A RAC-GEF network critical for early intestinal tumourigenesis.

RAC1 activity is critical for intestinal homeostasis, and is required for hyperproliferation driven by loss of the tumour suppressor gene Apc in the murine intestine. To avoid the impact of direct targeting upon homeostasis, we reasoned that indirect targeting of RAC1 via RAC-GEFs might be effective. Transcriptional profiling of Apc deficient intestinal tissue identified Vav3 and Tiam1 as key targets. Deletion of these indicated that while TIAM1 deficiency could suppress Apc-driven hyperproliferation, it had no impact upon tumourigenesis, while VAV3 deficiency had no effect. Intriguingly, deletion of either gene resulted in upregulation of Vav2, with subsequent targeting of all three (Vav2-/- Vav3-/- Tiam1-/-), profoundly suppressing hyperproliferation, tumourigenesis and RAC1 activity, without impacting normal homeostasis. Critically, the observed RAC-GEF dependency was negated by oncogenic KRAS mutation. Together, these data demonstrate that while targeting RAC-GEF molecules may have therapeutic impact at early stages, this benefit may be lost in late stage disease.

Transformation of truncated gold octahedrons into triangular nanoprisms through the heterogeneous nucleation of silver.

Described is a straightforward procedure for forming organized substrate-immobilized nanoprisms which are single crystalline, surfactant-free and which form a heteroepitaxial relationship with the underlying substrate. The devised route utilizes truncated Au octahedrons formed through solid state dewetting techniques as high temperature heterogeneous nucleation sites for Ag adatoms which are arriving to the substrate surface in the vapour phase. Observed is a morphological and compositional transformation of the Au structures to triangular nanoprisms comprised of a homogeneous AuAg alloy. During this transformation, the localized surface plasmon resonance red-shifts, broadens and increases in strength. The shape transformation, which cannot be rationalized using thermodynamic arguments dependent on the surface energy minimization, is described in terms of a kinetically driven growth mode, previously predicted by molecular dynamic simulations. The so-formed structures, when coated with a thin layer of Pd, are demonstrated as plasmonic sensing elements for hydrogen detection.

Altering the dewetting characteristics of ultrathin gold and silver films using a sacrificial antimony layer.

Solid state dewetting of ultrathin films is the most straightforward means of fabricating substrate-supported noble metal nanostructures. This assembly process is, however, quite inflexible, yielding either densely packed smaller structures or widely spaced larger structures. Here, we demonstrate the utility of introducing a sacrificial antimony layer between the substrate and noble metal overlayer. We observe an agglomeration process which is radically altered by the concurrent sublimation of antimony. In stark contrast with conventional dewetting, where the thickness of the deposited metal film determines the characteristic length scales of the assembly process, it is the thickness of the sacrificial antimony layer which dictates both the nanoparticle size and interparticle spacing. The result is a far more flexible self-assembly process where the nanoparticle size and areal density can be varied widely. Demonstrations show nanoparticle areal densities which are varied over four orders of magnitude assembled from the identical gold layer thickness, where the accompanying changes to nanostructure size see a systematic shift in the wavelength of the localized surface plasmon resonance. As a pliable self-assembly process, it offers the opportunity to tailor the properties of an ensemble of nanostructures to meet the needs of specific applications.

Impact of IMCI training and language used by provider on quality of counseling provided to parents of sick children in Bougouni District, Mali.

This study evaluates the impact of the Integrated Management Of Childhood Illness (IMCI) training on quality of counseling provided to caregivers about administration of antimalarials to their children. Ten community health centers in southern Mali were randomized to either training or comparison arms of the study, and health providers' consultations with caregivers were observed. Out of a 10-point counseling scale (Cronbach's alpha=0.77), IMCI-trained providers completed an average of 1.47 (95% CI, -0.25, 3.2) more tasks than did providers who had not received IMCI training in a linear regression analysis that accounted for intra-provider correlations. Drug consultations done in both French and the local language, Bambara, had higher scores than those conducted exclusively in Bambara. The effect of providers receiving IMCI training was more pronounced in bilingual consultations, with an average increase of 2.49 (95% CI, 0.76, 4.22) in IMCI, bilingual consultations, and average increase of 0.87 (95% CI, -0.95, 2.69) in IMCI monolingual (Bambara) consultations as compared to non-IMCI-trained providers in monolingual consultations. IMCI training showed a non-significant trend overall in improving drug counseling provided to caregivers, with significant improvements in bilingual consultations. The IMCI program in Mali should consider strategies such as role-playing of counseling in Bambara or other local languages during training to improve patient-provider communication. Similar problems related to counseling by health workers in local languages are likely to be present throughout Africa, and warrant further study.

Increases in correct administration of chloroquine in the home and referral of sick children to health facilities through a community-based intervention in Bougouni District, Mali.

Save the Children/USA in collaboration with the Ministry of Health of Mali has established over 300 village drug kits in southern Mali since 1996. A cluster-randomized trial was conducted between November 2001 and February 2002 in 10 health zones of Bougouni District to evaluate an intervention to (i) improve the skills of the village drug kit managers to counsel parents on correct home administration of chloroquine (CQ), and (ii) increase the referral of sick children to community health centres (CHC). Children's carers were interviewed 5 d after the sale of CQ about knowledge of danger signs requiring referral, quality of counselling, administration of CQ, and referral. The intervention was associated with significant increases in knowledge of danger signs requiring referral, reported quality of counselling by the manger of the drug kit, and correct administration of CQ in the home. Parents reported that 42.1% of children in the intervention group were referred to the CHC by the drug kit manager compared with 11.2% in the comparison group (odds ratio = 7.12, 95% CI 2.62-19.38). CHC registers indicated that 87.0% of referrals recorded in drug kit referral notebooks arrived at the health centre. Further research is needed to increase the effectiveness of the counselling and the community referral mechanism tested in this study.