Demographic and therapeutic determinants of pain reactivity in very low birth weight neonates at 32 Weeks' postconceptional Age

Management of pain in very low birth weight infants is limited by a lack of empiric knowledge about the multiple determinants of biobehavioral reactivity in infants receiving neonatal intensive care.

Epigenetics in Vascular Disease - Therapeutic Potential of New Agents

Vascular diseases, including atherosclerosis, angioplasty-induced restenosis, vessel graft arteriosclerosis and hypertension-related stenosis, remain the most prevalent cause of death in the developed world. The aetiology of vascular diseases is multifactorial with both genetic and environmental factors. Recently, some of the most promising research identifies the epigenetic modification of the genome to play a major role in the disease development, linking the environmental insults with gene regulation. In this process, modification of DNA by methylation, and histone modification by acetylation, methylation, phosphorylation and/or SUMOylation are reported. Importantly, recent studies demonstrated that histone deacetylase (HDAC) enzymes are crucial in endothelial integrity, smooth muscle proliferation and in the formation of arteriosclerosis in animal models. The study of HDACs has shown remarkable specificity of HDAC family members in vascular cell growth/death that influences the disease process. Interestingly, the effects of HDACs on arteriosclerosis development in animal models have been observed after HDAC inhibition using specific inhibitors. This provides a new approach for the treatment of vascular disease using the agents that influence the epigenetic process in vascular cells. This review updates the rapid advances in epigenetics of vascular diseases focusing on the role of HDAC family in atherosclerosis. It will also discuss the underlying mechanisms of histone acetylation in vascular cells and highlight the therapeutic potential of such agents.

Maternal Religiosity, Family Resources and Stressors, and Parent-Child Attachment Security in Northern Ireland

This study explores the associations between mothers' religiosity, and families' and children's functioning in a stratified random sample of 695 Catholic and Protestant motherchild dyads in socially deprived areas in Belfast, Northern Ireland, a region which has experienced centuries of sectarian conflict between Protestant Unionists and Catholics Nationalists. Findings based on mother and child surveys indicated that even in this context of historical political violence associated with religious affiliation, mothers' religiosity played a consistently positive role, including associations with multiple indicators of better family functioning (i.e., more cohesion and behavioral control and less conflict, psychological distress, and adjustment problems) and greater parentchild attachment security. Mothers' religiosity also moderated the association between parentchild attachment security and family resources and family stressors, enhancing positive effects of cohesion and mother behavioral control on motherchild attachment security, and providing protection against risks associated with mothers' psychological distress. Findings are discussed in terms of implications for understanding the role of religiosity in serving as a protective or risk factor for children and families.

Therapeutic Effects of Human Mesenchymal Stem Cells in Ex Vivo Human Lungs Injured with Live Bacteria

Rationale: Mesenchymal stem cells secrete paracrine factors that can regulate lung permeability and decrease inflammation, making it a potentially attractive therapy for acute lung injury. However, concerns exist whether mesenchymal stem cells' immunomodulatory properties may have detrimental effects if targeted toward infectious causes of lung injury. Objectives: Therefore, we tested the effect of mesenchymal stem cells on lung fluid balance, acute inflammation, and bacterial clearance. Methods: We developed an Escherichia coli pneumonia model in our ex vivo perfused human lung to test the therapeutic effects of mesenchymal stem cells on bacterial-induced acute lung injury. Measurements and Main Results: Clinical-grade human mesenchymal stem cells restored alveolar fluid clearance to a normal level, decreased inflammation, and were associated with increased bacterial killing and reduced bacteremia, in part through increased alveolar macrophage phagocytosis and secretion of antimicrobial factors. Keratinocyte growth factor, a soluble factor secreted by mesenchymal stem cells, duplicated most of the antimicrobial effects. In subsequent in vitro studies, we discovered that human monocytes expressed the keratinocyte growth factor receptor, and that keratinocyte growth factor decreased apoptosis of human monocytes through AKT phosphorylation, an effect that increased bacterial clearance. Inhibition of keratinocyte growth factor by a neutralizing antibody reduced the antimicrobial effects of mesenchymal stem cells in the ex vivo perfused human lung and monocytes grown in vitro injured with E. coli bacteria. Conclusions: In E. coli-injured human lungs, mesenchymal stem cells restored alveolar fluid clearance, reduced inflammation, and exerted antimicrobial activity, in part through keratinocyte growth factor secretion.

Prognostic and therapeutic relevance of c-FLIP in acute myeloid leukaemia

Chemoresistance is a major contributor to the aggressiveness of AML and is often due to insufficient apoptosis. The CFLAR gene is expressed as long and short splice forms encoding the anti-apoptotic proteins c-FLIP(L) and c-FLIP(S) (CFLAR(L) and CFLAR(S) , respectively) that play important roles in drug resistance. In univariate analyses of CFLAR mRNA expression in adult AML patients, those individuals with higher than median mRNA expression of the long splice form CFLAR(L) (but not the short splice form) had significantly lower 3 year overall survival (P = 0·04) compared to those with low expression. In cell line studies, simultaneous down-regulation of c-FLIP(L) and c-FLIP(S) proteins using siRNA induced apoptosis in U937 and NB-4 AML cells, but not K562 or OCI-AML3 cells. However, dual c-FLIP(L/S) downregulation sensitized all four cell lines to apoptosis induced by recombinant tumour necrosis factor-related apoptosis-inducing ligand (rTRAIL). Moreover, specific downregulation of c-FLIP(L) was found to recapitulate the phenotypic effects of dual c-FLIP(L/S) downregulation. The histone deacetylase (HDAC)1/2/3/6 inhibitor Vorinostat was found to potently down-regulate c-FLIP(L) expression by transcriptional and post-transcriptional mechanisms and to sensitize AML cells to rTRAIL. Further analyses using more selective HDAC inhibitors revealed that HDAC6 inhibition was not required for c-FLIP(L) down-regulation. These results suggest that c-FLIP(L) may have clinical relevance both as a prognostic biomarker and potential therapeutic target for HDAC inhibitors in AML although this requires further study.

JISC Workshop Report: E-Research Resources, Tools and Methods for Historic Place Name Analysis

A substantial amount of the 'critical mass' of digital data available to scholarship contains place-names, and it is now recognised that spatial and temporal data points, including place-names, are a vital part of the e-research infrastructure that supports the use, re-use and advanced analysis of data using ICT tools and methods. Place-names can also be linked semantically to contribute to the web of data, and to enrich content through linking existing data, and identifying new collections for digitization to strategically enhance existing digital collections. However, existing e-projects rely on modern gazetteers limiting them to the modern and the near-contemporary. This workshop explored how to further integrate the wealth of historical place-name scholarship, and the resulting digital resources generated within UK academia, so enabling integration of local knowledge over much longer periods.

In Demand: Therapeutic Services for Children and Young People Who Have Experienced Sexual Abuse

This paper describes the key findings of an NSPCC study estimating need, in the UK, for therapeutic services for children who have experienced sexual abuse. This is based upon current estimates of the prevalence and impact of sexual abuse towards children and young people against the availability of therapeutic services in the UK. Data were collected on service location, availability, scope and coverage across England, Wales, Northern Ireland and Scotland. Researchers: (1) mapped 508 services; (2) collected data from 195 services via a structured questionnaire; (3) followed up 21 service managers and 11 service commissioners with a semi-structured interview; and (4) carried out two focus groups with young people. Data were collected on service location, availability, scope and coverage The overall level of specialist provision is low, with less than one service available per 10 000 children and young people in the UK. Calculations of need indicate that 57 156 children across the UK in the last year may have been unable to access a service. Findings from services support the view that need outstrips availability; that referral routes are limited, leaving few options for young people who have been raped or seriously sexually assaulted to directly access support; that significant waiting lists mean services must focus on reactive, rather than preventive, work; and that services are less accessible for certain groups, especially sexually abused teenagers, children with disabilities and those from Black, Asian, Minority Ethnic and Refugee backgrounds. Copyright (c) 2012 John Wiley & Sons, Ltd. Key Practitioner Messages Relevant professionals must be adequately trained to talk to children about sexual abuse and to identify those vulnerable in order to identify need. Expert specialist services are well placed to share learning on early help and identification with broader children's service providers. Active steps need to be taken by commissioners in consultation with young people, voluntary sector and adult sexual violence service providers to meet the shortfall at the level of local authorities.

Molecular mapping the presence of druggable targets in preinvasive and precursor breast lesions:a comprehensive review of biomarkers related to therapeutic interventions

The analysis of clinical breast samples using biomarkers is integral to current breast cancer management. Currently, a limited number of targeted therapies are standard of care in breast cancer treatment. However, these targeted therapies are only suitable for a subset of patients and resistance may occur. Strategies to prevent the occurrence of invasive lesions are required to reduce the morbidity and mortality associated with the development of cancer. In theory, application of targeted therapies to pre-invasive lesions will prevent their progression to invasive lesions with full malignant potential. The diagnostic challenge for pathologists is to make interpretative decisions on early detected pre-invasive lesions. Overall, only a small proportion of these pre-invasive lesions will progress to invasive carcinoma and morphological assessment is an imprecise and subjective means to differentiate histologically identical lesions with varying malignant potential. Therefore differential biomarker analysis in pre-invasive lesions may prevent overtreatment with surgery and provide a predictive indicator of response to therapy. There follows a review of established and emerging potential druggable targets in pre-invasive lesions and correlation with lesion morphology.

Clinical and therapeutic relevance of PIM1 kinase in gastric cancer

Gastric cancer is a leading cause of cancer-related mortality, and chemotherapeutic options are currently limited. PIM1 kinase, an oncogene that promotes tumorigenesis in several cancer types, might represent a novel therapeutic target in gastric cancer.

Casualty - Human Resources

Episode of the popular BBC 1 returning drama