A Review of Treatment for Acute and Chronic Pars Fractures in the Lumbar Spine.

PURPOSE OF REVIEW: Spondylolysis remains one of the most common causes of lower back pain in the pediatric and adolescent populations and is particularly prevalent in young sporting individuals. Despite this, approaches to diagnostic imaging and both conservative and surgical treatment vary widely among surgeons. The current review investigates recent literature on the etiology, clinical presentation, diagnosis, and treatment of spondylolysis. In particular, it interrogates the use of various advanced imaging modalities (CT, MRI, SPECT) in diagnosis as well as common surgical approaches to the condition. RECENT FINDINGS: Recent data has provided more information on how pars defect laterality, stage, and presence or absence of bone marrow edema impact healing potential. Other studies have highlighted the advantages of using MRI for spondylolysis diagnosis. Other data has provided more clarity on which adults may benefit from direct pars repair, while other studies have compared the various techniques for direct repair of pars defects. While the exact cause of spondylolysis remains unclear, there is growing understanding of the behavioral, genetic, and biomechanical risk factors that predispose individuals to the condition. MRI may be emerging as the advanced imaging modality of choice for diagnosis due to its lack of radiation and comparable sensitivity to other advanced imaging techniques. Conservative treatment remains the first step in management due to excellent outcomes in most patients, with surgical intervention rarely necessary. In patients that do require surgery, direct repair using a pedicle screw-based approach is preferred over spinal fusion and other direct repair techniques.

Unbiased immune profiling reveals a natural killer cell-peripheral nerve axis in fibromyalgia.

ABSTRACT: The pathophysiology of fibromyalgia syndrome (FMS) remains elusive, leading to a lack of objective diagnostic criteria and targeted treatment. We globally evaluated immune system changes in FMS by conducting multiparametric flow cytometry analyses of peripheral blood mononuclear cells and identified a natural killer (NK) cell decrease in patients with FMS. Circulating NK cells in FMS were exhausted yet activated, evidenced by lower surface expression of CD16, CD96, and CD226 and more CD107a and TIGIT. These NK cells were hyperresponsive, with increased CCL4 production and expression of CD107a when co-cultured with human leukocyte antigen null target cells. Genetic and transcriptomic pathway analyses identified significant enrichment of cell activation pathways in FMS driven by NK cells. Skin biopsies showed increased expression of NK activation ligand, unique long 16-binding protein, on subepidermal nerves of patients FMS and the presence of NK cells near peripheral nerves. Collectively, our results suggest that chronic activation and redistribution of circulating NK cells to the peripheral nerves contribute to the immunopathology associated with FMS.

Identification and characterization of novel candidate compounds targeting 6- and 7-transmembrane µ-opioid receptor isoforms.

BACKGROUND AND PURPOSE: The µ-opioid receptor (µ receptor) is the primary target for opioid analgesics. The 7-transmembrane (TM) and 6TM µ receptor isoforms mediate inhibitory and excitatory cellular effects. Here, we developed compounds selective for 6TM- or 7TM-µ receptors to further our understanding of the pharmacodynamic properties of µ receptors. EXPERIMENTAL APPROACH: We performed virtual screening of the ZINC Drug Now library of compounds using in silico 7TM- and 6TM-µ receptor structural models and identified potential compounds that are selective for 6TM- and/or 7TM-µ receptors. Subsequently, we characterized the most promising candidate compounds in functional in vitro studies using Be2C neuroblastoma transfected cells, behavioural in vivo pain assays using various knockout mice and in ex vivo electrophysiology studies. KEY RESULTS: Our virtual screen identified 30 potential candidate compounds. Subsequent functional in vitro cellular assays shortlisted four compounds (#5, 10, 11 and 25) that demonstrated 6TM- or 7TM-µ receptor-dependent NO release. In in vivo pain assays these compounds also produced dose-dependent hyperalgesic responses. Studies using mice that lack specific opioid receptors further established the µ receptor-dependent nature of identified novel ligands. Ex vivo electrophysiological studies on spontaneous excitatory postsynaptic currents in isolated spinal cord slices also validated the hyperalgesic properties of the most potent 6TM- (#10) and 7TM-µ receptor (#5) ligands. CONCLUSION AND IMPLICATIONS: Our novel compounds represent a new class of ligands for µ receptors and will serve as valuable research tools to facilitate the development of opioids with significant analgesic efficacy and fewer side-effects.

Stabilization of µ-opioid receptor facilitates its cellular translocation and signaling.

The G protein-coupled µ-opioid receptor (µ-OR) mediates the majority of analgesia effects for morphine and other pain relievers. Despite extensive studies of its structure and activation mechanisms, the inherently low maturation efficiency of µ-OR represents a major hurdle to understanding its function. Here we computationally designed µ-OR mutants with altered stability to probe the relationship between cell-surface targeting, signal transduction, and agonist efficacy. The stabilizing mutation T315Y enhanced µ-OR trafficking to the plasma membrane and significantly promoted the morphine-mediated inhibition of downstream signaling. In contrast, the destabilizing mutation R165Y led to intracellular retention of µ-OR and reduced the response to morphine stimulation. These findings suggest that µ-OR stability is an important factor in regulating receptor signaling and provide a viable avenue to improve the efficacy of analgesics.