Paradoxical effects of tumour necrosis factor-α in adjuvant-induced arthritis

Anti-tumour necrosis factor (TNF)α therapy is highly effective in rheumatoid arthritis and it is surprising, therefore, that a recent study showed that intraperitoneal administration of recombinant TNFα reduced the severity of adjuvant-induced arthritis and decreased IFNγ expression in cultured draining lymph node cells. Furthermore, in untreated arthritic rats, maximal TNFα expression in draining lymph node cells coincided with spontaneous disease remission, suggesting a role for endogenous TNFα in recovery from arthritis. If confirmed in further studies, these findings suggest that, in addition to its well-established pro-inflammatory properties, TNFα may also play a disease-limiting role in this model of rheumatoid arthritis by suppressing effector T cell responses

Down-regulation of human topoisomerase IIα expression correlates with relative amounts of specificity factors Sp1 and Sp3 bound at proximal and distal promoter regions

<p>Abstract</p> <p>Background</p> <p>Topoisomerase IIα has been shown to be down-regulated in doxorubicin-resistant cell lines. The specificity proteins Sp1 and Sp3 have been implicated in regulation of topoisomerase IIα transcription, although the mechanism by which they regulate expression is not fully understood. Sp1 has been shown to bind specifically to both proximal and distal GC elements of the human topoisomerase IIα promoter <it>in vitro</it>, while Sp3 binds only to the distal GC element unless additional flanking sequences are included. While Sp1 is thought to be an activator of human topoisomerase IIα, the functional significance of Sp3 binding is not known. Therefore, we sought to determine the functional relationship between Sp1 and Sp3 binding to the topoisomerase IIα promoter <it>in vivo</it>. We investigated endogenous levels of Sp1, Sp3 and topoisomerase IIα as well as binding of both Sp1 and Sp3 to the GC boxes of the topoisomerase IIα promoter in breast cancer cell lines <it>in vivo </it>after short term doxorubicin exposure.</p> <p>Results</p> <p>Functional effects of Sp1 and Sp3 were studied using transient cotransfection assays using a topoisomerase IIα promoter reporter construct. The <it>in vivo </it>interactions of Sp1 and Sp3 with the GC elements of the topoisomerase IIα promoter were studied in doxorubicin-treated breast cancer cell lines using chromatin immunoprecipitation assays. Relative amounts of endogenous proteins were measured using immunoblotting. <it>In vivo </it>DNA looping mediated by proteins bound at the GC1 and GC2 elements was studied using the chromatin conformation capture assay. Both Sp1 and Sp3 bound to the GC1 and GC2 regions. Sp1 and Sp3 were transcriptional activators and repressors respectively, with Sp3 repression being dominant over Sp1-mediated activation. The GC1 and GC2 elements are linked <it>in vivo </it>to form a loop, thus bringing distal regulatory elements and their cognate transcription factors into close proximity with the transcription start site.</p> <p>Conclusion</p> <p>These observations provide a mechanistic explanation for the modulation of topoisomerase IIα and concomitant down-regulation that can be mediated by topoisomerase II poisons. Competition between Sp1 and Sp3 for the same cognate DNA would result in activation or repression depending on absolute amounts of each transcription factor in cells treated with doxorubicin.</p

Two infrared Yang-Mills solutions in stochastic quantization and in an effective action formalism

Three decades of work on the quantum field equations of pure Yang-Mills theory have distilled two families of solutions in Landau gauge. Both coincide for high (Euclidean) momentum with known perturbation theory, and both predict an infrared suppressed transverse gluon propagator, but whereas the solution known as "scaling" features an infrared power law for the gluon and ghost propagators, the "massive" solution rather describes the gluon as a vector boson that features a finite Debye screening mass. In this work we examine the gauge dependence of these solutions by adopting stochastic quantization. What we find, in four dimensions and in a rainbow approximation, is that stochastic quantization supports both solutions in Landau gauge but the scaling solution abruptly disappears when the parameter controlling the drift force is separated from zero (soft gauge-fixing), recovering only the perturbative propagators; the massive solution seems to survive the extension outside Landau gauge. These results are consistent with the scaling solution being related to the existence of a Gribov horizon, with the massive one being more general. We also examine the effective action in Faddeev-Popov quantization that generates the rainbow and we find, for a bare vertex approximation, that the the massive-type solutions minimise the quantum effective action.Comment: 13 pages, 7 figures. Change of title to reflect version accepted for publicatio

Strip casting with fluxing agent applied to casting roll

A strip caster (10) for producing a continuous strip (24) includes a tundish (12) for containing a melt (14), a pair of horizontally disposed water cooled casting rolls (22) and devices (29) for electrostatically coating the outer peripheral chill surfaces (44) of the casting rolls with a powder flux material (56). The casting rolls are juxtaposed relative to one another for forming a pouting basin (18) for receiving the melt through a teeming tube (16) thereby establishing a meniscus (20) between the rolls for forming the strip. The melt is protected from the outside air by a non-oxidizing gas passed through a supply line (28) to a sealing chamber (26). A preferred flux is boron oxide having a melting point of about 550° C. The flux coating enhances wetting of the steel melt to the casting roll and dissolves any metal oxide formed on the roll

Recent developments in targeting access to high cost medicines in Australia

BACKGROUND: In Australia, the Pharmaceutical Benefits Scheme (PBS) has developed a set of arrangements to control access to high-cost medicines to ensure their use is cost-effective. These medicines include the tumour necrosis factor-alpha inhibitors (TNFIs) for the treatment of rheumatoid arthritis. The aim of this first phase of a qualitative study was to explore basic views on the restricted access to TNFIs in order to confirm where further investigation should take place in the next phase. METHODS: Semi-structured interviews were conducted in 2004 with a member of the four relevant stakeholder groups. Participants were asked their opinions about features of the establishment, process and effects of the system of restricted access to TNFIs. Views on the collaboration between stakeholder groups in the decision-making process were also collected. RESULTS: The principle of 'controlled access' to TNFIs was supported in general. There were concerns regarding some of the specific eligibility criteria. Wider and more transparent stakeholder consultation was judged desirable. Some flexibility around prescribing of TNFIs by physicians, and regular review of the arrangements were proposed. These themes will inform the next phase of the study. CONCLUSION: This first phase highlighted a range of issues associated with the PBS arrangements restricting access to TNFIs. Timely review and report of issues and concerns associated with such policy developments that arose in practice are essential. There is a need for a more comprehensive exploration across a wide range of stakeholders with different perspectives that will in turn be helpful in guiding policy and practice around national arrangements to manage access to high-cost medicines

The drag on a microcantilever oscillating near a wall

Motivated by devices such as the atomic force microscope, we compute the drag experienced by a cylindrical body of circular or rectangular cross-section oscillating at small amplitude near a plane wall. The body lies parallel to the wall and oscillates normally to it; the body is assumed to be long enough for the dominant flow to be two-dimensional. The flow is parameterized by a frequency parameter γ² (a Strouhal number) and the wall–body separation Δ (scaled on body radius). Numerical solutions of the unsteady Stokes equations obtained using finite-difference computations in bipolar coordinates (for circular cross-sections) and boundary-element computations (for rectangular cross-sections) are used to determine the drag on the body. Numerical results are validated and extended using asymptotic predictions (for circular cylinders) obtained at all extremes of (γ, Δ)-parameter space. Regions in parameter space for which the wall has a significant effect on drag are identified.R. J. Clarke, S. M. Cox, P. M. Williams and O. E. Jense

Atrazine Transport Within a Coastal Zone in Southeastern Puerto Rico: a Sensitivity Analysis of an Agricultural Field Model and Riparian Zone Management Model

Agrichemical runoff from farmland may adversely impact coastal water quality. Two models, the Agricultural Policy/Environmental eXtender (APEX) and the Riparian Ecosystem Management Model (REMM), were used to evaluate the movement of the herbicide atrazine to the Jobos Bay National Estuarine Research Reserve from adjacent fields. The reserve is located on Puerto Rico’s southeast coast. Edge-of-field atrazine outputs simulated with the APEX were routed through a grass-forest buffer using the REMM. Atrazine DT50 (half-life) values measured in both field and buffer soils indicated that accelerated degradation conditions had developed in the field soil due to repeated atrazine application. APEX simulations examined both the measured field and buffer soil atrazine DT50 and the model’s default value. The use of the measured field soil atrazine degradation rate in the APEX resulted in 33 % lower atrazine transport from the field. REMMsimulations indicated that the buffer system had the potential to reduce dissolved atrazine transport in surface runoff by 77%during non-tropical stormevents by increasing infiltration, slowing transport, and increasing time for pesticide degradation. During a large runoff event due to a tropical stormthat occurred close to the time of an atrazine application, the REMM simulated only a 37 % reduction in atrazine transport. The results indicate that large storm events soon after herbicide application likely dominate herbicide transport to coastal waters in the region. These results agree with water quality measurements in the reserve. This study demonstrated the sensitivity of these models to variations in DT50 values in evaluating atrazine fate and transport in the region and emphasizes that the use of measured DT50 values can improve model accuracy