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Ngeow W.C.,University of Sheffield | Ngeow W.C.,University of Malaya | Atkins S.,University of Sheffield | Morgan C.R.,University of Sheffield | And 4 more authors.
Brain Research | Year: 2011

We have determined the effect of applying Mannose-6-Phosphate (M6P), a scar reducing agent, to a site of sciatic nerve repair. In anaesthetised C57-Black-6 mice, the left sciatic nerve was sectioned and repaired using 4 epineurial sutures. Either 100 μl of 600 mM Mannose-6-Phosphate (29 animals), or 100 μl of phosphate buffered saline as a placebo control (29 animals), was injected into and around the nerve repair site. A further group acted as sham-operated controls. After 6 or 12 weeks of recovery the extent of regeneration was assessed electrophysiologically and the percentage area of collagen staining at the repair site was analysed using picrosirius red and image analysis. Gait analysis was undertaken pre-operatively and at 1, 3, 6, 9 and 12 weeks postoperatively, to assess functional recovery. At 6 weeks the compound action potentials recorded from the regenerated nerves in the M6P group were significantly larger than in the placebo controls (P = 0.015), and the conduction velocities were significantly faster (P = 0.005), but there were no significant differences between these groups at 12 weeks. Gait analysis suggested better early functional recovery in the M6P group. In both repair groups there was a significant reduction in collagen staining between 6 and 12 weeks, suggestive of scar remodelling. We conclude that the normal scar remodelling process aids long term recovery in repaired nerves. Administration of 600 mM M6P to the nerve repair site enhances nerve regeneration and functional recovery in the early stages, and may lead to improved outcomes. © 2011 Elsevier B.V. All rights reserved.

Dalbeth N.,University of Auckland | Milligan A.,Auckland District Health Board | Doyle A.J.,University of Auckland | Clark B.,Grafton Group | McQueen F.M.,University of Auckland
Arthritis Research and Therapy | Year: 2012

Introduction: Radiographic descriptions of gout have noted the tendency to hypertrophic bone changes. The aim of this study was to characterize the features of new bone formation (NBF) in gout, and to determine the relationship between NBF and other radiographic features of disease, particularly erosion and tophus.Methods: Paired plain radiographs (XR) and computed tomography (CT) scans of 798 individual hand and wrist joints from 20 patients with gout were analyzed. Following a structured review of a separate set of images, films were scored for the presence of the following features of NBF: spur, osteophyte, periosteal NBF, ankylosis and sclerosis. The relationship between NBF and other radiographic features was analyzed.Results: The most frequent forms of NBF were bone sclerosis and osteophyte. Spur and periosteal NBF were less common, and ankylosis was rare. On both XR and CT, joints with bone erosion were more likely to have NBF; for CT, if erosion was present, the odds ratios (OR) was 45.1 for spur, 3.3 for osteophyte, 16.6 for periosteal NBF, 26.6 for ankylosis and 32.3 for sclerosis, P for all < 0.01. Similarly, on CT, joints with intraosseous tophus were more likely to have NBF; if tophus was present, the OR was 48.4 for spur, 3.3 for osteophyte, 14.5 for periosteal NBF, 35.1 for ankylosis and 39.1 for sclerosis; P for all < 0.001.Conclusions: This detailed quantitative analysis has demonstrated that NBF occurs more frequently in joints affected by other features of gout. This work suggests a connection between bone loss, tophus, and formation of new bone during the process of joint remodelling in gout. © 2012 Dalbeth et al.; licensee BioMed Central Ltd.

Harding A.J.,University of Sheffield | Christmas C.R.,University of Sheffield | Ferguson M.W.J.,Grafton Group | Ferguson M.W.J.,University of Manchester | And 3 more authors.
Neuroscience | Year: 2014

The formation of scar tissue following nerve injury has been shown to adversely affect nerve regeneration and evidence suggests that mannose-6-phosphate (M6P), a potential scar reducing agent that affects transforming growth factor (TGF)-β activation, may enhance nerve regeneration. In this study we utilized thy-1-YFP-H mice - a transgenic strain expressing yellow fluorescent protein (YFP) within a subset of axons - to enable visual analysis of axons regenerating through a nerve graft. Using this strain of mouse we have developed analysis techniques to visualize and quantify regeneration of individual axons across the injury site following the application of either M6P or vehicle to the site of nerve injury.No significant differences were found in the proportion of axons regenerating through the graft between M6P- and vehicle-treated grafts at any point along the graft length. Maximal sprouting occurred at 1.0. mm from the proximal graft ending in both groups. The maximum change in sprouting levels for both treatment groups occurred between the graft start and 0.5-mm interval for both treatment groups. The difference between repair groups was significant at this point with a greater increase seen in the vehicle group than the M6P group. The average length of axons regenerating across the initial graft entry was significantly shorter in M6P- than in vehicle-treated grafts, indicating that they encountered less impedance.Application of M6P appears to reduce the disruption of regenerating axons and may therefore facilitate quicker recovery; this is likely to result from altered scar tissue formation in M6P grafts in the early stages of recovery. This study also establishes the usefulness of our methods of analysis using the thy-1-YFP-H mouse strain to visualize and quantify regeneration at the level of the individual axon. © 2014 The Authors.

Beliaev A.M.,Auckland City Hospital | Marshall R.J.,University of Auckland | Gordon M.,Grafton Group | Smith W.,Auckland City Hospital | Windsor J.A.,University of Auckland
Vox Sanguinis | Year: 2012

Background It is well known that blood transfusion is life-saving, but also that it carries a serious risk of transmitting viral infections. Introduction of new methods of testing for transmissible diseases, blood banking and dispatch regulations has considerably increased the cost of blood products. However, the clinical benefits and cost-effectiveness of allogeneic red-blood-cell (ARBC) transfusion remain assumed yet undetermined. We assessed the clinical benefits and cost-effectiveness of ARBC transfusion in severe anaemia. Methods This was a multicenter observational study comparing Jehovah's Witness (JW) patients with matched ARBC-transfused patients. Inclusion criteria were age ≥15years and severe anaemia (haemoglobin≤80g/l). Two JW patients with palliative care cancer and five JW patients with haemoglobin (Hb) concentration between 70·1 and 80g/l, mild symptoms of anaemia and Auckland Anaemia Mortality Risk Score of 0-3 were excluded. Results The entry criteria were met by 103 JW patients and the same number of patients treated with ARBC transfusion. ARBC transfusion reduced mortality by 94%, shock by 88%, gastrointestinal bleeding by 81%, infective complications by 81%, cardiac arrhythmia by 96%, angina by 86%, ischaemic myocardial injury by 81%, acute/acute on chronic renal failure by 66%, neurologic complications by 92%, delirium by 76%, depression by 91% and syncopal episodes by 95%. The incremental cost-effectiveness ratio of ARBC transfusion was 2011 US$22515 for death prevented. Conclusion ARBC transfusion in anaemic patients is clinically beneficial and cost-effective. © 2011 International Society of Blood Transfusion.

Rutter M.K.,University of Manchester | Rutter M.K.,Manchester Diabetes Center | Rutter M.K.,Grafton Group | Nesto R.W.,Lahey Clinic
Diabetes and Vascular Disease Research | Year: 2010

The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial randomized 2368 patients with type 2 diabetes (T2DM) and coronary artery disease to either prompt revascularization or intensive medical therapy alone; and to either insulin-sensitization or insulin-provision diabetes therapy. Randomization was stratified by proposed revascularization method. Five-year survival and major cardiovascular events (MACE) were similar in study subgroups except in the coronary bypass surgery (CABG) stratum where there were fewer MACE after revascularization. There was less hypoglycaemia and weight gain, and greater apparent benefit from CABG in the insulin sensitization group. BARI 2D has provided important data for clinicians. © The Author(s) 2010.

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