Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to at least one tumor necrosis factor inhibitor: results of a forty-eight­week randomized, double-blind, placebo-controlled, parallel-group phase III trial.

OBJECTIVE: To evaluate the safety and efficacy of ocrelizumab plus methotrexate (MTX) or leflunomide (LEF) in patients with active rheumatoid arthritis (RA) and an inadequate response to tumor necrosis factor α inhibitors. METHODS: This was a multicenter randomized, double-blind, placebo-controlled, parallel-group study that continued over 48 weeks. Patients receiving stable doses of MTX or LEF were randomized to receive 2 infusions of placebo (n = 277), ocrelizumab 200 mg (n = 278), or ocrelizumab 500 mg (n = 285) on days 1 and 15 as well as at weeks 24 and 26. Coprimary end points were the proportion of patients with response according to the American College of Rheumatology 20% improvement criteria (ACR20) at weeks 24 and 48. Secondary end points included the change from baseline in the modified Sharp/van der Heijde score (SHS) and the ACR50/70 responses. RESULTS: ACR20 responses were 22.0% in the placebo group, 42.2% in the ocrelizumab 200 mg group, and 47.9% in the ocrelizumab 500 mg group at 24 weeks and 19.5%, 48.7%, and 50.7%, respectively, at 48 weeks (P < 0.0001 versus placebo for each comparison at each time point). At 48 weeks, patients receiving both doses of ocrelizumab showed significantly improved ACR50 and ACR70 responses of ~3-fold versus placebo. Only those in the ocrelizumab 500 mg group showed statistically significant (P = 0.0017) inhibition of joint damage progression (mean change in the SHS) relative to placebo (61% inhibition) at 48 weeks. Overall adverse events and infections during the 48 weeks of study were comparable in all treatment groups. Serious infections were observed more frequently in patients taking ocrelizumab (5.1% and 4.3%) than in those taking placebo (2.5%). CONCLUSION: Patients in both of the ocrelizumab groups met the clinical primary efficacy end points. Inhibition of change in the SHS was statistically significant at 48 weeks for those in the ocrelizumab 500 mg group. The rate of serious infections in this trial was higher for both ocrelizumab doses as compared with placebo.

Zyxin and vinculin distribution at the cell-extracellular matrix attachment complex (CMAX) in corneal epithelial tissue are actin dependent.

Avian embryonic corneal epithelia are two cell layers thick. If isolated without (-) basal lamina, the basal cells have unorganized actin and project cytoplasmic protrusions termed blebs. The actin-based cytoskeleton at the cell-extracellular matrix junction (termed the actin cortical mat) is disrupted. These epithelia respond to soluble extracellular matrix molecules by reorganizing the actin cortical mat. Sheets of epithelia were isolated + or -basal lamina. Epithelia isolated -basal lamina were cultured +/- laminin-1 and/or +/- cytochalasin D (CD). The intracellular localization of zyxin, vinculin, paxillin, focal adhesion kinase, and tensin was determined using indirect immunohistochemistry. Protein levels were determined by Western blot analysis. Zyxin and vinculin were concentrated in two areas of the tissue. The interface between the upper cell layer (periderm) and the basal cells. The second area of concentration was at the inferior 1-4 microns of the basal cells in an area with multiple actin bundles termed the actin cortical mat. The actin bundles align toward zyxin and vinculin that were located near basal lateral membranes. Zyxin was displaced from the basal compartment of blebbing basal cells. In contrast tensin, vinculin and focal adhesion kinase were found diffusely throughout the blebs. Zyxin and vinculin redistributed to the basal-lateral membranes as actin bundles reorganized in laminin-stimulated epithelia. In contrast to the altered protein distribution, extractable protein levels were similar in blebbing and laminin-stimulated epithelia. Zyxin, vinculin, and other associated proteins were disrupted in the CD-treated tissues and do not colocalize with each other or CD-induced actin aggregates. The intracellular localization of zyxin and vinculin were concentrated in distinct areas along the inferior basolateral membranes of basal cells termed the cell-extracellular matrix attachment complex (CMAX). The distribution of CMAX proteins was dependent upon actin bundle organization.

A two-dimensional Doppler ultrasonic probe for flow measurement.

The use of a single-transducer pulsed-Doppler ultrasound system in clinical practice has been severely limited, not only by the effects of acoustics and physiologic parameters, but also by inaccuracy because the Doppler angle between the transducer axis and the flow velocity is unknown. In this study, a dual-transducer pulsed-Doppler ultrasound system was used because the Doppler angle could be directly calculated for more accurate determination of the fluid flow velocity vector. From the velocity estimate and velocity profiles, other flow characteristics such as volume flow rates and shear stress can also be estimated. Experimental results indicated that the new transducer model could increase the accuracy of fluid flow velocity measurement and thereby improve the ability to estimate the characteristics of turbulent fluid flow for research and diagnostic purposes.

Effects of amrinone and dopamine on uterine blood flow and vascular responses in the gravid baboon.

Amrinone is a bipyridine derivative with positive inotropic and vasodilator properties. We investigated its effects on uterine and iliac artery blood flow, blood pressure, and heart rate in 10 acutely instrumented gravid baboons. Amrinone was compared with dopamine, infused systemically or regionally via the common iliac artery. When given intravenously at a constant rate of 40 micrograms/kg/min, amrinone produced a slight increase in iliac artery blood flow but did not significantly alter mean arterial pressure, heart rate, or uterine artery blood flow. Dopamine at an intravenous dose of 40 micrograms/kg/min produced a mean (+/- SD) 49.2% +/- 18.7% increase in mean arterial pressure (p less than 0.01) and a 84.2% +/- 56.1% increase in uterine vascular resistance (p less than 0.01), but caused no changes in heart rate, uterine artery blood flow, or iliac artery blood flow. Regional infusion of amrinone at the rate of 25 micrograms/kg/min produced a significant increase in iliac artery blood flow (p less than 0.01) without changing uterine artery blood flow, heart rate, or mean arterial pressure. Regional infusion of dopamine at concentrations of 2.5 to 25 micrograms/kg/min produced decreases in flow (p less than 0.01) and increases in resistance (p less than 0.01) in the uterine and iliac vascular beds. We conclude that amrinone dilates the vascular bed of the external iliac artery, but has no remarkable effect on the uterine vascular bed. Dopamine increases uterine vascular resistance and may impair uteroplacental perfusion.

Analysis of velocity estimation error for a multidimensional Doppler ultrasound system.

The error characteristics of a single-transducer (one dimensional), dual-transducer (two-dimensional), and triple-transducer (three-dimensional) system for velocity estimation are examined. A velocity vector is completely characterized by the magnitude and the directional angles. For a single-transducer case, the velocity magnitude alone can be estimated. The variation in the directional angles for a single-transducer case cannot be accounted for in the estimation process, thus resulting in large errors. For a dual transducer, both the velocity magnitude and the angle on the x-y plane can be estimated. The use of an extra transducer provides added flexibility in the estimation process. Variation in one of the directional angles is accounted for in the estimation process, thus resulting in smaller error than the single-transducer case. For a triple-transducer case, if the normal angles between the three transducer axes are known, then the complete velocity vector with all the directional angles can be estimated.