Identification of diarylsulfonamides as agonists of the free fatty acid receptor 4 (FFA4/GPR120).

The exploration of a diarylsulfonamide series of free fatty acid receptor 4 (FFA4/GPR120) agonists is described. This work led to the identification of selective FFA4 agonist 8 (GSK137647A) and selective FFA4 antagonist 39. The in vitro profile of compounds 8 and 39 is presented herein.

Postcode lotteries in public health--the NHS Health Checks Programme in North West London.

BACKGROUND: Postcode lotteries in health refer to differences in health care between different geographic areas. These have been previously associated with clinical services. However there has been little documentation of postcode lotteries relating to preventative health care services. This paper describes a postcode lottery effect in relation to the NHS Health Checks Programme (a national cardiovascular screening programme in England) in eight PCTs in the North West sector of London. METHODS: A descriptive cross-sectional analysis of the Health Checks Programme was carried out in eight PCTs in North West London using a structured data-collecting instrument. RESULTS: The analysis found variation in the implementation of the national Health Checks Programme in terms of: the screening approach taken; the allocated budget (which varied from £69,000 to £1.4 million per 100,000 eligible population); payment rates made to providers of Health Checks; tools used to identify and measure risk of cardiovascular disease and diabetes; monitoring and evaluation; and preventative services available following the health check. CONCLUSIONS: This study identifies a postcode lottery effect related to a national public health programme. Although it is important to allow enough flexibility in the design of the Health Checks Programme so that it fits in with local factors, aspects of the programme may benefit from greater standardisation or stronger national guidance.

Pharmacological regulation of insulin secretion in MIN6 cells through the fatty acid receptor GPR40: identification of agonist and antagonist small molecules.

1. Long chain fatty acids have recently been identified as agonists for the G protein-coupled receptors GPR40 and GPR120. Here, we present the first description of GW9508, a small-molecule agonist of the fatty acid receptors GPR40 and GPR120. In addition, we also describe the pharmacology of GW1100, a selective GPR40 antagonist. These molecules were used to further investigate the role of GPR40 in glucose-stimulated insulin secretion in the MIN6 mouse pancreatic beta-cell line. 2. GW9508 and linoleic acid both stimulated intracellular Ca2+ mobilization in human embryonic kidney (HEK)293 cells expressing GPR40 (pEC50 values of 7.32+/-0.03 and 5.65+/-0.06, respectively) or GPR120 (pEC50 values of 5.46+/-0.09 and 5.89+/-0.04, respectively), but not in the parent HEK-293 cell line. 3. GW1100 dose dependently inhibited GPR40-mediated Ca2+ elevations stimulated by GW9508 and linoleic acid (pIC50 values of 5.99+/-0.03 and 5.99+/-0.06, respectively). GW1100 had no effect on the GPR120-mediated stimulation of intracellular Ca2+ release produced by either GW9508 or linoleic acid. 4. GW9508 dose dependently potentiated glucose-stimulated insulin secretion in MIN6 cells, but not in primary rat or mouse islets. Furthermore, GW9508 was able to potentiate the KCl-mediated increase in insulin secretion in MIN6 cells. The effects of GW9508 on insulin secretion were reversed by GW1100, while linoleic acid-stimulated insulin secretion was partially attenuated by GW1100. 5. These results add further evidence to a link between GPR40 and the ability of fatty acids to acutely potentiate insulin secretion and demonstrate that small-molecule GPR40 agonists are glucose-sensitive insulin secretagogues.

Development of a novel high-throughput surrogate assay to measure HIV envelope/CCR5/CD4-mediated viral/cell fusion using BacMam baculovirus technology.

The initial event by which M-tropic HIV strains gain access to cells is via interaction of the viral envelope protein gp120 with the host cell CCR5 coreceptor and CD4. Inhibition of this event reduces viral fusion and entry into cells in vitro. The authors have employed BacMam baculovirus-mediated gene transduction to develop a cell/cell fusion assay that mimics the HIV viral/cell fusion process and allows high-throughput quantification of this fusion event. The assay design uses human osteosarcoma (HOS) cells stably transfected with cDNAs expressing CCR5, CD4, and long terminal repeat (LTR)-luciferase as the recipient host cell. An HEK-293 cell line transduced with BacMam viral constructs to express the viral proteins gp120, gp41, tat, and rev represents the virus. Interaction of gp120 with CCR5/CD4 results in the fusion of the 2 cells and transfer of tat to the HOS cell cytosol; tat, in turn, binds to the LTR region on the luciferase reporter and activates transcription, resulting in an increase in cellular luciferase activity. In conclusion, the cell/cell fusion assay developed has been demonstrated to be a robust and reproducible high-throughput surrogate assay that can be used to assess the effects of compounds on gp120/CCR5/CD4-mediated viral fusion into host cells.

A systematic review of the literature for evidence on health facility committees in low- and middle-income countries.

Community participation in health (CPH) has been advocated as a health-improving strategy for many decades. However, CPH comes in many different forms, one of which is the use of health facility committees (HFCs) on which there is community representation. This paper presents the findings of a systematic literature review of: (a) the evidence of HFCs' effectiveness, and (b) the factors that influence the performance and effectiveness of HFCs. Four electronic databases and the websites of eight key organizations were searched. Out of 341 potentially relevant publications, only four provided reasonable evidence of the effectiveness of HFCs. A further 37 papers were selected and used to draw out data on the factors that influence the functioning of HFCs. A conceptual model was developed to describe the key factors. It consists of, firstly, the features of the HFC, community and facility, and their interactions; secondly, process factors relating to the way HFCs are established and supported; and finally, a set of contextual factors. The review found some evidence that HFCs can be effective in terms of improving the quality and coverage of health care, as well as impacting on health outcomes. However, the external validity of these studies is inevitably limited. Given the different potential roles/functions of HFCs and the complex and multiple set of factors influencing their functioning, there is no 'one size fits all' approach to CPH via HFCs, nor to the evaluation of HFCs. However, there are plenty of experiences and lessons in the literature which decision makers and managers can use to optimize HFCs.

Translating words into actions: are governments acting on the advice of the World health report?

Every year, WHO produces the World health report: the 2005 report concentrated on maternal, neonatal and child health. But what is the value of these reports? Are they ritualistic publications designed to promote WHO, or are they worthy of proper discussion and debate? One would think that given the current crises in global health, the annual report of the UN's primary agency for health would be important. However, unless there is evidence that these reports are taken seriously, discussed and debated, and shown to have an effect, a conclusion might be drawn that they are largely insignificant. And that would consign WHO to a level of insignificance that it does not warrant. In this discussion of the 2005 report, I aim to provoke a response from both WHO and the international health community to demonstrate that the annual World health reports are meaningful. Furthermore, I suggest here that WHO shows its commitment to the recommendations of the 2005 report by monitoring how well recommendations have been taken forward.