John M. O'Byrne

Nontuberculous pyogenic spinal infection in adults: a 12-year experience from a tertiary referral center.

Study Design. We performed a retrospective review of 48 cases of pyogenic spinal infection presenting over a 12-year period to the National Spinal Injuries Unit (NSIU) of the Republic of Ireland. The NSIU is the tertiary referral center for all adult spinal injuries and diseases of the spine warranting surgical intervention in the Republic of Ireland. Objectives. The objective of this study was to analyze the presentation, etiology, management, and outcome of nontuberculous pyogenic spinal infection in adults. Summary of Background Data. Pyogenic spinal infection encompasses a broad range of clinical entities, including spondylodiscitis, septic discitis, vertebral osteomyelitis, and epidural abscess. Management of pyogenic spinal infection can involve conservative methods and surgical intervention. Methods. The medical records, radiologic imaging, and bacteriology results of 48 patients with pyogenic vertebral osteomyelitis from 1992 through 2004 were reviewed. The Hospital Inpatient Enquiry (HIPE) System and the NSIU Database were used to identify our study cohort. Results. The average age of presentation was 59 years with an even distribution between males and females. Most patients (21 of 48) were symptomatic for between 2 and 6 weeks before presenting to hospital. The most frequently isolated pathogen was Staphylococcus aureus, in 23 of 48 cases (48%); 35 of 48 cases (73%) were managed by conservative measures alone, including antibiotic therapy and spinal bracing. However, in 13 of 48 cases (27%), surgical intervention was required because of neurologic compromise or mechanical instability. Conclusions. In the majority of cases, conservative management of pyogenic spinal infection with antibiotic therapy and spinal bracing is very successful. However, in a minority of cases, surgical intervention is warranted and referral to a specialist center is appropriate.

The role of Dkk1 in bone mass regulation: correlating serum Dkk1 expression with bone mineral density.

The Wnt/β‐catenin pathway is a major signaling cascade in bone biology, playing a key role in regulating bone development and remodeling, with aberrations in signaling resulting in disturbances in bone mass. The objectives of our study were to correlate serum Dkk1 expression with bone mineral density (BMD) and assess the potential role of Dkk1 as a serological marker of bone mass. Serum was collected from a cohort of patients (n = 36), 18 patients with a reduced BMD and 18 control patients. Serum Dkk1 expression as quantified by ELISA was correlated with lumbar and femoral t‐ and z‐scores. Serum Dkk1 concentration in the osteoporosis group was significantly higher than control group (941 ± 116 vs. 558 ± 47 pg/ml, p < 0.01). Serum Dkk1 expression was highly correlated with bone mass variables with inverse associations found between serum Dkk1 expression and lumbar t‐score (r = −0.34, p = 0.00433), lumbar z‐score (r = −0.22, p = 0.1907), femur t‐score (r = −0.42, p = 0.0101), and femur z‐score (r = −0.43, p = 0.0089). Our data further emphasizes the pivotal role played by Wnt/β‐catenin signaling in bone mass regulation. Dkk1, a powerful antagonist of canonical Wnt signaling, may have a role to play as a serological marker for disorders of bone mass, warranting further evaluation.

Cobalt Ions Induce Chemokine Secretion in Primary Human Osteoblasts

Chemokines are major regulators of the inflammatory response and have been shown to play an important role in periprosthetic osteolysis. Titanium particles have previously been shown to induce IL‐8 and MCP‐1 secretion in osteoblasts. These chemokines result in the chemotaxis and activation of neutrophils and macrophages, respectively. Despite a resurgence in the use of cobalt‐chromium‐molybdenum alloys in metal‐on‐metal arthroplasty, cobalt and chromium ion toxicity in the periprosthetic area has been insufficiently studied. In this study we investigate the in vitro effect of cobalt ions on primary human osteoblast activity. We demonstrate that cobalt ions rapidly induce the protein secretion of IL‐8 and MCP‐1 in primary human osteoblasts. This elevated chemokine secretion is preceded by an increase in the transcription of the corresponding chemokine gene. Using a Transwell migration chemotaxis assay we also demonstrate that the chemokines secreted are capable of inducing neutrophil and macrophage migration. Furthermore, cobalt ions significantly inhibit osteoblast function as demonstrated by reduced alkaline phosphatase activity and calcium deposition. In aggregate these data demonstrate that cobalt ions can activate transcription of the chemokine genes IL‐8 and MCP‐1 in primary human osteoblasts. Cobalt ions are not benign and may play an important role in the pathogenesis of osteolysis by suppressing osteoblast function and stimulating the production and secretion of chemokines that attract inflammatory and osteoclastic cells to the periprosthetic area.

Silencing Dkk1 expression rescues dexamethasone-induced suppression of primary human osteoblast differentiation

BackgroundThe Wnt/β-catenin pathway is a major signaling cascade in bone biology, playing a key role in bone development and remodeling. The objectives of this study were firstly, to determine the effects of dexamethasone exposure on Wnt/β-catenin signaling at an intracellular and transcriptional level, and secondly, to assess the phenotypic effects of silencing the Wnt antagonist, Dickkopf-1 (Dkk1) in the setting of dexamethasone exposure.MethodsPrimary human osteoblasts were exposed in vitro to 10-8 M dexamethasone over a 72 h time course. The phenotypic marker of osteoblast differentiation was analyzed was alkaline phosphatase activity. Intracellular β-catenin trafficking was assessed using immunoflourescence staining and TCF/LEF mediated transcription was analyzed using a Wnt luciferase reporter assay. Dkk1 expression was silenced using small interfering RNA (siRNA).ResultsPrimary human osteoblasts exposed to dexamethasone displayed a significant reductions in alkaline phosphatase activity over a 72 h time course. Immunoflourescence analaysis of β-catenin localization demonstrated a significant reduction in intracytosolic and intranuclear β-catenin in response to dexamethasone exposure. These changes were associated with a reduction of TCF/LEF mediated transcription. Silencing Dkk1 expression in primary human osteoblasts exposed to dexamethasone resulted in an increase in alkaline phosphatase activity when compared to scrambled control.ConclusionsWnt/β-catenin signaling plays a key role in regulating glucocorticoid-induced osteoporosis in vitro. Silencing Dkk1 expression rescues dexamethasone-induced suppression of primary human osteoblast differentiation. Targeting of the Wnt/β-catenin signaling pathway offers an exciting opportunity to develop novel anabolic bone agents to treat osteoporosis and disorders of bone mass.

Cobalt ions induce chemokine secretion in a variety of systemic cell lines

Background and purpose Metal ion toxicity both locally and systemically following MoM hip replacements remains a concern. Cobalt ions have been shown to induce secretion of proinflammatory chemokines locally; however, little is known about their effect systemically. We investigated the in vitro effect of cobalt ions on a variety of cell lines by measuring production of the proinflammatory chemokines IL-8 and MCP-1. Method Renal, gastrointestinal, and respiratory epithelium and also neutrophils and monocytes were exposed to cobalt ions at 4, 12, 24, and 48 hours. Results We found that cobalt ions enhanced the secretion of IL-8 and MCP-1 in renal epithelial cells, gastric and colon epithelium, monocytes and neutrophils, and small airway epithelial cells but not in alveolar cells. Secretion of IL-8 and MCP-1 was markedly elevated in renal epithelium, where a 16-fold and 7-fold increase occurred compared to controls. There was a 6-fold and 4-fold increase in IL-8 and MCP-1 secretion in colon epithelium and a 4-fold and 3-fold increase in gastric epithelium. Small airway epithelial cells showed a maximum increase in secretion of 8-fold (IL-8) and of 4-fold (MCP-1). The increase in chemokine secretion observed in alveolar cells was moderate and did not reach statistical significance. Monocytes and neutrophils showed a 2.5-fold and 2-fold increase in IL-8 secretion and a 6-fold and 4-fold increase in MCP-1 secretion at 48 and 24 hours, respectively. Interpretation These data demonstrate the potent bioactivity of cobalt ions in a variety of cell types and the potential to induce a proinflammatory response.

The Natural History and Clinical Syndromes of Degenerative Cervical Spondylosis

Cervical spondylosis is a broad term which describes the age related chronic disc degeneration, which can also affect the cervical vertebrae, the facet and other joints and their associated soft tissue supports. Evidence of spondylitic change is frequently found in many asymptomatic adults. Radiculopathy is a result of intervertebral foramina narrowing. Narrowing of the spinal canal can result in spinal cord compression, ultimately resulting in cervical spondylosis myelopathy. This review article examines the current literature in relation to the cervical spondylosis and describes the three clinical syndromes of axial neck pain, cervical radiculopathy and cervical myelopathy

Assessment of a new undergraduate module in musculoskeletal medicine

BACKGROUND Despite the high prevalence of musculoskeletal disorders seen by primary care physicians, numerous studies have demonstrated deficiencies in the adequacy of musculoskeletal education at multiple stages of medical education. The aim of this study was to assess a newly developed module in musculoskeletal medicine for use at European undergraduate level (i.e., the medical-school level). METHODS A two-week module in musculoskeletal medicine was designed to cover common musculoskeletal disorders that are typically seen in primary care. The module incorporated an integrated approach, including core lectures, bedside clinical examination, and demonstration of basic practical procedures. A previously validated examination in musculoskeletal medicine was used to assess the cognitive knowledge of ninety-two students on completion of the module. A historical control group (seventy-two students) from a prior course was used for comparison. RESULTS The new module group (2009) performed significantly better than the historical (2006) control group in terms of score (62.3% versus 54.3%, respectively; p < 0.001) and pass rate (38.4% versus 12.5%, respectively; p = 0.0002). In a subgroup analysis of the new module group, students who enrolled in the graduate entry program (an accelerated four-year curriculum consisting of students who have already completed an undergraduate university degree) were more likely to perform better in terms of average score (72.2% versus 57%, respectively; p < 0.001) and pass rates (70.9% versus 21.4%, respectively; p < 0.001) compared with students who had enrolled via the traditional undergraduate route. In terms of satisfaction rates, the new module group reported a significantly higher satisfaction rate than that reported by the historical control group (63% versus 15%, respectively; p < 0.001). CONCLUSIONS In conclusion, the musculoskeletal module described in this paper represents an educational advance at undergraduate (i.e., medical-school) level as demonstrated by the improvement in scores in a validated examination. As pressure on medical curricula grows to accommodate advancing medical knowledge, it is important to continue to improve, assess, and consolidate the position of musculoskeletal medicine in contemporary medical education.

Nonoperative Modalities to Treat Symptomatic Cervical Spondylosis

Cervical spondylosis is a common and disabling condition. It is generally felt that the initial management should be nonoperative, and these modalities include physiotherapy, analgesia and selective nerve root injections. Surgery should be reserved for moderate to severe myelopathy patients who have failed a period of conservative treatment and patients whose symptoms are not adequately controlled by nonoperative means. A review of the literature supporting various modalities of conservative management is presented, and it is concluded that although effective, nonoperative treatment is labour intensive, requiring regular review and careful selection of medications and physical therapy on a case by case basis.

HIV-1 protein induced modulation of primary human osteoblast differentiation and function via a Wnt/β-catenin-dependent mechanism.

HIV infection is associated with metabolic bone disease resulting in bone demineralization and reduced bone mass. The molecular mechanisms driving this disease process have yet to be elucidated. Wnt/β‐catenin signaling plays a key role in bone development and remodeling. We attempted to determine the effects of the HIV‐1 protein, gp120, on Wnt/β‐catenin signaling at an intracellular and transcriptional level in primary human osteoblasts (HOBs). This work, inclusive of experimental controls, was part of a greater project assessing the effects of a variety of different agents on Wnt/β‐catenin signaling (BMC Musculoskelet Disord 2010;11:210).We examined the phenotypic effects of silencing and overexpressing the Wnt antagonist, Dickkopf‐1 (Dkk1) in HOBs treated with gp120. HOBs exposed to gp120 displayed a significant reduction in alkaline phosphatase activity (ALP) activity and cell proliferation and increased cellular apoptosis over a 48 h time course. Immunocytochemistry demonstrated a significant reduction in intracytosolic and intranuclear β‐catenin in response to HIV‐1 protein exposure. These changes were associated with a reduction of TCF/LEF‐mediated transcription, the transcriptional outcome of canonical Wnt β‐catenin signaling. Silencing Dkk1 expression in HOBs exposed to gp120 resulted in increased ALP activity and cell proliferation, and decreased cellular apoptosis relative to scrambled control. Dkk1 overexpression exacerbated the inhibitory effect of gp120 on HOB function, with decreases in ALP activity and cell proliferation and increased cellular apoptosis relative to vector control. Wnt/β‐catenin signaling plays a key regulatory role in HIV‐associated bone loss, with Dkk1, aputative central mediator in this degenerative process.

Degenerative Cervical Spondylosis: Natural History, Pathogenesis, and Current Management Strategies

Degenerative cervical spondylosis is a common, mostly asymptomatic condition, occurring as a result of age-related degenerative changes in the cervical spine. Symptoms caused by cervical spondylosis can be categorized broadly into three clinical syndromes: axial neck pain, cervical radiculopathy, and cervical myelopathy; with patients commonly having a combination of these syndromes. This special issue contains eleven papers summarizing our present knowledge and understanding of the natural history, pathogenesis, and current management strategies for degenerative cervical spondylosis.