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    ABSTRACT: Xanthogranulomatous hypophysitis (XGH) is a very rare form of pituitary hypophysitis that may present both clinically and radiologically as a neoplastic lesion. It may either be primary with an autoimmune aetiology and can occur in isolation or as a part of autoimmune systemic disease or secondary as a reactive degenerative response to an epithelial lesion (e.g. craniopharyngioma (CP), Rathke's cleft cyst, germinoma and pituitary adenomas) or as a part of a multiorgan systemic involvement such as tuberculosis, sarcoidosis or granulomatosis. It may also present with a variation of symptoms in children and adults. Our case series compares the paediatric and adult presentations of XGH and the differential diagnoses considered in one child and two adult patients, highlighting the wide spectrum of this condition. Endocrine investigations suggested panhypopituitarism in all three patients and imaging revealed a suprasellar mass compressing the optic chiasm suggestive of CP or Rathke's cleft cyst in one patient and non-functioning pituitary macroadenoma in two patients. Magnetic resonance imaging (MRI) demonstrated mixed signal intensities on T1- and T2-weighted sequences. Following endoscopic transsphenoidal surgery, histological analysis revealed necrotic material with a xanthogranulomatous reaction confirming XGH in two patients and a necrobiotic granulomatous chronic inflammatory infiltrate with neutrophils in one patient, which is not typical of current descriptions of this disorder. This case series describes the wide spectrum of XGH disease that is yet to be defined. Mixed signal intensities on T1- and T2-weighted MRI sequences may indicate XGH and diagnosis is confirmed by histology. Histological variation may indicate an underlying systemic process. XGH is a rare form of pituitary hypophysitis with a wide clinical and histological spectrum and can mimic a neoplastic lesion.XGH primarily presents with growth arrest in children and pubertal arrest in adolescents. In adults, the presentation may vary.A combination of hypopituitarism and mixed signal intensity lesion on MRI is suggestive of XGH and should be considered in the differential diagnosis of sellar lesions.Radical surgery is the treatment of choice and carries an excellent prognosis with no recurrence.
    03/2015; 2015:140089. DOI:10.1530/EDM-14-0089

  • Current Opinion in Pharmacology 06/2014; 16. DOI:10.1016/j.coph.2014.06.001
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    ABSTRACT: Cathepsin K inhibitors, such as ONO-5334, are being developed for the treatment of postmenopausal osteoporosis. However, their relative effects on bone resorption and formation, and how quickly the effects resolve after treatment cessation, are uncertain. The aim of this study was to examine the efficacy and safety of 24 months treatment with ONO-5334 and to assess the effect of treatment cessation over 2 months. We studied 197 postmenopausal women with osteoporosis or osteopenia with one fragility fracture. Patients were randomised to ONO-5334 50 mg twice daily, 100 mg or 300 mg once daily, alendronate 70 mg once weekly (positive control) or placebo for 24 months. After 24 months, all ONO-5334 doses were associated with increased bone mineral density (BMD) for lumbar spine, total hip and femoral neck (p < 0.001). ONO-5334 300 mg significantly suppressed the bone-resorption markers urinary (u) NTX and serum and uCTX-I throughout 24 months of treatment, and to a similar extent as alendronate; other resorption marker levels remained similar to placebo (fDPD for ONO-5334 300 mg qd) or were increased (ICTP, TRAP5b, all ONO-5334 doses). Levels of B-ALP and PINP were suppressed in all groups (including placebo) for approximately 6 months, but then increased for ONO-5334 to close to baseline levels by 12-24 months. On treatment cessation, there were increases above baseline in uCTX-I, uNTX and TRAP5b, and decreases in ICTP and fDPD. There were no clinically relevant safety concerns. Cathepsin K inhibition with ONO-5334 resulted in decreases in most resorption markers over 2 years, but did not decrease most bone formation markers. This was associated with an increase in BMD; the effect on biochemical markers was rapidly reversible on treatment cessation.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 02/2014; 29(2). DOI:10.1002/jbmr.2047
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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(12):f6842. DOI:10.1136/bmj.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; 17(1). DOI:10.1016/j.jocd.2013.09.005
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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; 94(2). DOI:10.1007/s00223-013-9798-3

  • Regenerative Medicine 09/2013; 8(5):523-5. DOI:10.2217/rme.13.57
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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; 77(4). DOI:10.1111/bcp.12226
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    Purinergic Signalling 08/2013; 9(3). DOI:10.1007/s11302-013-9384-1
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