Local and systemic glucocorticoid metabolism in inflammatory arthritis

Background: Isolated, primary synovial fibroblasts generate active glucocorticoids through expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). This enzyme produces cortisol from inactive cortisone (and prednisolone from prednisone). Objective: To determine how intact synovial tissue metabolises glucocorticoids and to identify the local and systemic consequences of this activity by examination of glucocorticoid metabolism in patients with rheumatoid arthritis (RA). Methods: Synovial tissue was taken from patients with RA during joint replacement surgery. Glucocorticoid metabolism in explants was assessed by thin-layer chromatography and specific enzyme inhibitors. RT-PCR and immunohistochemistry were used to determine expression and distribution of 11β-HSD enzymes. Systemic glucocorticoid metabolism was examined in patients with RA using gas chromatography/mass spectrometry. Results: Synovial tissue synthesised cortisol from cortisone, confirming functional 11β-HSD1 expression. In patients with RA, enzyme activity correlated with donor erythrocyte sedimentation rate (ESR). Synovial tissues could also convert cortisol back to cortisone. Inhibitor studies and immunohistochemistry suggested this was owing to 11β-HSD2 expression in synovial macrophages, whereas 11β-HSD1 expression occurred primarily in fibroblasts. Synovial fluids exhibited lower cortisone levels than matched serum samples, indicating net local steroid activation. Urinary analyses indicated high 11β-HSD1 activity in untreated patients with RA compared with controls and a significant correlation between total body 11β-HSD1 activity and ESR. Conclusions: Synovial tissue metabolises glucocorticoids, the predominant effect being glucocorticoid activation, and this increases with inflammation. Endogenous glucocorticoid production in the joint is likely to have an impact on local inflammation and bone integrity

Clinical effectiveness of denosumab, raloxifene, romosozumab, and teriparatide for the prevention of osteoporotic fragility fractures : a systematic review and network meta-analysis

Objectives: To determine the clinical effectiveness of denosumab (DEN), raloxifene (RLX), romosozumab (ROMO) and teriparatide (TPTD), within their licensed (or anticipated licensed) indications, for the treatment of osteoporosis. Methods: A systematic review was conducted. Nine electronic databases and trial registries were searched up to the end of July 2018. Studies were eligible for inclusion if they were randomised controlled trials (RCT) in a population at risk of osteoporotic fracture, comparing these four non-bisphosphonates DEN, RLX, ROMO, or TPTD with each other, a non-active treatment, or the bisphosphonates alendronate (ALN), risedronate (RIS), ibandronate (IBN) and zoledronic acid (ZOL). Quality of included studies was assessed using the Cochrane Risk of Bias tool. Network metaanalyses (NMA) were used to determine the relative effectiveness of treatments. Results: The systematic review identified 7,898 citations. Forty-six RCTs of non-bisphosphonates met the inclusion criteria for the review and provided data for analyses. Additionally 49 RCTs of bisphosphonates were used in the NMAs. Forty-six RCTs were included in the NMA of vertebral fracture data, 23 RCTs for hip fractures and 73 RCTs in the NMA of femoral neck bone mineral density (FN BMD). For vertebral fractures, all four non-bisphosphonates showed statistically significant benefit relative to placebo: TPTD HR 0.23 (95% credible internal (CrI) 0.16, 0.32); ROMO followed by ALN 0.25 (95% CrI 0.15, 0.43); DEN HR 0.30 (95% CrI 0.21, 0.43); RLX HR 0.61 (95% CrI 0.44, 0.80). The four non-bisphosphonates interventions studied also showed statistically significant benefit relative to placebo for FN BMD, and for hip fractures TPTD, ROMO followed by ALN, and DEN showed statistically significant benefit relative to placebo. Conclusions: The four non-bisphosphonate interventions studied were all statistically significantly clinically effective for reducing vertebral fractures when compared to placebo, and were beneficial for change in FN BMD compared to placebo. All reduced hip fractures, and this was statistically significant for TPTD, ROMO followed by ALN, and DEN

Coordination as a function of skill level in the gymnastics longswing

The purpose of this study was to investigate the nature of inter-joint coordination at different levels of skilled performance to: (1) distinguish learners who were successful versus unsuccessful in terms of their task performance; (2) investigate the pathways of change during the learning of a new coordination pattern and (3) examine how the learner’s coordination patterns relate to those of experts in the longswing gymnastics skill. Continuous relative phase of hip and shoulder joint motions was examined for longswings performed by two groups of novices, successful (n = 4) and unsuccessful (n = 4) over five practice sessions, and two expert gymnasts. Principal component analysis showed that during longswing positions where least continuous relative phase variability occurred for expert gymnasts, high variability distinguished the successful from the unsuccessful novice group. Continuous relative phase profiles of successful novices became more out-of-phase over practice and less similar to the closely in-phase coupling of the expert gymnasts. Collectively, the findings support the proposition that at the level in inter-joint coordination a technique emerges that facilitates successful performance but is not more like an expert’s movement coordination. This finding questions the appropriateness of inferring development towards a “gold champion” movement coordination

25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 exert distinct effects on human skeletal muscle function and gene expression

Age-associated decline in muscle function represents a significant public health burden. Vitamin D-deficiency is also prevalent in aging subjects, and has been linked to loss of muscle mass and strength (sarcopenia), but the precise role of specific vitamin D metabolites in determining muscle phenotype and function is still unclear. To address this we quantified serum concentrations of multiple vitamin D metabolites, and assessed the impact of these metabolites on body composition/muscle function parameters, and muscle biopsy gene expression in a retrospective study of a cohort of healthy volunteers. Active serum 1,25-dihydroxyvitamin D3 (1α,25(OH)2D3), but not inactive 25-hydroxyvitamin D3 (25OHD3), correlated positively with measures of lower limb strength including power (rho = 0.42, p = 0.02), velocity (Vmax, rho = 0.40, p = 0.02) and jump height (rho = 0.36, p = 0.04). Lean mass correlated positively with 1α,25(OH)2D3 (rho = 0.47, p = 0.02), in women. Serum 25OHD3 and inactive 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) had an inverse relationship with body fat (rho = -0.30, p = 0.02 and rho = -0.33, p = 0.01, respectively). Serum 25OHD3 and 24,25(OH)2D3 were also correlated with urinary steroid metabolites, suggesting a link with glucocorticoid metabolism. PCR array analysis of 92 muscle genes identified vitamin D receptor (VDR) mRNA in all muscle biopsies, with this expression being negatively correlated with serum 25OHD3, and Vmax, and positively correlated with fat mass. Of the other 91 muscle genes analysed by PCR array, 24 were positively correlated with 25OHD3, but only 4 were correlated with active 1α,25(OH)2D3. These data show that although 25OHD3 has potent actions on muscle gene expression, the circulating concentrations of this metabolite are more closely linked to body fat mass, suggesting that 25OHD3 can influence muscle function via indirect effects on adipose tissue. By contrast, serum 1α,25(OH)2D3 has limited effects on muscle gene expression, but is associated with increased muscle strength and lean mass in women. These pleiotropic effects of the vitamin D ‘metabolome’ on muscle function indicate that future supplementation studies should not be restricted to conventional analysis of the major circulating form of vitamin D, 25OHD3

Results of endoscopic transsphenoidal pituitary surgery in 40 patients with a growth hormone-secreting macroadenoma

Contains fulltext : 96290.pdf (Publisher’s version ) (Open Access)OBJECTIVE: Transsphenoidal pituitary surgery (TS) is the primary treatment of choice for patients with acromegaly. Macroadenomas (>1 cm) are more difficult to resect than microadenomas (remission rate +/- 50% compared to +/- 90%). Besides the conventional microscopic TS, the more recently introduced endoscopic technique is nowadays frequently used. However, no large series reporting on its results have yet been published. We evaluated the outcome of endoscopic TS in 40 patients with a growth hormone (GH)-secreting macroadenoma treated in our hospital between 1998 and 2007. METHODS: Medical records were retrospectively reviewed. Remission was defined as disappearance of clinical symptoms of acromegaly, normal serum insulin-like growth factor-1 levels (</=2 SD) and serum GH levels suppressed to <2 mU/l after an oral glucose tolerance test within the first 4 months after TS. RESULTS: In four patients TS aimed at debulking of the tumour. In the remaining 36 patients, remission was achieved in 20 patients. In the first 5 years remission was achieved in 6 out of 18 patients (33%) compared to 14 out of 22 patients (63%) in the following 5 years (p = 0.06). Thirteen patients had a mild perioperative complication. Before TS 15 patients received hormonal substitution therapy compared to 12 patients (33%) after TS. CONCLUSION: Endoscopic TS is a good primary therapeutic option for patients with a GH-secreting macroadenoma, resulting in a remission rate of up to 63% in experienced hands. This technique can potentially improve the outcome of TS in these patients

Management of acromegaly in Latin America: expert panel recommendations

Although there are international guidelines orienting physicians on how to manage patients with acromegaly, such guidelines should be adapted for use in distinct regions of the world. A panel of neuroendocrinologists convened in Mexico City in August of 2007 to discuss specific considerations in Latin America. Of major discussion was the laboratory evaluation of acromegaly, which requires the use of appropriate tests and the adoption of local institutional standards. As a general rule to ensure diagnosis, the patient’s GH level during an oral glucose tolerance test and IGF-1 level should be evaluated. Furthermore, to guide treatment decisions, both GH and IGF-1 assessments are required. The treatment of patients with acromegaly in Latin America is influenced by local issues of cost, availability and expertise of pituitary neurosurgeons, which should dictate therapeutic choices. Such treatment has undergone profound changes because of the introduction of effective medical interventions that may be used after surgical debulking or as first-line medical therapy in selected cases. Surgical resection remains the mainstay of therapy for small pituitary adenomas (microadenomas), potentially resectable macroadenomas and invasive adenomas causing visual defects. Radiotherapy may be indicated in selected cases when no disease control is achieved despite optimal surgical debulking and medical therapy, when there is no access to somatostatin analogues, or when local issues of cost preclude other therapies. Since not all the diagnostic tools and treatment options are available in all Latin American countries, physicians need to adapt their clinical management decisions to the available local resources and therapeutic options

Pituitary-hormone secretion by thyrotropinomas

Hormone secretion by somatotropinomas, corticotropinomas and prolactinomas exhibits increased pulse frequency, basal and pulsatile secretion, accompanied by greater disorderliness. Increased concentrations of growth hormone (GH) or prolactin (PRL) are observed in about 30% of thyrotropinomas leading to acromegaly or disturbed sexual functions beyond thyrotropin (TSH)-induced hyperthyroidism. Regulation of non-TSH pituitary hormones in this context is not well understood. We there therefore evaluated TSH, GH and PRL secretion in 6 patients with up-to-date analytical and mathematical tools by 24-h blood sampling at 10-min intervals in a clinical research laboratory. The profiles were analyzed with a new deconvolution method, approximate entropy, cross-approximate entropy, cross-correlation and cosinor regression. TSH burst frequency and basal and pulsatile secretion were increased in patients compared with controls. TSH secretion patterns in patients were more irregular, but the diurnal rhythm was preserved at a higher mean with a 2.5 h phase delay. Although only one patient had clinical acromegaly, GH secretion and IGF-I levels were increased in two other patients and all three had a significant cross-correlation between the GH and TSH. PRL secretion was increased in one patient, but all patients had a significant cross-correlation with TSH and showed decreased PRL regularity. Cross-ApEn synchrony between TSH and GH did not differ between patients and controls, but TSH and PRL synchrony was reduced in patients. We conclude that TSH secretion by thyrotropinomas shares many characteristics of other pituitary hormone-secreting adenomas. In addition, abnormalities in GH and PRL secretion exist ranging from decreased (joint) regularity to overt hypersecretion, although not always clinically obvious, suggesting tumoral transformation of thyrotrope lineage cells