The negative bone effects of the disease and of chronic corticosteroid treatment in premenopausal women affected by rheumatoid arthritis

Osteoporosis is a well-known extra-articular complication in rheumatoid arthritis (RA). The chronic corticosteroid treatment, the functional impairment associated with RA and the disease itself appear to be the most relevant determinants. Most of the previous studies involved postmenopausal women, in whom the estrogenic deficiency might amplify the negative effect towards bone of both RA and corticosteroid therapy. We decided to evaluate bone health in a cohort of premenopausal RA patients. The study population includes 47 premenopausal women attending our outpatient clinic for RA and twice as many healthy age-matched control women selected from the hospital personnel. The bone density at the spine and femoral neck were significantly lower in patients with RA as compared with controls. When spine bone mineral density (BMD) values were adjusted for the cumulative glucocorticoid (GC) dose alone and for the cumulative GC dose plus body mass index (BMI) the mean differences between two groups decreased but they remained statistically significant. We found no difference when the spine BMD was adjusted for cumulative GC dose, BMI and health assessment questionnaire. The difference in femoral neck BMD remained statistically significant also after all the same adjustments. In conclusion, our study shows that a BMD deficiency is frequent also in premenopausal women affected by RA, especially at femoral site and that the main determinants of this bone loss are not only the disease-related weight loss, corticosteroid therapy and functional impairment, but also the systemic effects of the disease itself

The negative bone effects of the disease and of chronic corticosteroid treatment in premenopausal women affected by rheumatoid arthritis

Osteoporosis is a well-known extra-articular complication in rheumatoid arthritis (RA). The chronic corticosteroid treatment, the functional impairment associated with RA and the disease itself appear to be the most relevant determinants. Most of the previous studies involved postmenopausal women, in whom the estrogenic deficiency might amplify the negative effect towards bone of both RA and corticosteroid therapy. We decided to evaluate bone health in a cohort of premenopausal RA patients. The study population includes 47 premenopausal women attending our outpatient clinic for RA and twice as many healthy age-matched control women selected from the hospital personnel. The bone density at the spine and femoral neck were significantly lower in patients with RA as compared with controls. When spine bone mineral density (BMD) values were adjusted for the cumulative glucocorticoid (GC) dose alone and for the cumulative GC dose plus body mass index (BMI) the mean differences between two groups decreased but they remained statistically significant. We found no difference when the spine BMD was adjusted for cumulative GC dose, BMI and health assessment questionnaire. The difference in femoral neck BMD remained statistically significant also after all the same adjustments. In conclusion, our study shows that a BMD deficiency is frequent also in premenopausal women affected by RA, especially at femoral site and that the main determinants of this bone loss are not only the disease-related weight loss, corticosteroid therapy and functional impairment, but also the systemic effects of the disease itself

A 59.3fs Jitter and -62.1dBc Fractional-Spur Digital PLL Based on a Multi-Edge Power-Gating Phase-Detector

To unlock wide data-rates, wireless transceivers require ultra-Iow-jitter local-oscillators. Fractional-N PLLs achieve low-noise using a digital-to-time converter (DTC) to re-align the edges of the reference and divider signals in fractional mode (Fig. 1 top) [1]. However, the PLL jitter is limited by both DTC non-linearity, causing large fractional spurs, and DTC jitter, degrading PLL in-band noise. Unfortunately, DTCs suffer from a strong trade-off between linearity, noise and power [2], [3]. The technique in [2] improves both DTC linearity and jitter by reducing the required DTC delay range, but it can only achieve 2x range reduction. This work introduces a digital PLL leveraging a multi-edge power-gating phase-detector (MEPG-PD) to reduce the required DTC range by more than 10x, It achieves 59. 3fs jitter and -62.1 dBc fractional spur at near-integer 8. 75GHz channels. Figure 1 (bottom left) describes the MEPG-PD concept. The MEPG-PO comprises a phase-detector (PO), generating the error signal e[k], fed to the PLL digital loop filter (DLF), and an auxiliary oscillator operating in power-gating mode (denoted as PGO) [4]. The divd signal, derived by delaying the PLL divider output, div, via the DTC, and the PGO output, OSCPG, are fed to the PD. At the rising edge of the PLL reference signal, ref, the PGO is turned on for a Tw time-window, by powering the PGO via a switch driven by the SWPG signal. If the PGO period, TPGO, is smaller than TW, OSCPG has multiple rising edges before the PGO turns off. In a conventional fractional-N PLL, the DTC re-aligns ref and div to achieve a zero PO input time-error, requiring a DTC delay of at least one period, Tdco, of the digitally-controlled-oscillator (DCO) at the PLL output. In the MEPG-PD scheme, instead, a zero time-error can be reached by aligning divd to the closest OSCPG rising edge, with a DTC delay of at most TPGC. By using TPGO < < Tdco, the DTC delay range and, correspondingly, its non-linearity and jitter, are drastically reduced. Note that the MEPG-PO non-linearity contribution is ideally zero, since the PGO edges are linearly spaced by TPGO, Furthermore, the PGO noise can be minimized using a small Tw, as shown later. However, to achieve a drastic DTC range reduction, the PGO must run at a frequency significantly higher than the DCO (e.g., 10x reduction requires a 100GHz PGO for a 10GHz DCO). To solve this issue, the MEPG-PD is instead implemented with three PDs and a PGO based on a 3-stage ring-oscillator (RO) (bottom right). The PDs are fed with divd and the three RO stage outputs, oscPG, 0, oscPG,1 and OSCPG,2. By aligning divd to the closest among tne rising ana failing edges of the RO outputs, the required DTC range reduces to TPGO/6, thus achieving the same range reduction at a 6x smaller PGO frequency (e.g., 10x reduction requires a 17GHz PGO for a 10GHz DCO). The PO selection logic provides the MEPG-PD error signal, e[k] selecting the output of the PO with zero-input time-error among the three

Sclerostin and DKK1 in postmenopausal osteoporosis treated with Denosumab.

INTRODUCTION: The bone mass benefits of anti-resorbers in postmenopausal osteoporosis are limited by the rapid coupling of decreasing bone resorption with bone formation. The Wnt signalling is involved in this coupling process during treatment with bisphosphonates, while its role during treatment with the anti receptor activator of nuclear factor kappa B ligand (RANKL)antibodies, Denosumab is unknown.METHODS: The study population includes patients participating in a placebo controlled trial lasting 36 months: 19 women were on placebo and 24 on subcutaneous 60 mg Denosumab every 6months.RESULTS: All measured parameters (serum C-terminal telopeptide of type I collagen [sCTX], serum bone alkaline phosphatase [bAP], Dickkopf-1 (DKK1) and sclerostin) remained unchanged during the observation period in the placebo group. sCTX and bAP were significantly suppressed by Denosumab treatment over the entire follow-up. Denosumab treatment was associated with significant (p<0.05) increases (28-32%) in serum sclerostin over the entire study follow-up. Serum DKK1 significantly decreased within the first 6 months with a trend for further continuous decreases which reached statistical significance (P<0.05) versus placebo group from the 18th monthonward. The changes in DKK1 were significantly and positively related with the changes in sCTX and bAP and negatively with hip BMD changes. The changes in sclerostin were significantly andnegatively related only with those of bAP.CONCLUSION: The changes in bone turnover markers associated with Denosumab treatment of postmenopausal osteoporosis are associated with significant increase in sclerostin similar to thoseseen after long term treatment with bisphosphonates, and significant decrease in DKK1. This latter observation might explain the continuous increase over 5 years in BMD observed during treatment of postmenopausal osteoporosis with Denosumab

A Low-Spur and Low-Jitter Fractional-N Digital PLL Based on an Inverse-Constant-Slope DTC and FCW Subtractive Dithering

This work presents a low-spur and low-jitter fractional-N digital phase-locked loop (PLL). To reduce the fractional spurs caused by the non-linearity of the digital-to-time converter (DTC), two novel solutions are introduced. First, the inverse-constant-slope DTC achieves high-linearity, thanks to its immunity to channel-length modulation and non-linear parasitic capacitances. Second, the frequency-control-word (FCW) sub-tractive dithering technique randomizes the quantization error of the ?S modulator driving the PLL divider ratio without requiring an increased DTC dynamic range and pushing the fractional spurs outside the PLL bandwidth. The prototype, implemented in a 28-nm CMOS process, has an active area of 0.33 mm(2) and dissipates 17.2 mW. At fractional-N channels near 9.25 GHz, the measured in-band fractional spurs and the rms jitter are below -70 dBc and 77 fs, respectively, leading to a jitter-power figure of merit of -249.9 dB

In patients with rheumatoid arthritis, DKKopf-1 serum levels are correlated with parathyroid hormone, bone erosions and bone mineral density

OBJECTIVES:The objective of this study is to compare the serum levels of Dickkopf-1 (DKK1), a natural inhibitor of Wnt signalling, with parathyroid hormone (PTH) and bone involvement in patients with rheumatoid arthritis (RA).METHODS:This cross-sectional study includes 154 postmenopausal women with RA and 125 healthy controls. DKK1, 25OH vitamin D (25OHD), bone turnover markers, and PTH serum levels were measured by ELISA; lumbar spine and hip bone mineral density (BMD) and the erosion score were obtained.RESULTS:The RA patients and healthy controls were not significantly different in terms of age, body mass index, and 25OHD serum levels. The mean level of DKK1 and PTH were significantly higher in patients with RA than in healthy controls (172\ub168 [SD] vs. 96\ub155 pmoL/L, and 30\ub115 vs 22\ub111, respectively; p<0.0001). DKK1 serum levels were positively correlated with age (p<0.05) only in the healthy controls, while they were correlated with PTH serum levels only in the RA patients (p<0.0001). Among the RA patients, DKK1 levels adjusted for age, PTH and disease duration were significantly higher in patients with bone erosions (176 vs. 167 pmoL/L, respectively; p<0.05). DKK1 levels adjusted for age and PTH were negatively correlated with total hip BMD (p<0.05). In the RA patients not on treatment with bisphosphonates, DKK1 serum levels positively correlated with C-terminal telopeptides of type I collagene serum levels (p<0.05).CONCLUSIONS:In patients with RA, serum levels of DKK1 are significantly increased, correlate with PTH and are associated with increased risk of bone erosions and osteoporosis. However, this finding deserves confirmation in a larger and more selected population

Artrite Reumatoide e Metabolismo Minerale

Da tempo si sospetta che le tre manifestazioni classiche del coinvolgimento osseo in corso di Artrite Reumatoide (AR) (le erosioni focali, l\u2019osteoporosi iuxta-articolare e quella sistemica) possano essere la conseguenza di un comune meccanismo patogenetico (1), di natura infiammatoria ma probabilmente anche metabolica. E\u2019 noto infatti che la patogenesi infiammatoria non spiega tutte le manifestazioni scheletriche della malattia reumatoide e l\u2019evoluzione del coinvolgimento osseo di quest\u2019ultima \ue8 talora disgiunta dagli indici clinici di infiammazione (2). Anche sulla base di recenti esperienze personali si vuole in questa breve review fare il punto sulla componente patogenetica metabolica e ci si soffermer\ue0 in particolare sulle alterazioni del metabolismo osseo e minerale descritte in corso di AR

Wnt pathway in patients with primary hyperparathyroidism

In this research authors studied Wnt pathway in patients with primary hyperparathyroidis

Bone involvement in patient with clonal mast cell disorders

Study on Bone involvement in patient with clonal mast cell disorder