinical validation. Male SPARC-null and control mice received systemic Reparixin, a CXCR1/2 (receptors for IL-8 and murine analogues) inhibitor, for 8 weeks. Behavioral signs of axial discomfort and radiating pain were assessed. Following completion of the study, discs were excised and cultured, and conditioned media was evaluated with a protein array. FINDINGS: IL-8 was elevated in CSF of chronic LBP patients with DD compared to pain-free subjects with or without DD. Chronic inhibition with reparixin alleviated low back pain behaviors and attenuated disc inflammation in SPARC-null mice. INTERPRETATION: These studies suggest that the IL-8 signaling pathway is a viable therapy for chronic LBP. FUND: Supported by NIH, MMF, CIHR and FRQS.

Evidence for a Role of Nerve Injury in Painful Intervertebral Disc Degeneration: A Cross-Sectional Proteomic Analysis of Human Cerebrospinal Fluid.

Intervertebral disc degeneration (DD) is a cause of low back pain (LBP) in some individuals. However, although >30% of adults have DD, LBP only develops in a subset of individuals. To gain insight into the mechanisms underlying nonpainful versus painful DD, human cerebrospinal fluid (CSF) was examined using differential expression shotgun proteomic techniques comparing healthy control participants, subjects with nonpainful DD, and patients with painful DD scheduled for spinal fusion surgery. Eighty-eight proteins were detected, 27 of which were differentially expressed. Proteins associated with DD tended to be related to inflammation (eg, cystatin C) regardless of pain status. In contrast, most differentially expressed proteins in DD-associated chronic LBP patients were linked to nerve injury (eg, hemopexin). Cystatin C and hemopexin were selected for further examination using enzyme-linked immunosorbent assay in a larger cohort. While cystatin C correlated with DD severity but not pain or disability, hemopexin correlated with pain intensity, physical disability, and DD severity. This study shows that CSF can be used to study mechanisms underlying painful DD in humans, and suggests that while painful DD is associated with nerve injury, inflammation itself is not sufficient to develop LBP. PERSPECTIVE: CSF was examined for differential protein expression in healthy control participants, pain-free adults with asymptomatic intervertebral DD, and LBP patients with painful intervertebral DD. While DD was related to inflammation regardless of pain status, painful degeneration was associated with markers linked to nerve injury.

Feasibility of a perfused and ventilated cadaveric model for assessment of lifesaving traumatic hemorrhage and airway management skills.

BACKGROUND: Training health care providers to manage common life-threatening traumatic injuries is an important endeavor. A fresh perfused cadaveric model with high anatomic and tissue fidelity was developed to assess performance of hemorrhage and airway management skills during a simulated polytrauma scenario. METHODS: Fresh human cadavers were obtained within 96 hours of death. Hemorrhage from a right traumatic amputation and left inguinal wound was simulated using cannulation of the right popliteal and left femoral artery, respectively. The thoracic aorta (thoracotomy method) or external iliac arteries (Pfannenstiel method) were used for catheter access points. Lung ventilation to simulate chest rise and fall was achieved using bilateral chest tubes connected to a bag valve mask. Participants underwent a simulated nighttime field care scenario in which they attempted tourniquet placement, direct wound pressure and packing, and endotracheal intubation. RESULTS: Twenty-four donors were obtained (58-95 years old; mean, 77). There were 305 total scenarios completed using 23 cadavers (mean, approximately 13 scenarios per cadaver). The cost for acquisition and preparation of donors can be estimated at $3,611 to $9,399. CONCLUSION: This model successfully allowed for the demonstration of hemorrhage and airway management skills with high anatomic and tissue fidelity. For the assessment of critical lifesaving skills that are nondestructive in nature, the use of a fresh perfused cadaveric model is feasible and suitable for evaluation of these procedures.

Preliminary evaluation of the SimPORTAL major vessel injury (MVI) repair model.

BACKGROUND: Major vessel injury (MVI) is a dangerous complication associated with laparoscopic surgery that leads, if not properly handled, to blood loss, conversion to open surgery, and eventually death. In this paper, we describe the preliminary evaluation of the SimPORTAL MVI model, created with the goal of simulating an intra-corporeal injury to a large vessel. METHODS: For this study, we created MVI models for 17 residents (PGY 1-4). Each resident was asked to perform an intracorporeal knot on a penrose drain within a maximum time limit of 6 min (in accordance with European basic laparoscopic urological skills rules) and then to subsequently repair a vessel injury on the MVI model, which was perfused with synthetic blood, within a maximum blood loss of 3 L. During the vessel repair, low lights and pulse sounds were used to simulate the operating room environment. All participants filled out a survey pre- and post-task to score various aspects of the model. RESULTS: We successfully created a model that simulates a critical surgical event. None of the participants reported having previous experience repairing a MVI. Six participants were able to perform the intracorporeal knot, and 12 residents (70.5%) were able to repair the MVI model under the given time and blood loss limits. Eleven participants agreed that the MVI model behaves like a real vessel, and six felt to be capable of performing the task prior to attempting it. Sixteen participants thought that the MVI model should be part of laparoscopic curriculums during residency. CONCLUSIONS: The SimPORTAL MVI model is a feasible low-cost model that would be well appreciated as a part of laparoscopic curriculum for residents. Minor improvements, including pressure measurement in the vessel for task assessment, will be made in the future, and further studies are necessary to definitively validate this model.

Multi-Institutional Validation of an OSATS for the Assessment of Cystoscopic and Ureteroscopic Skills.

PURPOSE: We evaluated the internal and construct validity of an assessment tool for cystoscopic and ureteroscopic cognitive and psychomotor skills at a multi-institutional level. MATERIALS AND METHODS: Subjects included a total of 30 urology residents at Ohio State University, Columbus, Ohio; Penn Presbyterian Medical Center, Philadelphia, Pennsylvania; and Mayo Clinic, Rochester, Minnesota. A single external blinded reviewer evaluated cognitive and psychomotor skills associated with cystoscopic and ureteroscopic surgery using high fidelity bench models. Exercises included navigation, basketing and relocation; holmium laser lithotripsy; and cystoscope assembly. Each resident received a total cognitive score, checklist score and global psychomotor skills score. Construct validity was assessed by calculating correlations between training year and performance scores (both cognitive and psychomotor). Internal validity was confirmed by calculating correlations between test components. RESULTS: The median total cognitive score was 91 (IQR 86.25, 97). For psychomotor performance residents had a median total checklist score of 7 (IQR 5, 8) and a median global psychomotor skills score of 21 (IQR 18, 24.5). Construct validity was supported by the positive and statistically significant correlations between training year and total cognitive score (r = 0.66, 95% CI 0.39-0.82, p = 0.01), checklist scores (r = 0.66, 95% CI 0.35-0.84, p = 0.32) and global psychomotor skills score (r = 0.76, 95% CI 0.55-0.88, p = 0.002). The internal validity of OSATS was supported since total cognitive and checklist scores correlated with the global psychomotor skills score. CONCLUSIONS: In this multi-institutional study we successfully demonstrated the construct and internal validity of an objective assessment of cystoscopic and ureteroscopic cognitive and technical skills, including laser lithotripsy.

Validity and acceptability of a high-fidelity physical simulation model for training of laparoscopic pyeloplasty.

PURPOSE: The objective was to determine the acceptability and preliminary construct validity for a high-fidelity synthetic renal pelvis/ureter tissue analogue model for use as a simulation model for training of laparoscopic pyeloplasty. MATERIALS AND METHODS: The pyeloplasty model was designed with incorporated assessment lines for use in post-task Black Light Assessment of Surgical Technique (BLAST)™. Practicing urologists participating in the 2011 and 2012 American Urological Association Mentored Renal Laparoscopy courses performed a simulated laparoscopic pyeloplasty procedure and completed a post-task evaluation of the model. RESULTS: Practicing urologists found the model acceptable and rated the model favorably in terms of content and face validity. Urologists who had performed a laparoscopic pyeloplasty procedure in the last 5 years outperformed those who had not by demonstrating increased patency (P<0.05), decreased twisting (P<0.05), and decreased leakage (P<0.10) at the anastomosis. CONCLUSIONS: The BLAST™ pyeloplasty model demonstrated evidence of acceptability and content, face, and construct validity for training practicing urologists to perform laparoscopic pyeloplasty.