Oxidative stress via hydrogen peroxide and menadione does not induce the secretion of IGFBP-5 in primary rat hepatocytes

Conference abstract describing how oxidative stress via hydrogen peroxide and menadione does not induce the secretion of IGFBP-5 in primary rat hepatocytes. Presented at the 2010 annual congress of the british toxicology societ

Poly-substance use and sexual risk behaviours: a cross-sectional comparison of adolescents in mainstream and alternative education settings

Background: Surveys of young people under-represent those in alternative education settings (AES), potentially disguising health inequalities. We present the first quantitative UK evidence of health inequalities between AES and mainstream education school (MES) pupils, assessing whether observed inequalities are attributable to socioeconomic, familial, educational and peer factors. Methods: Cross-sectional, self-reported data on individual- and poly-substance use (PSU: combined tobacco, alcohol and cannabis use) and sexual risk-taking from 219 pupils in AES (mean age 15.9 years) were compared with data from 4024 pupils in MES (mean age 15.5 years). Data were collected from 2008 to 2009 as part of the quasi-experimental evaluation of Healthy Respect 2 (HR2). Results: AES pupils reported higher levels of substance use, including tobacco use, weekly drunkenness, using cannabis at least once a week and engaging in PSU at least once a week. AES pupils also reported higher levels of sexual health risk behaviours than their MES counterparts, including: earlier sexual activity; less protection against sexually transmitted infections (STIs); and having 3+ lifetime sexual partners. In multivariate analyses, inequalities in sexual risk-taking were fully explained after adjusting for higher deprivation, lower parental monitoring, lower parent-child connectedness, school disengagement and heightened intentions towards early parenthood among AES vs MES pupils. However, an increased risk (OR = 1.73, 95% CI 1.15, 2.60) of weekly PSU was found for AES vs MES pupils after adjusting for these factors and the influence of peer behaviours. Conclusion: AES pupils are more likely to engage in health risk behaviours, including PSU and sexual risk-taking, compared with MES pupils. AES pupils are a vulnerable group who may not be easily targeted by conventional population-level public health programmes. Health promotion interventions need to be tailored and contextualised for AES pupils, in particular for sexual health and PSU. These could be included within interventions designed to promote broader outcomes such as mental wellbeing, educational engagement, raise future aspirations and promote resilience

Can we spot deleterious ageing in two waves of data? The Lothian Birth Cohort 1936 from ages 70 to 73

‘Younger ’ old age (the late 60s through early 70s) is, for many, a period of stability of lifestyle and considerable freedom to pursue leisure activities. Despite the stability that many enjoy, the mortality rate is about 2 % per year in western nations. This increases to about 5 % by age 80. It would be useful to know if those most vulnerable can be identified through patterns of deleterious ageing, and especially if this could be accomplished with just two waves of data. The Lothian Birth Cohort 1936 was surveyed on a host of individual difference variables including cognition, personality, biomarkers of physical health, and activities at ages 70 and 73 years. Overall, the group showed the expected basic stability in mean levels for these variables, but some individuals had died and others did show substantial changes that could be considered statistically reliable. These presumably reliable changes were at least as likely to be positive (reflecting improved condition/ability) as negative (reflecting decline/ageing). Moreover, limitations in the estimated reliabilities of the measures meant that most of the observed changes could not be considered reliable. The changes clustered only weakly around general health to predict death over the next approximately two years. We concluded that two waves of longitudinal data were not sufficient to assess meaningful patterns of ageing, despite often being used to do so

Pax9 and Gbx2 interact in the pharyngeal endoderm to control cardiovascular development.

The correct formation of the aortic arch arteries depends on a coordinated and regulated gene expression profile within the tissues of the pharyngeal arches. Perturbation of the gene regulatory networks in these tissues results in congenital heart defects affecting the arch arteries and the outflow tract of the heart. Aberrant development of these structures leads to interruption of the aortic arch and double outlet right ventricle, abnormalities that are a leading cause of morbidity in 22q11 Deletion Syndrome (DS) patients. We have recently shown that Pax9 functionally interacts with the 22q11DS gene Tbx1 in the pharyngeal endoderm for 4th pharyngeal arch artery morphogenesis, with double heterozygous mice dying at birth with interrupted aortic arch. Mice lacking Pax9 die perinatally with complex cardiovascular defects and in this study we sought to validate further potential genetic interacting partners of Pax9, focussing on Gbx2 which is down-regulated in the pharyngeal endoderm of Pax9-null embryos. Here, we describe the Gbx2-null cardiovascular phenotype and demonstrate a genetic interaction between Gbx2 and Pax9 in the pharyngeal endoderm during cardiovascular development

An evaluation of Minor Groove Binders as anti-lung cancer therapeutics

A series of 47 structurally diverse MGBs, derived from the natural product distamycin, was evaluated for anti-lung cancer activity by screening against the melanoma cancer cell line B16-F10. Five compounds have been found to possess significant activity, more so than a standard therapy, Gemcitabine. Moreover, one compound has been found to have an activity around 70-fold that of Gemcitabine and has a favourable selectivity index of greater than 125. Furthermore, initial studies have revealed this compound to be metabolically stable and thus it represents a lead for further optimisation towards a novel treatment for lung cance

Investigating cobalt toxicity in the context of joint replacement patients - cobalt uptake in primary cardiac fibroblasts and in 3T3 cells

Cobalt leaches out from cobalt/chromium metal-on-metal hip implants into patient blood, and its effects are thought to be toxic. There has been a 5% estimated incidence of adverse effects, including toxicity to the heart, in joint implant patients over the last 40 years. This was investigated by examination of the effects of CoCl2 on cell proliferation and viability performed using a range of assays. To assess effects on proliferation, MTT, neutral red and crystal violet assays were all used to compare effects of increasing concentrations of CoCl2 on the Swiss 3T3 fibroblast cell line (3T3s) and primary cardiac fibroblasts (CFs). CoCl2 induced toxicity in both 3T3s and CFs in a time- and dose-dependent manner with IC50 values for CoCl2 in the range of ~300 µM in both cells. Over 72h, increasing CoCl2 concentrations (up to 500 µM) resulted in decreased proliferation. Interestingly, in terms of proliferation, the 3T3s were more tolerant of CoCl2 than CFs. Uptake of CoCl2 into the 3T3s and CFs was measured by detecting intracellular metal content using ICP-MS. Cells were cultured and exposed to various concentrations of CoCl2 (0-72 ppm) and different exposure times (24, 48 and 72 h). Analysis of cobalt content of cells revealed that with increasing medium concentration of CoCl2 intracellular Co concentration on both 3T3s and CFs increased, to a range between 0-50 ppb and 0-120 ppb, respectively. Uptake into CFs was greater than into the 3T3s, and this at least partly explains the difference in toxicity between the two cell types

Reduced relative volume in motor and attention regions in developmental coordination disorder: a voxel-based morphometry study.

Background and Objectives: Developmental coordination disorder (DCD) is a prevalent childhood movement disorder, impacting the ability to perform movement skills at an age appropriate level. Although differences in grey matter (GM) volumes have been found in related developmental disorders, no such evidence has been linked with DCD to date. This cross-sectional study assessed structural brain differences in children with and without DCD. Methods: High-resolution structural images were acquired from 44 children aged 7.8–12 years, including 22 children with DCD (≤16th percentile on MABC-2; no ADHD/ASD), and 22 typically developing controls (≥20th percentile on MABC-2). Structural voxel-based morphology analysis was performed to determine group differences in focal GM volumes. Results: Children with DCD were found to have significant, large, right lateralised reductions in grey matter volume in the medial and middle frontal, and superior frontal gyri compared to controls. The addition of motor proficiency as a covariate explained the between-group GM volume differences, suggesting that GM volumes in motor regions are reflective of the level of motor proficiency. A positive correlation between motor proficiency and relative GM volume was also identified in the left posterior cingulate and precuneus. Conclusions: GM volume reductions in premotor frontal regions may underlie the motor difficulties characteristic of DCD. It is possible that intervention approaches targeting motor planning, attention, and executive functioning processes associated with the regions of reduced GM volume may result in functional improvements in children with DCD

A generalised module for the selective extracellular accumulation of recombinant proteins

Background: It is widely believed that laboratory strains of Escherichia coli, including those used for industrial production of proteins, do not secrete proteins to the extracellular milieu.Results: Here, we report the development of a generalised module, based on an E. coli autotransporter secretion system, for the production of extracellular recombinant proteins. We demonstrate that a wide variety of structurally diverse proteins can be secreted as soluble proteins when linked to the autotransporter module. Yields were comparable to those achieved with other bacterial secretion systems.Conclusions: The advantage of this module is that it relies on a relatively simple and easily manipulated secretion system, exhibits no apparent limitation to the size of the secreted protein and can deliver proteins to the extracellular environment at levels of purity and yields sufficient for many biotechnological applications

Impairment of early fracture healing by skeletal muscle trauma is restored by FK506

BACKGROUND: Heightened local inflammation due to muscle trauma or disease is associated with impaired bone regeneration. METHODS: We hypothesized that FK506, an FDA approved immunomodulatory compound with neurotrophic and osteogenic effects, will rescue the early phase of fracture healing which is impaired by concomitant muscle trauma in male (~4 months old) Lewis rats. FK506 (1 mg/kg; i.p.) or saline was administered systemically for 14 days after an endogenously healing tibia osteotomy was created and fixed with an intermedullary pin, and the overlying tibialis anterior (TA) muscle was either left uninjured or incurred volumetric muscle loss injury (6 mm full thickness biopsy from middle third of the muscle). RESULTS: The salient observations of this study were that 1) concomitant TA muscle trauma impaired recovery of tibia mechanical properties 28 days post-injury, 2) FK506 administration rescued the recovery of tibia mechanical properties in the presence of concomitant TA muscle trauma but did not augment mechanical recovery of an isolated osteotomy (no muscle trauma), 3) T lymphocytes and macrophage presence within the traumatized musculature were heightened by trauma and attenuated by FK506 3 days post-injury, and 4) T lymphocyte but not macrophage presence within the fracture callus were attenuated by FK506 at 14 days post-injury. FK506 did not improve TA muscle isometric torque production CONCLUSION: Collectively, these findings support the administration of FK506 to ameliorate healing of fractures with severe muscle trauma comorbidity. The results suggest one potential mechanism of action is a reduction in local T lymphocytes within the injured musculoskeletal tissue, though other mechanisms to include direct osteogenic effects of FK506 require further investigation