Understanding the mechanism by which Gd(III) coiled coils achieve magnetic resonance relaxivity - a study into the water coordination chemistry.

A class of Gd(III) coiled coils achieve high MRI relaxivity, in part due to their slow rotational correlation time. However, extending their length is unable to further enhance performance, as the mechanism by which relaxivity is achieved is dominated by the presence of three inner sphere waters in rapid exchange, through an associative mechanism.

Genome-wide association analysis implicates the involvement of eight loci with response to tocilizumab for the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease affecting the joints. A heterogeneous response to available therapies demonstrates the need to identify those patients likely to benefit from a particular therapy. Our objective was to identify genetic factors associated with response to tocilizumab, a humanized monoclonal antibody targeting the interleukin (IL)-6 receptor, recently approved for treating RA. We report the first genome-wide association study on the response to tocilizumab in 1683 subjects with RA from six clinical studies. Putative associations were identified with eight loci, previously unrecognized as linked to the IL-6 pathway or associated with RA risk. This study suggests that it is unlikely that a major genetic determinant of response exists, and it illustrates the complexity of performing genome-wide association scans in clinical trials.

Long-term administration of quarterly IV ibandronate is effective and well tolerated in postmenopausal osteoporosis: 5-year data from the DIVA study long-term extension.

UNLABELLED: Long-term bone mineral density (BMD) gains, bone marker levels, and safety of 3 mg quarterly intravenous (IV) ibandronate were studied in this 3-year extension to the Dosing IntraVenous Administration (DIVA) trial. Quarterly IV ibandronate consistently increased lumbar spine bone mineral density measured with dual-energy X-ray absorptiometry (DXA-BMD) over 5 years (8.1%) and was well tolerated in women with postmenopausal osteoporosis. INTRODUCTION: Treatment with IV ibandronate regimens, 2 mg bimonthly and 3 mg quarterly, has been studied for up to 5 years in a long-term extension (LTE) to the 2-year DIVA trial. METHODS: DIVA LTE is an open-label extension to a 2-year randomized, double-blind, double-dummy, noninferiority, phase III study (DIVA core). DIVA LTE involved postmenopausal women who had completed 2 years of DIVA core, comparing daily oral and IV ibandronate (≥75% adherence with IV ibandronate in year 2 of DIVA). Patients previously treated with 2 mg bimonthly or 3 mg quarterly IV ibandronate continued on the same regimen; patients who had received 2.5 mg daily oral ibandronate and placebo IV in DIVA core were switched to IV ibandronate. RESULTS: Pooled analysis of 497 intent-to-treat (ITT) patients receiving IV ibandronate from DIVA core baseline showed consistent increases over 5 years in lumbar spine DXA-BMD (8.4% [95% confidence interval (CI) = 7.5, 9.3] with 2 mg bimonthly and 8.1% [95% CI = 7.2, 8.9] with 3 mg quarterly). Three-year data relative to DIVA LTE baseline in the full ITT population (756 patients randomized or reallocated from DIVA, including those previously on daily treatment) showed maintenance of DXA-BMD gains from DIVA core with further gains in lumbar spine DXA-BMD. These benefits are supported by sustained reductions in markers of bone metabolism. No tolerability concerns or new safety signals were observed. CONCLUSIONS: Treatment with IV ibandronate 2 mg bimonthly or 3 mg quarterly is effective and well tolerated for up to 5 years in women with postmenopausal osteoporosis.

Efficacy of monthly oral ibandronate is sustained over 5 years: the MOBILE long-term extension study.

UNLABELLED: The long-term efficacy and safety of once-monthly ibandronate were studied in this extension to the 2-year Monthly Oral Ibandronate in Ladies (MOBILE) trial. Over 5 years, lumbar spine bone mineral density (BMD) increased from baseline with monthly ibandronate 150 mg (8.4%). Long-term monthly ibandronate is effective and well tolerated for up to 5 years in women with postmenopausal osteoporosis. INTRODUCTION: Once-monthly therapy with ibandronate has been studied for up to 5 years in a long-term extension (LTE) to the 2 year MOBILE trial. METHODS: This multicenter, double-blind extension study of monthly ibandronate involved postmenopausal women who had completed 2 years of the MOBILE core study, with ≥75% adherence. Patients were reallocated, or were randomized from daily therapy, to ibandronate 100 mg monthly or 150 mg monthly for a further 3 years. RESULTS: A pooled intent-to-treat (ITT) analysis of 344 patients receiving monthly ibandronate from the core MOBILE baseline showed increases over 5 years in lumbar spine BMD (8.2% with 100 mg and 8.4% with 150 mg). Three-year data relative to MOBILE LTE baseline in the full ITT population of all 698 patients randomized or reallocated from MOBILE (including those previously on daily treatment) showed, on average, maintenance of proximal femur BMD gains achieved in the core 2-year study, with further small gains in lumbar spine BMD. In general, maintenance of efficacy was also indicated by markers of bone metabolism. CONCLUSIONS: There were no tolerability concerns or new safety signals. Monthly treatment with ibandronate 100 and 150 mg is effective and well tolerated for up to 5 years in women with postmenopausal osteoporosis.

Methods for correlating T1rho and FID components in wideline 1H NMR studies of motionally heterogeneous polymer systems.

We address the problem of correlating the observed FID and T1rho components in wideline 1H relaxation measurements of motionally heterogeneous polymers, and show that different methods of data treatment can highlight different aspects of the correlations present. For a sample of polypropylene we find that the T1rho relaxation behaviour is driven by relaxation associated with the intermediate FID component, which strongly suggests a motionally inhomogeneous amorphous region in the sample.

A method for analysing proton NMR relaxation data from motionally heterogenous polymer systems.

Historically, the results of studies of the motional processes present in polymers above the glass transition temperature (Tg) by proton NMR spin-lattice relaxation in either the laboratory or rotating frames (T1 or T1p) have shown poor agreement with the results from similar studies carried out using other techniques such as dielectric or mechanical relaxation. We believe that this is mainly because of the complication of the NMR results due to magnetisation transport, either by spin diffusion or by bulk diffusion of the polymer. We suggest a novel approach to the analysis of proton NMR relaxation data from a motionally heterogeneous polymer, and show that the results of such an analysis are intrinsically reasonable and of the form expected for dielectric or mechanical relaxation.

Analysis of spin-diffusion measurements by iterative optimisation of numerical models.

This work shows how information from a number of solid-state 1H NMR experiments can be combined in a numerical model of a heterogeneous polymer system, which can then be iteratively optimised by varying a small number of parameters to fully represent the spin-diffusion and relaxation behaviour of the system. In this way useful information can be obtained not only about the size of the heterogeneities present, but also about the intrinsic relaxation behavior of the different regions.

Effect of propionic acid on urea synthesis by sheep liver.

Propionate reduced substantially the rate of ureagenesis by slices of sheep liver whereas butyrate did not inhibit urea synthesis. The site of inhibition of urea synthesis by propionate occurs at some point between the fixation of ammonia and the formation of citrulline since 0.5 mM propionate inhibited by 80 per cent the synthesis of citrulline by mitochondria isolated from sheep liver. Since the apparent Ki for propionate is approximately 1.7 mM, the inhibitory effect of propionate on urea synthesis could be of physiological significance in sheep.