Denosumab-mediated increase in hand bone mineral density associated with decreased progression of bone erosion in rheumatoid arthritis patients.

OBJECTIVE: Periarticular osteoporosis is one of the earliest radiographic signs of bone damage in rheumatoid arthritis (RA). Denosumab, an investigational fully human monoclonal antibody that binds to RANKL, inhibits bone erosion and systemic bone loss in clinical studies of patients with RA. In this hand bone mineral density (BMD) substudy, we investigated the effects of denosumab on hand BMD and its correlation with hand erosion scores. METHODS: Patients receiving methotrexate for erosive RA were randomized in a 1:1:1 ratio to receive subcutaneous placebo, denosumab 60 mg, or denosumab 180 mg at 0 and 6 months. Measurements included BMD (by dual x-ray absorptiometry [DXA]) of both hands (0, 1, 6, and 12 months), magnetic resonance images of the hands/wrists (0 and 6 months), and radiographs of the hands/wrists and feet (0, 6, and 12 months). RESULTS: There were 56 patients (13 placebo, 21 denosumab 60 mg, and 22 denosumab 180 mg). Mean changes in hand BMD at 6 and 12 months were: +0.8% and +1.0%, respectively, for denosumab 60 mg; +2.0% and +2.5%, respectively, for denosumab 180 mg; and -1.2% and -2.0%, respectively, for placebo. Erosion scores remained near baseline in the denosumab groups and increased from baseline in the placebo group. A negative correlation was observed between hand BMD and erosion scores. CONCLUSION: In patients with RA, denosumab provided protection against erosion, and not only prevented bone loss but increased hand BMD as measured by DXA.

The influence of the resolution and contrast on measuring the articular cartilage volume in magnetic resonance images.

The progression of OA in patients may be followed by measuring the volume of articular cartilage from MR images. We attempted to determine the reproducibility of volume measurements of articular cartilage made from magnetic resonance images of the knees and the dependence of the reproducibility on image resolution and contrast-to-noise. A fat-suppressed 3D technique was used to generate four image sets with different image resolution. Each patient was imaged twice to obtain image pairs at each resolution. To assess the dependence of reproducibility on noise we generated six image sets for each patient by adding noise to the original images and repeating the comparison. On each image set, the femoral, tibial, and patellar cartilage were outlined by a combination of computer and manual methods, and the images were used to calculate the volume of each cartilage plate. Comparing the coefficient of variance between the volume measurements made from the two visits, the volume measurements made from images with the highest resolution (0.275 x 0.275 x 1.0 mm) had the highest reproducibility. The high resolution images of the tibia and femur had the least partial-volume averaging and, as a result, better defined the boundaries between cartilage and adjacent tissues. A different trend was evident for the patella. For studies of osteoarthritis therapies, we recommend using MR images with the highest possible in-plane spatial resolution to provide the most reproducible volume measurements of knee cartilage.

Brain N-acetyl-L-aspartic acid in Alzheimer's disease: a proton magnetic resonance spectroscopy study.

This study was performed in order to measure changes in brain N-acetyl-L-aspartic acid (NAA) in post-mortem brain tissue in Alzheimer's disease (AD) in comparison to normal control subjects using the technique of magnetic resonance spectroscopy. Brain tissue was obtained at autopsy and frozen until use, from seven patients diagnosed according to current research criteria for AD and 7 control subjects. Detailed clinical evaluations were available for all the dementia cases. Representative brain samples were obtained from three neocortical regions and a limbic region (parahippocampal gyrus) in white and grey matter. NAA was quantified on perchloric acid extracts using proton nuclear magnetic resonance (NMR) spectroscopy. Regional NAA did not vary significantly with age. In AD, reductions were present in the grey matter of the neocortex but not in the white matter. Within the parahippocampal gyrus there were reductions in both tissue types; only cortical levels correlated with clinical scales of dementia severity. A pattern of increasing correlation was observed between dementia severity as measured by the mini mental state examination during life and NAA levels from brain areas of increasing pathological predilection in AD. These post-mortem studies show reductions in brain NAA in AD which correlate with dementia severity during life and which support the use of future in vivo NAA spectroscopic images in the evaluation of AD patients.

3H nuclear magnetic resonance study of anaerobic glycolysis in packed erythrocytes.

The utility and power of 3H NMR spectroscopy as a technique for monitoring biological systems in vivo is illustrated with glucose metabolism in erythrocytes. Use of C-1-tritiated glucose allowed us to monitor the disappearance of the alpha and beta tritons, with the production of lactate and 1H3HO (HTO), as well as some intermediates. Spin lattice relaxation times (T1) were measured to avoid T1 distortion of the spectral intensities. Detection of the formation of 1 mM tritiated water in the presence of 110 M H2O protons and deuterons allows the eventual fate of the label in the pentose shunt to be observed in vivo.

Resolution of flecainide acetate, N-(2-piperidylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzam ide acetate, and antiarrhythmic properties of the enantiomers.

The antiarrhythmic agent flecainide acetate was resolved by fractional crystallization of its diastereomeric alpha-bromocamphor-pi-sulfonate salts. Optical purity of the two enantiomers was shown to be greater than 99% by an NMR technique using the chiral shift reagent Eu(hfbc)3. Antiarrhythmic effects of flecainide and its enantiomers were assessed in two different animal models, chloroform-induced ventricular fibrillation in mice and ouabain-induced ventricular tachycardia in dogs. The two enantiomers were highly effective in suppressing both of these experimental arrhythmias and appeared to be essentially equipotent. No significant differences were found either between the two enantiomers or between the enantiomers and racemic flecainide.