Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis.

BACKGROUND: An open-label study indicated that selective depletion of B cells with the use of rituximab led to sustained clinical improvements for patients with rheumatoid arthritis. To confirm these observations, we conducted a randomized, double-blind, controlled study. METHODS: We randomly assigned 161 patients who had active rheumatoid arthritis despite treatment with methotrexate to receive one of four treatments: oral methotrexate (> or =10 mg per week) (control); rituximab (1000 mg on days 1 and 15); rituximab plus cyclophosphamide (750 mg on days 3 and 17); or rituximab plus methotrexate. Responses defined according to the criteria of the American College of Rheumatology (ACR) and the European League against Rheumatism (EULAR) were assessed at week 24 (primary analyses) and week 48 (exploratory analyses). RESULTS: At week 24, the proportion of patients with 50 percent improvement in disease symptoms according to the ACR criteria, the primary end point, was significantly greater with the rituximab-methotrexate combination (43 percent, P=0.005) and the rituximab-cyclophosphamide combination (41 percent, P=0.005) than with methotrexate alone (13 percent). In all groups treated with rituximab, a significantly higher proportion of patients had a 20 percent improvement in disease symptoms according to the ACR criteria (65 to 76 percent vs. 38 percent, P< or =0.025) or had EULAR responses (83 to 85 percent vs. 50 percent, P< or =0.004). All ACR responses were maintained at week 48 in the rituximab-methotrexate group. The majority of adverse events occurred with the first rituximab infusion: at 24 weeks, serious infections occurred in one patient (2.5 percent) in the control group and in four patients (3.3 percent) in the rituximab groups. Peripheral-blood immunoglobulin concentrations remained within normal ranges. CONCLUSIONS: In patients with active rheumatoid arthritis despite methotrexate treatment, a single course of two infusions of rituximab, alone or in combination with either cyclophosphamide or continued methotrexate, provided significant improvement in disease symptoms at both weeks 24 and 48

Comparison of the effect of locking vs standard screws on the mechanical properties of bone-plate constructs in a comminuted diaphyseal fracture model

The purpose of this study was to compare the mechanical properties of bone-plate constructs with locking compression plates (LCP) used either with standard screws or with locking screws on an experimental model of comminuted fracture

Dynamics, correlations and phases of the micromaser

The micromaser possesses a variety of dynamical phase transitions parametrized by the flux of atoms and the time-of-flight of the atom within the cavity. We discuss how these phases may be revealed to an observer outside the cavity using the long-time correlation length in the atomic beam. Some of the phase transitions are not reflected in the average excitation level of the outgoing atom, which is the commonly used observable. The correlation length is directly related to the leading eigenvalue of the time evolution operator, which we study in order to elucidate the phase structure. We find that as a function of the time-of-flight the transition from the thermal to the maser phase is characterized by a sharp peak in the correlation length. For longer times-of-flight there is a transition to a phase where the correlation length grows exponentially with the flux. We present a detailed numerical and analytical treatment of the different phases and discuss the physics behind them.Comment: 60 pages, 18 figure files, Latex + \special{} for the figures, (some redundant figures are eliminated and others are changed

Non-equilibrium states of a photon cavity pumped by an atomic beam

We consider a beam of two-level randomly excited atoms that pass one-by-one through a one-mode cavity. We show that in the case of an ideal cavity, i.e. no leaking of photons from the cavity, the pumping by the beam leads to an unlimited increase in the photon number in the cavity. We derive an expression for the mean photon number for all times. Taking into account leaking of the cavity, we prove that the mean photon number in the cavity stabilizes in time. The limiting state of the cavity in this case exists and it is independent of the initial state. We calculate the characteristic functional of this non-quasi-free non-equilibrium state. We also calculate the energy flux in both the ideal and open cavity and the entropy production for the ideal cavity.Comment: Corrected energy production calculations and made some changes to ease the readin

Effects of Dicer and Argonaute down-regulation on mRNA levels in human HEK293 cells

RNA interference and the microRNA (miRNA) pathway can induce sequence-specific mRNA degradation and/or translational repression. The human genome encodes hundreds of miRNAs that can post-transcriptionally repress thousands of genes. Using reporter constructs, we observed that degradation of mRNAs bearing sites imperfectly complementary to the endogenous let-7 miRNA is considerably stronger in human HEK293 than HeLa cells. The degradation did not result from the Ago2-mediated endonucleolytic cleavage but it was Dicer- and Ago2-dependent. We used this feature of HEK293 to address the size of a pool of transcripts regulated by RNA silencing in a single cell type. We generated HEK293 cell lines depleted of Dicer or individual Ago proteins. The cell lines were used for microarray analyses to obtain a comprehensive picture of RNA silencing. The 3'-untranslated region sequences of a few hundred transcripts that were commonly up-regulated upon Ago2 and Dicer knock-downs showed a significant enrichment of putative miRNA-binding sites. The up-regulation upon Ago2 and Dicer knock-downs was moderate and we found no evidence, at the mRNA level, for activation of silenced genes. Taken together, our data suggest that, independent of the effect on translation, miRNAs affect levels of a few hundred mRNAs in HEK293 cells

Macroscopic Interference Effects in Resonant Cavities

We investigate the possibility of interference effects induced by macroscopic quantum-mechanical superpositions of almost othogonal coherent states - a Schroedinger cats state - in a resonant microcavity. Despite the fact that a single atom, used as a probe of the cat state, on the average only change the mean number of photons by one unit, we show that this single atom can change the system drastically. Interference between the initial and almost orthogonal macroscopic quantum states of the radiation field can now take place. Dissipation under current experimental conditions is taken into account and it is found that this does not necessarily change the intereference effects dramatically.Comment: 20 pages, 3 figure

Squeezing generation and revivals in a cavity-ion system in contact with a reservoir

We consider a system consisting of a single two-level ion in a harmonic trap, which is localized inside a non-ideal optical cavity at zero temperature and subjected to the action of two external lasers. We are able to obtain an analytical solution for the total density operator of the system and show that squeezing in the motion of the ion and in the cavity field is generated. We also show that complete revivals of the states of the motion of the ion and of the cavity field occur periodically.Comment: 9 pages, 3 figure