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    ABSTRACT: It is widely recognized that purinergic signalling, extracellular nucleotides acting at purinergic receptors, is the most primitive and ubiquitous signalling system participating in numerous biological processes in almost all tissue types. The P2 receptors, including P2X and P2Y purinoceptor subtypes, have been proposed to play important roles in the musculoskeletal systems since the early 1990s. During the past five years, significant progress in this field has been made; this review will summarize these most recent developments and highlight the pharmaceutical potential from these findings.
    Current Opinion in Pharmacology 01/2014; 16:122–126.
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    ABSTRACT: We compared the short-term precision of pelvic periprosthetic bone mineral density (BMD) measurement around a cementless acetabular prosthesis (n = 29) vs a cemented all-polyethylene acetabular prosthesis (n = 19) in patients after total hip arthroplasty. Two dual-energy x-ray absorptiometry scans of the pelvis were made on the same day in each subject with subject repositioning between scans and analyzed independently with a 4-region of interest model. Precision was expressed as coefficient of variation (CV%). The measured BMD around the cemented prostheses was greater than the cementless prostheses p < 0.004, all analyses). The net CV for pelvic BMD measurements around the cementless prosthesis was 1.9% vs 3.6% around the cemented prosthesis (F-test p < 0.001). The CVs of individual regions of interest was between 2.8% and 4.8% for the cementless prosthesis vs 4.4% to 8.4% for the cemented prosthesis (F-test; p < 0.05, all comparisons). Prospective studies would require 57 subjects to detect a 10% change in net pelvic BMD around a cementless prosthesis and 122 to detect a similar change around a cemented prosthesis with 90% power and with an alpha error of 0.05. In conclusion, the precision of pelvic BMD measurements made around cementless prostheses are better vs those for cemented prostheses. Dual-energy x-ray absorptiometry studies of cemented prosthesis require approximately double the number of subjects vs cementless prostheses to achieve a similar level of power.
    Journal of Clinical Densitometry 10/2013;
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    ABSTRACT: High-resolution peripheral quantitative computed tomography (HR-pQCT) is increasingly being used in the research setting to assess the effects of osteoporosis treatments and disease on trabecular and cortical bone compartments. Further in-depth study of HR-pQCT measurement variables is essential to ensure study strength and statistical confidence when designing large multicenter studies. Duplicate HR-pQCT examinations of the distal radius and tibia were performed in 180 healthy men and women ages 16-18, 30-32, and >70 years. HR-pQCT images were processed using standard and extended cortical bone analysis techniques. Biomechanical properties of bone were assessed using finite element analysis. Percent root mean square coefficient of variation (RMSCV) was calculated for each measurement variable. Age, site, and gender influences on measurement variability were investigated using variance ratio tests. Smaller precision errors were observed for densitometric (0.2-5.5 %) than for microstructural (1.2-7.0 %), extended cortical bone (3.4-20.3 %), and biomechanical (0.3-9.9 %) measures at both the radius and tibia. Tibial measurements (RMSCVs = 0.2-7.4 %) tended to be more precise than radial measurements (RMSCVs = 0.7-20.3 %). Variability was influenced by age, site, and gender (all p < 0.05). HR-pQCT measurements for the tibia were more precise than those for the radius, and this may be explained by the larger bone volumes examined and the reduced likelihood of movement artifact. The greater measurement variability observed for older volunteers may be due to the loss of bone density and microstructural integrity with age.
    Calcified Tissue International 09/2013;
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    ABSTRACT: The activity of the enzyme thiopurine methyltransferase (TPMT) is regulated by a common genetic polymorphism, one in 300 individuals lack enzyme activity and 11% are heterozygous for a variant low activity allele; they have an intermediate activity. The thiopurine drugs azathioprine, mercaptopurine and thioguanine are substrates for TPMT; these drugs exhibit well documented myelosuppressive effects on haematopoietic cells and have a track record of idiosyncratic drug reactions. The development of severe bone marrow toxicity, in patients taking standard doses of thiopurine drugs, is associated with TPMT deficiency whilst the TPMT heterozygote is at an increased risk of developing myelosuppression. Factors influencing TPMT enzyme activity, as measured in the surrogate red blood cell, are discussed in this review to enable an appreciation of why concordance between TPMT genotype and phenotype is not 100%; this is particularly important for lower/intermediate TPMT activities to avoid misclassification of TPMT status. TPMT testing is now widely available in routine service laboratories; the British National Formulary suggests TPMT testing before starting thiopurine drugs. Dermatologists were quick to adopt routine TPMT testing whilst gastroenterologists do not specifically recommend TPMT screening. TPMT testing is mandatory prior to the use of mercaptopurine in childhood leukaemia. Thiopurine drug dose and other treatment related influences on cell counts explain some of the differing recommendations between clinical specialities. TPMT testing is cost-effective and the major role is in the identification of the TPMT deficient individual prior to the start of thiopurine drugs.
    British Journal of Clinical Pharmacology 08/2013;
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    Purinergic Signalling 08/2013;
  • The Lancet 05/2013;
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    ABSTRACT: Context:Gut-derived serotonin has been proposed as a regulator of bone formation, and inhibition of gut serotonin synthesis increases bone formation in rodents. Carcinoid neuroendocrine tumors can produce very high levels of circulating serotonin and so offer a model of serotonin excess in humans.Objectives:To determine if patients with carcinoid syndrome have lower bone formation markers, lower bone density or poor bone structure compared with healthy controls.Design:We conducted a cross-sectional study of 25 patients with carcinoid syndrome and 25 healthy controls, individually matched to carcinoid patients by gender, age, height and BMI.Outcome measures:We measured circulating serotonin in blood and plasma, and 5HIAA in plasma and urine. We measured lumbar spine and hip BMD by DXA, the distal radius and tibia with high-resolution pQCT, and bone turnover with serum osteocalcin, PINP and CTX.Results:All measures of serotonin and 5HIAA were higher in carcinoid patients than in controls. No measures of bone density or bone structure differed significantly between cases and controls. Osteocalcin was higher in cases than controls (26.0 vs 21.1 ng/ml, p 0.02). PINP and CTX did not differ between cases and controls. In patients with carcinoid syndrome, plasma 5HIAA was positively correlated with osteocalcin. In controls, whole blood serotonin was positively correlated with osteocalcin, PINP and CTX. (R values 0.40 to 0.47, all p <0.05.)Conclusions:High circulating serotonin in carcinoid syndrome is not associated with clinically significant lower bone density, poorer bone structure or lower bone formation markers.
    The Journal of clinical endocrinology and metabolism 04/2013;
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    ABSTRACT: Background Melanoma is an immunogenic tumour. The development of skin depigmentation or melanoma-associated leucoderma (MAL) has been associated with favourable clinical outcome in patients with metastatic melanoma, especially after immunotherapy. Evidence for clinically meaningful enhancement of melanoma-directed autoimmunity, as indicated by MAL, after radiotherapy without immunotherapy has not yet been published. Objectives We investigated whether a patient with stage IV melanoma, who developed leucoderma in the irradiated skin areas following radiotherapy and experienced exceptional disease-free survival of 3 years despite brain metastasis, possessed antimelanoma immunity that could be linked to the favourable disease course. Methods A detailed immunological analysis was performed consisting of immunohistochemistry of several melanoma tissues, and analyses of T cells isolated from the blood and MAL skin tissue for melanocyte/melanoma specificity and functionality, as well as the presence of a melanoma-specific antibody response. Results Immunological analyses showed the presence of CD8+ T cells and antibody responses directed against melanocyte differentiation antigens expressed in the primary tumour, lymph node and brain metastasis, indicating adequate tumour recognition by activated T cells. Conclusion The immune responses found in this patient, probably enhanced by radiotherapy, are thought to have contributed to his favourable clinical course. Radiotherapy may act as local immunotherapy in patients with melanoma by destroying melanocytes, leading to the induction, or enhancement, of already existent antimelanoma immunity. As in patients treated with immunotherapy, this may lead to MAL, also at distant sites from the treated area. This patient is a clear example of the positive prognostic value of MAL, which is possibly induced by radiotherapy, for patients with melanoma.
    British Journal of Dermatology 02/2013;
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    ABSTRACT: ATP release and subsequent activation of purinergic receptors has been suggested to be one of the key transduction pathways activated by mechanical stimulation of bone. The P2Y(13) receptor, recently found to be expressed by osteoblasts, has been suggested to provide a negative feedback pathway for ATP release in different cell types. Therefore, we hypothesised that the P2Y(13) receptor may contribute to the mediation of osteogenic responses to mechanical stimulation by regulating ATP metabolism by osteoblasts. To test this hypothesis, wild type (WT) and P2Y(13) receptor knock-out (P2Y(13) R(-/-) ) mice were subject to non-invasive axial mechanical loading of the left tibiae to induce an osteogenic response. Micro-Computed Tomography analysis showed mechanical loading induced an osteogenic response in both strains of mice in terms of increased total bone volume and cortical bone volume, with the P2Y(13) R(-/-) mice having a significantly greater response. The extent of the increased osteogenic response was defined by dynamic histomorphometry data showing dramatically increased bone formation and mineral apposition rates in P2Y(13) R(-/-) mice compared with controls. In vitro, primary P2Y(13) R(-/-) osteoblasts had an accumulation of mechanically induced extracellular ATP and reduced levels of hydrolysis. In addition, P2Y(13) R(-/-) osteoblasts also had a reduction in their maximal alkaline phosphatase (ALP) activity, one of the main ecto-enzymes expressed by osteoblasts which hydrolyses extracellular ATP. In conclusion, deletion of the P2Y(13) receptor leads to an enhanced osteogenic response to mechanical loading in vivo, possibly due to the reduced extracellular ATP degradation by ALP. The augmented osteogenic response to mechanical stimulation, combined with suppressed bone remodelling activities and protection from OVX-induced bone loss after P2Y(13) receptor depletion as previously described, suggests a potential role for P2Y(13) receptor antagonist-based therapy, possibly in combination with mechanical loading, for the treatment of osteoporosis. © 2013 American Society for Bone and Mineral Research.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 01/2013;
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    ABSTRACT: Context:Pendrin is a transmembrane protein located at the apical end of the thyrocyte in which it mediates the efflux of iodide through the thyroid follicular cell. Recently pendrin was described as a significant antibody target in Japanese patients with Graves' disease (GD) or autoimmune hypothyroidism (AH) using an immunoblotting assay. However, a subsequent study failed to verify this in autoimmune thyroid disease (ATD) patients of Tunisian origin.Objective:The aim of the current study was to evaluate a UK population of patients with ATD for the presence of pendrin autoantibodies using a novel radioligand binding assay (RBA).Results:Sera from 71 GD and 66 AH patients and 28 healthy controls were evaluated for pendrin autoantibody reactivity in RBAs. The results indicated that 8.8% of patients with ATD (9.9% GD and 7.6% AH) were positive for pendrin autoantibodies. Overall, the frequency of pendrin autoantibodies did not differ significantly between the ATD patient cohorts and the healthy control group: P = .186 and P = .317 for GD and AH patients, respectively.Conclusion:Pendrin autoantibodies, detected using a novel RBA, are not widely prevalent in UK patients with ATD, nor do they differ in frequency between GD and AH. These autoantibodies are therefore unlikely to be a useful marker for disease diagnosis, although the role that pendrin may play as an autoantigen in the initiation or maintenance of thyroid autoimmunity remains to be established.
    The Journal of clinical endocrinology and metabolism 01/2013;
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