R1467H variant in the rho guanine nucleotide exchange factor 11 (<Emphasis Type="Italic">ARHGEF11</Emphasis>) is associated with impaired glucose tolerance and type 2 diabetes in German Caucasians

The human rho guanine nucleotide exchange factor 11 (ARHGEF11) functions as an activator of rho GTPases and is supposed to influence insulin signalling. We investigated the effects of the previously reported R1467H variant in individual’s susceptibility to type 2 diabetes (T2D) and impaired glucose tolerance (IGT) as well as related traits in a German Caucasian cohort. Our study replicated associations of the R1467H with increased risk of T2D or T2D/IGT, thus, implicating a potential role of ARHGEF11 in the aetiology of T2D and IGT.     

The identification of a small molecule inhibitor that specifically reduces T cell-mediated adaptive but not LPS-mediated innate immunity by T cell membrane-monocyte contact bioassay

Proinflammatory cytokines such as TNFalpha and IL-1beta are produced in lesional skin of chronic plaque psoriasis patients, and at other sites of chronic inflammation such as arthritic joints. They play vital roles in maintaining inflammation. It has recently been suggested that activated T cell contact-mediated monocyte activation, leading to the production of proinflammatory cytokines, contributes to the pathogenesis of psoriasis and other chronic inflammatory diseases such as psoriatic arthritis and rheumatoid arthritis. Using a T cell membrane-monocyte contact bioassay, we have identified small molecule antagonists that differentially block anti-CD3/anti-CD28 activated T cell-mediated, but not LPS-stimulated, TNFalpha production from monocytes. We selected several kinase inhibitors from the Berlex/Schering kinase library and tested the effect of these compounds in blocking TNFalpha production in the T cell membrane-monocyte contact bioassay. We have demonstrated that one compound BLX-1, from a p38 MAP kinase inhibitor project, inhibited T cell-mediated TNFalpha production from monocytes by about 80%, without any effect on TNFalpha production from LPS-stimulated monocytes. Other BLX-1 analogs showed 32-83% inhibition of TNFalpha production with LPS stimulation as compared to almost 100% inhibition of T cell-mediated TNFalpha production. In contrast, PKC inhibitors BLX-5, Go6983, and Ro-31-8220, inhibited TNFalpha production from both activated T cell membrane- and LPS-stimulated monocytes to the same extent (in the range of 50-100% inhibition). Therefore, the activated T cell membrane-monocyte contact bioassay can be used to screen small molecule antagonists that specifically target adaptive but not LPS-mediated innate immunity. Small molecule TNFalpha inhibitors interfering specifically with activated T cell contact-mediated TNFalpha production from monocytes, but not with LPS-mediated TNFalpha production of myeloid cells, are predicted to have an improved side-effect profile and thus may provide more favorable therapeutics for the treatment of T cell-mediated inflammatory diseases.     

The secretome of the filarial parasite, Brugia malayi: proteomic profile of adult excretory-secretory products

The secretome of a parasite in its definitive host can be considered to be its genome in trans, to the extent that secreted products encoded by the parasite fulfill their function in the host milieu. The 'extended phenotype' of the filarial parasite, Brugia malayi, is of particular interest because of the evidence that infection results in potent down-modulation of the host immune response. We collected B. malayi 'excretory-secretory' (BES) proteins from adult parasites and using a combination of shotgun LC-MS/MS and 2D gel electrophoresis, identified 80 B. malayi and two host proteins in BES, of which 31 (38%) were detectable in whole worm extract (BmA). Products which were enriched in BES relative to BmA included phosphatidylethanolamine-binding protein (PEB), leucyl aminopeptidase (LAP, homologue of ES-62 from the related filaria Acanthocheilonema viteae), N-acetylglucosaminyltransferase (GlcNAcT) and galectin-1, in addition to the previously described major surface glycoprotein, glutathione peroxidase (gp29, GPX-1) and the cytokine homologue macrophage migration inhibitory factor (MIF-1). One of the most abundant released proteins was triose phosphate isomerase (TPI), yet many other glycolytic enzymes (such as aldolase and GAPDH) were found only in the somatic extract. Among the more prominent novel products identified in BES were a set of 11 small transthyretin-like proteins, and three glutamine-rich-repeat mucin-like proteins. Notably, no evidence was found of any secreted protein corresponding to the genome of the Wolbachia endosymbiont present in B. malayi. Western blotting with anti-phosphorylcholine (PC) monoclonal antibody identified that GlcNAcT, and not the ES-62 homologue, is the major PC-bearing protein in BES, while probing with human filariasis sera showed preferential reactivity to galectin-1 and to processed forms of myotactin. Overall, this analysis demonstrates selective release of a suite of newly identified proteins not previously suspected to be involved at the host-parasite interface, and provides important new perspectives on the biology of the filarial parasite.     

The course of mental health problems in children presenting with abdominal pain in general practice

Objective

To investigate the course of mental health problems in children presenting to general practice with abdominal pain and to evaluate the extent to which abdominal pain characteristics during follow-up predict the presence of mental health problems at 12 months’ follow-up.

Design

A prospective cohort study with one-year follow-up.

Setting

53 general practices in the Netherlands, between May 2004 and March 2006.

Subjects

281 children aged 4–17 years.

Main outcome measures

The presence of a depressive problem, an anxiety problem, and multiple non-specific somatic symptoms at follow-up and odds ratios of duration, frequency, and severity of abdominal pain with these mental health problems at follow-up.

Results

A depressive problem persisted in 24/74 children (32.9%; 95% CI 22.3–44.9%), an anxiety problem in 13/43 (30.2%; 95% CI 17.2–46.1%) and the presence of multiple non-specific somatic symptoms in 75/170 children (44.1%; 95% CI 36.7–51.6%). None of the abdominal pain characteristics predicted a depressive or an anxiety problem at 12 months’ follow-up. More moments of moderate to severe abdominal pain predicted the presence of multiple non-specific somatic symptoms at follow-up.

Conclusions

In one-third of the children presenting to general practice for abdominal pain, anxiety and depressive problems persist during one year of follow-up. Characteristics of the abdominal pain during the follow-up period do not predict anxiety or depressive problems after one-year follow-up. We recommend following over time children seen in primary care with abdominal pain.Key Words: Abdominal pain, adolescent, child, cohort study, family practice, mental disorders, prognosisChildren with abdominal pain often have mental health problems; however, the prognosis of these problems is unknown. This follow-up study showed that:

• in one-third of the children depressive and anxiety problems persist over one year;
• characteristics of the abdominal pain during follow-up do not predict the presence of depressive and anxiety problems at 12 months’ follow-up;
• in children with persisting moderate to severe abdominal pain other non-specific somatic symptoms also persist.