Limitations of fasting indices in the measurement of insulin sensitivity in Afro-Caribbean adults

In young Afro-Caribbean adults, HOMA-IR compared poorly with other measures of insulin sensitivity. It remains important to determine whether similar findings occur in a more insulin resistant population. However, HOMA-IR correlated with clinical measures of insulin sensitivity (i.e. adiposity), so it may still be useful in epidemiological studies

Differential responses to kinase inhibition in FGFR2-addicted triple negative breast cancer cells: a quantitative phosphoproteomics study

Fibroblast Growth Factor (FGF) dependent signalling is frequently activated in cancer by a variety of different mechanisms. However, the downstream signal transduction pathways involved are poorly characterised. Here a quantitative differential phosphoproteomics approach, SILAC, is applied to identify FGF-regulated phosphorylation events in two triple- negative breast tumour cell lines, MFM223 and SUM52, that exhibit amplified expression of FGF receptor 2 (FGFR2) and are dependent on continued FGFR2 signalling for cell viability. Comparative Gene Ontology proteome analysis revealed that SUM52 cells were enriched in proteins associated with cell metabolism and MFM223 cells enriched in proteins associated with cell adhesion and migration. FGFR2 inhibition by SU5402 impacts a significant fraction of the observed phosphoproteome of these cells. This study expands the known landscape of FGF signalling and identifies many new targets for functional investigation. FGF signalling pathways are found to be flexible in architecture as both shared, and divergent, responses to inhibition of FGFR2 kinase activity in the canonical RAF/MAPK/ERK/RSK and PI3K/AKT/PDK/mTOR/S6K pathways are identified. Inhibition of phosphorylation-dependent negative-feedback pathways is observed, defining mechanisms of intrinsic resistance to FGFR2 inhibition. These findings have implications for the therapeutic application of FGFR inhibitors as they identify both common and divergent responses in cells harbouring the same genetic lesion and pathways of drug resistance

Passive immunisation of convalescent human anti-Zika plasma protects against challenge with New World Zika virus in cynomolgus macaques.

Zika virus (ZIKV) causes neurological complications in susceptible individuals, highlighted in the recent South American epidemic. Natural ZIKV infection elicits host responses capable of preventing subsequent re-infection, raising expectations for effective vaccination. Defining protective immune correlates will inform viral intervention strategies, particularly vaccine development. Non-human primate (NHP) species are susceptible to ZIKV and represent models for vaccine development. The protective efficacy of a human anti-ZIKV convalescent plasma pool (16/320-14) developed as a candidate reference material for a WHO International Standard was evaluated in macaques. Convalescent plasma administered to four cynomolgus macaques (Macaca fascicularis) intra-peritoneally 24 hrs prior to sub-cutaneous challenge with 103 pfu ZIKVPRVABC59 protected against detectable infection, with absence of detectable ZIKV RNA in blood and lymphoid tissues. Passively immunised anti-ZIKV immunoglobulin administered prior to time of challenge remained present only at very low levels 42 days post-challenge. Absence of de novo antibody responses in passively immunised macaques indicate sterilising immunity compared with naïve challenge controls that exhibited active ZIKV-specific IgM and IgG responses post-challenge. Demonstration that the presence of convalescent anti-ZIKV at levels of 400 IU/mL neutralising antibody protects against virus challenge provides a scientific framework for development of anti-ZIKV vaccines and facilitates regulatory approval

Four-year longitudinal impact evaluation of the action for children UK neglect project : outcomes for the children, families, action for children, and the UK

Neglect has a devastating impact on children and is the most pervasive form of child maltreatment in the United Kingdom. The study purpose was to establish outcomes for neglected children following structured assessment and intervention to ascertain what worked and why it worked. This prospective cohort study included 85 cases of neglected children under 8 years of age from 7 centers across the United Kingdom. Data were collected between 2008 and 2012 through serial quantitative recording of the level of concern about neglect. Serial review of qualitative casefile data was undertaken for detail of assessment, interventions, and evidence of outcomes for the child. Data analysis was undertaken by paired t-test, Chi Square, descriptive statics for categorical data, and, for narrative data, identification of recurring factors and patterns, with correlation of presenting factors, interventions, and outcomes. Paired t-test demonstrated significant decrease in overall Action for Children Assessment Tool scores between assessment (M = 43.77, SD = 11.09) and closing the case (M = 35.47,SD = 9.6, t(84) = 6.77, p < 0.01). Improvement in the level of concern about neglect was shown in 79% of cases, with only 21% showing no improvement. In 59% of cases, concern about neglect was removed completely. Use of the assessment tool fostered engagement by parents. The relationship between lack of parental engagement and children being taken into care was statistically significant, with a large effect size (χ2 10.66, df1, p = 0.0001,OR = 17.24). When parents refused or were unable to respond positively to the intervention, children benefited from an expedited move into care

Whitefield News

File includes: January 2017 Volume 4, Issue 7 February 2017 Volume 4, Issue 8 March 2017 Volume 4, Issue 9 April 2017 Volume 4, Issue 10 May 2017 Volume 4, Issue 11 June 2017 Volume 4, Issue 12 July 2017 Volume 5, Issue 1 August 2017 Volume 5, Issue 2 September 2017 Volume 5, Issue 3 October 2017 Volume 5, Issue 4 November 2017 Volume 5, Issue 5 December 2017 Volume 5, Issue

Neuropathology of wild-type and nef-attenuated T cell tropic simian immunodeficiency virus (SIVmac32H) and macrophage tropic neurovirulent SIVmac17E-Fr in cynomolgus macaques

The neuropathology of simian immunodeficiency (SIV) infection in cynomolgus macaques (Macaca fascicularis) was investigated following infection with either T cell tropic SIVmacJ5, SIVmacC8 or macrophage tropic SIVmac17E-Fr. Formalin fixed, paraffin embedded brain tissue sections were analysed using a combination of in situ techniques. Macaques infected with either wild-type SIVmacJ5 or neurovirulent SIVmac17E-Fr showed evidence of neuronal dephosphorylation, loss of oligodendrocyte and CCR5 staining, lack of microglial MHC II expression, infiltration by CD4+ and CD8+ T cells and mild astrocytosis. SIVmacJ5-infected animals exhibited activation of microglia whilst those infected with SIVmac17E-Fr demonstrated a loss of microglia staining. These results are suggestive of impaired central nervous system (CNS) physiology. Furthermore, infiltration by T cells into the brain parenchyma indicated disruption of the blood brain barrier (BBB). Animals infected with the Δnef-attenuated SIVmacC8 showed microglial activation and astrogliosis indicative of an inflammatory response, lack of MHC II and CCR5 staining and infiltration by CD8+ T cells. These results demonstrate that the SIV infection of cynomolgus macaque can be used as a model to replicate the range of CNS pathologies observed following HIV infection of humans and to investigate the pathogenesis of HIV associated neuropathology