On-treatment function testing of platelets and long-term outcome of patients with peripheral arterial disease undergoing transluminal angioplasty

OBJECTIVE: To assess the clinical importance of on-treatment function testing of platelets in patients on aspirin after catheter-based vascular interventions. MATERIALS AND METHODS: In 109 patients with symptomatic peripheral arterial disease (PAD) of the lower limbs, platelet function testing (adenosine diphosphate-, collagen- and epinephrine-induced aggregation using light transmission aggregometry) was performed before and at multiple time points up to 1 year after a percutaneous angioplasty. Using univariate mixture models and Box-Cox transformation to ensure normally distributed individual variances, we investigated if an intraindividual variability exists and if it has a consequence for clinical outcome. RESULTS: Response to aspirin as measured by platelet aggregometry varies considerably over time in most patients. However, the intraindividual variance over time was not significantly correlated either with restenosis/reocclusion after 1 year or with adverse long-term outcome (occurrence of death for cardiovascular cause, stroke or myocardial infarction in up to 8 years follow-up). CONCLUSIONS: Response to aspirin does not seem to have a role in determining long-term outcome in patients with symptomatic PAD. The fact that testing of platelet function at only one time point has reduced significance may have implications for all clinical settings in which aspirin is used for the prevention of thrombo-embolic events

Immunocytokines: the long awaited therapeutic magic bullet in rheumatoid arthritis?

Modulatory cytokines such as IL-4 and IL-10 looked promising biologicals, but suffered from poor exposure at the inflamed joints when administered via the patient-friendly subcutaneous route. Immunocytokines have now been engineered with tissue targeting potential and are a possible solution to this problem, although challenges still exist. Local inflammatory processes cause destruction of extracellular matrix (ECM) components, leading to neo-eptitopes, and/or elicit the synthesis of new ECM components. This makes ECM elements interesting targets for antibody-mediated recognition and retention, to achieve higher levels of immunocytokines at the site of therapeutic interference. The study presented by Schwager and colleagues shows that targeted delivery of IL-10 is more efficacious in experimental arthritis. Clinical studies are warranted to show whether this strategy works for all rheumatoid arthritis patients or is better for subgroups with a defined ECM phenotype. In principle, the scFv-targeting system is plastic enough to allow for personalized strategies

GMC Collisions as Triggers of Star Formation. I. Parameter Space Exploration with 2D Simulations

We utilize magnetohydrodynamic (MHD) simulations to develop a numerical model for GMC-GMC collisions between nearly magnetically critical clouds. The goal is to determine if, and under what circumstances, cloud collisions can cause pre-existing magnetically subcritical clumps to become supercritical and undergo gravitational collapse. We first develop and implement new photodissociation region (PDR) based heating and cooling functions that span the atomic to molecular transition, creating a multiphase ISM and allowing modeling of non-equilibrium temperature structures. Then in 2D and with ideal MHD, we explore a wide parameter space of magnetic field strength, magnetic field geometry, collision velocity, and impact parameter, and compare isolated versus colliding clouds. We find factors of ~2-3 increase in mean clump density from typical collisions, with strong dependence on collision velocity and magnetic field strength, but ultimately limited by flux-freezing in 2D geometries. For geometries enabling flow along magnetic field lines, greater degrees of collapse are seen. We discuss observational diagnostics of cloud collisions, focussing on 13CO(J=2-1), 13CO(J=3-2), and 12CO(J=8-7) integrated intensity maps and spectra, which we synthesize from our simulation outputs. We find the ratio of J=8-7 to lower-J emission is a powerful diagnostic probe of GMC collisions

Trapped in a vicious loop: Toll-like receptors sustain the spontaneous cytokine production by rheumatoid synovium

Synovial tissue of patients with rheumatoid arthritis (RA) spontaneously produces several cytokines, of which a fundamental role in joint inflammation and destruction has been established. However, the factors sustaining this phenomenon remain poorly understood. In a recent report, blockade of Toll-like receptor 2 (TLR2) was found to inhibit the spontaneous release of inflammatory cytokines by intact RA synovial explant cultures. Adding to the recent evidence implicating other TLRs (in particular, TLR4), this observation highlights the potential of TLRs as therapeutic targets to suppress the local production of multiple cytokines and to control the chronic inflammatory loop in RA

Gene therapy in animal models of rheumatoid arthritis: are we ready for the patients?

Rheumatoid arthritis (RA) is a chronic inflammatory disease of the synovial joints, with progressive destruction of cartilage and bone. Anti-tumour necrosis factor-α therapies (e.g. soluble tumour necrosis factor receptors) ameliorate disease in 60–70% of patients with RA. However, the need for repeated systemic administration of relatively high doses in order to achieve constant therapeutic levels in the joints, and the reported side effects are downsides to this systemic approach. Several gene therapeutic approaches have been developed to ameliorate disease in animal models of arthritis either by restoring the cytokine balance or by genetic synovectomy. In this review we summarize strategies to improve transduction of synovial cells, to achieve stable transgene expression using integrating viruses such as adeno-associated viruses, and to achieve transcriptionally regulated expression so that drug release can meet the variable demands imposed by the intermittent course of RA. Evidence from animal models convincingly supports the application of gene therapy in RA, and the feasibility of gene therapy was recently demonstrated in phase I clinical trials

Identifying tree populations for conservation action through geospatial analyses

Rapid development of information and communication technologies has made it possible to easily collect georeferenced information on species and their environment, and to use it for analyzing biological diversity, its distribution and threats to it. Such analyses can importantly inform development of conservation strategies and priorities, especially across countries or species distribution ranges (Guarino et al. 2002). Data for spatial analyses on species or genetic diversity and its distribution are collected in specifically designed studies, obtained from existing records of species occurrence, or both. Observations may be complemented by species distribution modelling, where the potential occurrence of a species is predicted based on its documented geographic distribution and climate in those areas. Results on the distribution of diversity, documented or modelled, can then be compared, for example, with existing protected areas, rates of forest degradation, threats of environmental changes, or socio-economic indicators, to identify priority tree populations and tailor strategies for their conservation and sustainable use (Pautasso 2009). In this paper recent case studies on spatial biodiversity analyses across the tropics are presented, demonstrating how such analyses can help to identify most unique or most threatened populations of a tree species for conservation actions. Insights on initiating collaborative research on diversity and distributions of important Asian tree species are also discussed