Agents which elevate cyclic AMP (cAMP) cause teleost retinal rods to contract. We have characterized this cAMP effect and have evaluated the role of the cytoskeleton in cyclic nucleotide-induced contraction, using actin and microtubule inhibitors. The necklike myoid region of the rod contracts in the dark and elongates in the light. If long, light-adapted rods are cultured with cAMP analogs and IBMX, rods contract to their short dark-adapted position. Cyclic nucleotide-induced rod contraction occurs in constant light, requires a phosphodiesterase inhibitor, and is specific to cAMP (db cyclic GMP, 8-bromocyclic GMP, 5'AMP, and adenosine have no effect on rod myoid length). Cyclic AMP effects on rod length are consistent with observations from several species that cAMP levels are higher in dark-adapted than in light-adapted retinas. Since rod myoids contain paraxially aligned actin filaments and microtubules, we have used the motility inhibitors cytochalasin D and cold and nocodazole to investigate the roles of these cytoskeletal elements in rod contraction. Cyclic nucleotide-induced contraction is not inhibited when myoid microtubules are disrupted with cold and nocodazole treatments, but contraction is blocked if myoid actin filaments are disrupted with cytochalasin D. Thus, we conclude that actin filaments, but not microtubules, are required for rod contraction. We propose that rod contraction in vivo is triggered by a rise of cytoplasmic cAMP at onset of darkness and that this contraction is mediated by an actin-dependent mechanism.

Teleost retinal rods elongate when exposed to light. Elongation is mediated by a narrow necklike region called the myoid. In the cichlid Sarotherodon mossambicus, the rod inner segment (composed of the myoid with adjacent ellipsoid) increases in length from 12 micrometers in the dark to 41 micrometers in the light. Long light-adapted myoids contain longitudinally oriented microtubules and bundles of parallel 60-A filaments that we have identified as actin by their ability to bind myosin subfragment 1. In short dark-adapted myoids, only microtubules are recognizable. Colchicine experiments reveal that light-induced rod elongation can occur in the absence of myoid microtubules. Intraocular injections of colchicine at concentrations that disrupt virtually all rod myoid microtubules do not block rod elongation. However, rod elongation is blocked by intraocular injections of cytochalasin B or cytochalasin D. The hierarchy of effectiveness of these drugs is consistent with their effectiveness in inhibiting actin assembly and in disrupting other actin-dependent motile processes. On the basis of ultrastructural observations and the results of these inhibitor studies, we propose that the forces responsible for rod elongation are dependent not on microtubules but on actin filament assembly.

A new low-power application-specific integrated circuit (ASIC) for Cadmium Zinc Telluride (CZT) detectors for single-photon emission computed tomography (SPECT) application is being developed at BNL. As the first step, a 32-channel prototype ASIC was designed and tested recently. Each channel has a preamplifier followed by CR-RC³ shaping circuits and three independent energy bins with comparators and 16-bit counters. The ASIC was fabricated with TSMC 0.35-μm complementary metal-oxide-semiconductor (CMOS) process and tested in laboratories. The power consumption is around 1 mW/ch with a 2.5-V supply. With a gain of 400 mV/fC and the peaking time of 500 ns, the equivalent noise charge (ENC) of 360 e- has been measured in room temperature while the crosstalk rate is less than 0.3%. The 10-bit DACs for global thresholds have an integral nonlinearity (INL) less than 0.56% and differential nonlinearity (DNL) less than 0.33%. In the presentation, we will report the detailed test results with this ASIC.

Baseline holder (BLH) circuits are used widely to stabilize the analog output of application-specific integrated circuits (ASICs) for high-count-rate applications. The careful design of BLH circuits is vital to the overall stability of the analog-signal-processing chain in ASICs. Recently, we observed self-triggered fluctuations in an ASIC in which the shaping circuits have a BLH circuit in the feedback loop. In fact, further investigations showed that methods of enhancing small-signal stabilities cause an even worse situation. To resolve this problem, we used large-signal analyses to study the circuit's stability. We found that a relatively small gain for the error amplifier and a small current in the non-linear stage of the BLH are required to enhance stability in large-signal analysis, which will compromise the properties of the BLH. These findings were verified by SPICE simulations. In this paper, we present our detailed analysis of the BLH circuits, and propose an improved version of them that have only minimal self-triggered fluctuations. We summarize the design considerations both for the stability and the properties of the BLH circuits.

Objectives

Abatacept is the only agent currently approved to treat rheumatoid arthritis (RA) that targets the co-stimulatory signal required for full T-cell activation. No studies have been conducted on its effect on the synovium, the primary site of pathology. The aim of this study was to determine the synovial effect of abatacept in patients with RA and an inadequate response to tumour necrosis factor alpha (TNFalpha) blocking therapy.

Methods

This first mechanistic study incorporated both dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and arthroscopy-acquired synovial biopsies before and 16 weeks after therapy, providing tissue for immunohistochemistry and quantitative real-time PCR analyses.

Results

Sixteen patients (13 women) were studied; all had previously failed TNFalpha-blocking therapy. Fifteen patients completed the study. Synovial biopsies showed a small reduction in cellular content, which was significant only for B cells. The quantitative PCR showed a reduction in expression for most inflammatory genes (Wald statistic of p<0.01 indicating a significant treatment effect), with particular reduction in IFNgamma of -52% (95% CI -73 to -15, p<0.05); this correlated well with MRI improvements. In addition, favourable changes in the osteoprotegerin and receptor activator of nuclear factor kappa B levels were noted. DCE-MRI showed a reduction of 15-40% in MRI parameters.

Conclusion

These results indicate that abatacept reduces the inflammatory status of the synovium without disrupting cellular homeostasis. The reductions in gene expression influence bone positively and suggest a basis for the recently demonstrated radiological improvements that have been seen with abatacept treatment in patients with RA.

The physics emphases of the PHENIX collaboration and the design and current status of the PHENIX detector are discussed. The plan of the collaboration for making the most effective use of the available luminosity in the first years of RHIC operation is also presented.