Summary Statement

IL-1β stimulation of human OA chondrocytes induces NFκB, ERK1/2, c-JUN, IκB and P38 signalling pathways. Pre-treatment with cannabinoid WIN-55 for 48 hours inhibits certain pathways, providing mechanisms for cannabinoids inhibitory actions on IL-1β induced cartilage degradation.

Matrix metalloproteinases (MMPs) are involved in extracellular matrix (ECM) breakdown in osteoarthritis (OA) and their expression is regulated by nuclear factor kappa B (NFκB). In addition signalling pathways ERK1/2, c-JUN, IκB and P38 are activated in OA and are induced by inflammatory cytokine interleukin 1 (IL-1). Cannabinoids have been shown to reduce joint damage in animal models of arthritis. Synthetic cannabinoid WIN-55, 212-2 mesylate (WIN-55) significantly reduces IL-1β induced expression of MMP-3 and -13 in human OA chondrocytes, indicating a possible mechanism via which cannabinoids may act to prevent ECM breakdown. Here the effects of WIN-55 on IL-1β induced NFκB, ERK1/2, c-JUN, IκB and P38 phosphorylation in human OA chondrocytes has been investigated.

Primary human chondrocytes were obtained from articular cartilage removed from patients with symptomatic OA during total knee replacement (Ethic approval:SMB002). Cartilage tissue was graded macroscopically 0–4 using the Outerbridge Classification method. Chondrocytes isolated from grade 2 cartilage and cultured in monolayer were pre-treated with 10 μM WIN-55 for 1 hour prior to stimulation with 10 ng/ml IL-1β for 30 minutes for investigation of NFκB, c-JUN, IκB and P38 phosphorylation. In addition chondrocytes were pre-treated with 10 μM WIN-55 for 30 minutes, 1, 3, 6, 24 and 48 hours prior to 10 ng/ml IL-1β stimulation for 30 minutes to investigate ERK1/2 phosphorylation.

Dimethyl sulfoxide (DMSO) was used as a vehicle control at 0.1%. Immunocytochemistry was used to investigate the phosphorylation and translocation of NFκB. ERK1/2, c-JUN, IκB, and P38 activation was investigated using cell based ELISA. Immunocytochemical analysis showed chondrocytes stimulated with IL-1β induced NFκB phosphorylation and translocation to the nucleus.

Chondrocytes treated with IL-1β with WIN-55 for 1 hour pre-treatment showed no inhibition of the IL-1β induced NFκB phosphorylation and translocation to the nucleus. WIN-55 treatment alone for 1 hour stimulated NFκB phosphorylation in the cytoplasm but not the nucleus. ELISA showed that phosphorylation of ERK1/2, c-JUN, IκB, and P38 was significantly induced by IL-1β following 30 minutes stimulation (p<0.05). Pre-treatment with WIN-55 for 1 hour had no significant effect on this IL-1β induced phosphorylation. However WIN-55 pre-treatment for 48 hours prior to IL-1β stimulation for 30 minutes, resulted in a significant decrease in ERK1/2 phosphorylation compared to IL-1β stimulation alone (p<0.05).

WIN-55 treatment alone for 1 hour significantly induced c-JUN phosphorylation (p<0.05), but had no effect on IκB and P38 phosphorylation compared to DMSO control. IL-1β stimulation of ERK1/2 phosphorylation was not significantly affected by WIN-55 pre-treatment of 30 minutes, 1, 3, 6 and 24 hours. WIN-55 treatment alone for 48 hours significantly reduced ERK1/2 phosphorylation compared to DMSO control (p<0.05). WIN-55 treatment alone for 30 min, 1, 3, 6 and 24 hours had no significant effect on ERK1/2 phosphorylation compared to DMSO control. The results show that following 48 hours pre-treatment WIN-55 inhibits IL-1β induced ERK1/2 phosphorylation in human OA chondrocytes. Thus inhibitory effects of cannabinoids on IL-1β induced cartilage degradation may be mediated via modulation of ERK1/2 signalling.

Although many authors have emphasised the importance of lumbar spinal decompression surgery for “leg dominant pain”, there is little objective evidence on the outcomes of surgery for varying degrees of back pain compared to leg pain. Moreover, it is unclear whether patients with radicular or claudication type leg pain, presenting with significant back pain as well, would benefit from surgical decompression. This study evaluated the outcomes of patients with

(i.) leg dominant pain compared to patients with

A prospective cohort of consenting adult patients, who have consecutively undergone elective primary posterior lumbar decompression surgery at a single academic institution by sub-specialty spinal surgeons were evaluated with longitudinal follow-up using standardised outcomes instruments. The cohort was analyzed into those with

(i.) leg dominant pain and those with

Univariate and multivariate analyses were used to adjust for potential confounding effects of demographic, surgical, waiting list and psychosocial factors.

Of the eighty-five eligible patients, sixty-nine (81.3%) had at least one year follow-up with a mean follow-up time of seventeen months. Baseline factors were similar between the two groups except for back and leg pain and wait times for consultation after referral. Patients with significant back pain waited significantly longer (p = 0.04) for consultation after referral than those with leg dominant pain. Significantly (p = 0.002) more patients (93%) in the leg dominant pain group reported clinically significant improvement in the Oswestry than the significant back pain group (59%). This effect remained after multivariate adjustments for other baseline factors.

This study is one of the first to provide objective evidence to support the notion that the primary indication and best predictor of outcome for lumbar decompression surgery is leg dominant pain. Presence of significant back pain, despite presence of leg pain, is a strong predictor of poorer post-operative results. Further research is required to determine if the current long waiting lists are a causative factor for development of significant back pain in surgical candidates.

Purpose: The purpose of this study was to analyse the learning curve of video-assisted thoracoscopic surgery in a consecutive series of 70 interventions for decompression and intervertebral fusion with rib bone grafts.

Material and methods: This series was composed of 70 patients followed for at least two years. The indication of video-assisted thoracoscopic surgery was idiopathic scoliosis (n=32), neuromuscular spinal malformation (n=13), neurofibromatosis (n=1), scoliosis secondary to Marfan disease (n=1), radiation-induced scoliosis (n=1), and nonunion (n=1). The first rib was resected in three patients due to compression. Resection of an intrath-roacic neurofibroma and a benign rib tumour was performed in two patients. Anterior fusion was necessary in one patient due to fracture-displacement of the thoracic spine.

Results: Mean operative time for thoracoscopic anterior decompression with discectomy and fusion was 256 minutes (range 150–405). On the average, eight discs were removed (range 4–11). Comparison of mean operative time per disc between the first interventions (n=31) and the later interventions (n=32) did not demonstrate any significant difference. Mean blood loss during thora-coscopic anterior decompression with discectomy and fusion was 285 ml (range 50–1300).

Discussion: Definitive postoperative correction was achieved in 68% and 90% of the patients with scoliosis and kyphosis respectively. A thoracoscopy-related complication was observed in three patients. Video-assisted thoracoscopic surgery is an interesting alternative to conventional thoracotomy allowing effective safe treatment of infantile spinal malformations despite a long learning curve.