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  • Current Opinion in Pharmacology 06/2014;
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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.
  • BMJ (online) 11/2013; 347:f6842.
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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;
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    ABSTRACT: There is public concern over the long term systemic health effects of metal released from hip replacement prostheses that use large-diameter metal-on-metal bearings. However, to date there has been no systematic study to determine which organs may be at risk, or the magnitude of any effect. We undertook a detailed cross-sectional health screen at a mean of 8 years after surgery in 35 asymptomatic patients who had previously received a metal-on-metal hip resurfacing (MoMHR) versus 35 individually age and sex matched asymptomatic patients who had received a conventional hip replacement. Total body bone mineral density was 5% higher (mean difference 0.05 g/cm(2), P = 0.02) and bone turnover was 14% lower (TRAP 5b, mean difference -0.56IU/L, P = 0.006; osteocalcin, mean difference -3.08 ng/mL, P = 0.03) in the hip resurfacing versus conventional hip replacement group. Cardiac ejection fraction was 7% lower (mean absolute difference -5%, P = 0.04) and left ventricular end-diastolic diameter was 6% larger (mean difference 2.7 mm, P = 0.007) in the hip resurfacing group versus those patients who received a conventional hip replacement. The urinary fractional excretion of metal was low (cobalt 5%, chromium 1.5%) in patients with MoMHR, but creatinine clearance was normal. Diuretic prescription was associated with a 40% increase in the fractional excretion of chromium (mean difference 0.5%, P = 0.03). There was no evidence of difference in neuropsychological, renal tubular, hepatic or endocrine function between groups (P>0.05). Our findings of differences in bone and cardiac function between patient groups suggest that chronic exposure to low elevated metal concentrations in patients with well-functioning MoMHR prostheses may have systemic effects. Long-term epidemiological studies in patients with well-functioning metal on metal hip prostheses should include musculoskeletal and cardiac endpoints to quantitate the risk of clinical disease.
    PLoS ONE 06/2013; 8(6):e66186.
  • The Lancet 05/2013; 382(9886).
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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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