IL-10 regulation of macrophage VEGF production is dependent on macrophage polarisation and hypoxia.

Vascular endothelial growth factor A (VEGF) is critical for vascular remodelling during tissue repair subsequent to inflammation or injury, but under pathological conditions, VEGF induces tissue damaging angiogenesis. Macrophages generate VEGF that supports angiogenesis, when they adapt to their environment and respond with a co-ordinated set of signals to promote or resolve inflammation. Depending on the stimulus, the phenotype of macrophage activation is broadly classified into M1 (NOS2(+)) and M2 (arginase-1(+)). In recent studies, IL-10, an anti-inflammatory cytokine that suppresses the M1 phenotype, has been shown to dampen the angiogenic switch and subsequent neovascularisation. However, as we show here, these effects are context dependent. In this study, we have demonstrated that IL-10 inhibits M1 bone marrow-derived macrophages (BMDMs) VEGF, stimulated by LPS/CGS21680 (adenosine A2A receptor agonist), but does not prevent VEGF production from M2 macrophages stimulated with prostaglandin E2 (PGE2). Furthermore, we show that hypoxic-conditioned BMDM generated VEGF was maintained in the presence of IL-10, but was suppressed when concomitantly stimulated with IFN-gamma. Finally, LPS/PGE2 generated an arginase-1(+) M2 macrophage that in addition to generating VEGF produced significant quantities of IL-10. Under these conditions, neither in IL-10 deficient macrophages nor following IL-10 neutralization was VEGF production affected. Our results indicate IL-10 suppressed M1 but not M2 derived VEGF, and that activation signals determined the influence of IL-10 on VEGF production. Consequently, therapies to suppress macrophage activation that as a result generate IL-10, or utilising IL-10 as a potential anti-angiogenic therapy, may result in a paradoxical support of neovascularisation and thus on-going tissue damage or aberrant repair.

Randomized controlled trial of assertive community treatment in intellectual disability: the TACTILD study.

BACKGROUND: There has been a policy shift away from hospital to community in the services of all those with psychiatric disorders, including those with intellectual disability (ID), in the last 50 years. This has been accompanied recently by the growth of assertive outreach services, but these have not been evaluated in ID services. METHOD: In a randomized controlled trial we compared assertive outreach with 'standard' community care, using global assessment of function (GAF) as the primary outcome measure, and burden and quality of life as secondary measures. RESULTS: We recruited 30 patients, considerably less than expected; no significant differences were found between the primary and secondary outcomes in the two groups. The differences were so small that a Type II error was unlikely. CONCLUSIONS: Reasons for this lack of specific efficacy of the assertive approach are discussed and it is suggested that there is a blurring of the differences between standard and assertive approaches in practice.

Difficulties in conducting a randomized controlled trial of health service interventions in intellectual disability: implications for evidence-based practice.

BACKGROUND: In an era of evidence-based medicine, practice is constantly monitored for quality in accordance with the needs of clinical governance (Oyebode et al. 1999). This is likely to lead to a dramatic change in the treatment of those with intellectual disability (ID), in which evidence for effective intervention is limited for much that happens in ordinary practice. As Fraser (2000, p. 10) has commented, the word that best explains "the transformation of learning disability practice in the past 30 years is 'enlightenment'." This is not enough to satisfy the demands of evidence, and Fraser exhorted us to embrace more research-based practice in a subject that has previously escaped randomized controlled trials (RCTs) of treatment because of ethical concerns over capacity and consent, which constitute a denial of opportunity which "is now at last regarded as disenfranchising". CONCLUSIONS: The present paper describes the difficulties encountered in setting up a RCT of a common intervention, i.e. assertive community treatment, and concludes that a fundamental change in attitudes to health service research in ID is needed if proper evaluation is to prosper.