The Early Effects of Rapid Androgen Deprivation on Human Prostate Cancer

The androgen receptor (AR) is the dominant growth factor in prostate cancer (PCa). Therefore, understanding how ARs regulate the human transcriptome is of paramount importance. The early effects of castration on human PCa have not previously been studied 27 patients medically castrated with degarelix 7 d before radical prostatectomy. We used mass spectrometry, immunohistochemistry, and gene expression array (validated by reverse transcription-polymerase chain reaction) to compare resected tumour with matched, controlled, untreated PCa tissue. All patients had levels of serum androgen, with reduced levels of intraprostatic androgen at prostatectomy. We observed differential expression of known androgen-regulated genes (TMPRSS2, KLK3, CAMKK2, FKBP5). We identified 749 genes downregulated and 908 genes upregulated following castration. AR regulation of α-methylacyl-CoA racemase expression and three other genes (FAM129A, RAB27A, and KIAA0101) was confirmed. Upregulation of oestrogen receptor 1 (ESR1) expression was observed in malignant epithelia and was associated with differential expression of ESR1-regulated genes and correlated with proliferation (Ki-67 expression).

PATIENT SUMMARY: This first-in-man study defines the rapid gene expression changes taking place in prostate cancer (PCa) following castration. Expression levels of the genes that the androgen receptor regulates are predictive of treatment outcome. Upregulation of oestrogen receptor 1 is a mechanism by which PCa cells may survive despite castration.

Relationships Between Deprivation and the Self-reported Health of Older People in Northern Ireland

Objectives: There are few studies on relationships between deprivation and the self-reported health of people aged over 64 years, and no studies fully representative of Northern Ireland’s older population. This paper addresses this gap. Methods: Deprivation of older people as reported in the 2001 and 2011 Censuses and the relationship with self-reported health are analyzed over a ten-year span using multilevel modeling. The data are from the Northern Ireland Longitudinal Study (NILS) linked to 2001-11 Census returns. Deprivation measures include housing tenure, property-value, access to a car, educational, employment and area-level income-deprivation. Results: Older people suffering deprivation face a significant health disadvantage over a ten-year time span. Discussion: This health disadvantage is stronger in men than in women, likely due to conservative gender roles prevalent among Northern Ireland’s older population, leading to psychological distress among deprived men. The analysis found strongly significant area-level effects, aggravating the health impact of deprivation.

Individual differences in speech and language ability profiles in areas of high deprivation

Speech and language ability is not a unitary concept; rather, it is made up of multiple abilities such as grammar, articulation and vocabulary. Young children from socio-economically deprived areas are more likely to experience language difficulties than those living in more affluent areas. However, less is known about individual differences in language difficulties amongst young children from socio-economically deprived backgrounds. The present research examined 172 four-year-old children from socio-economically deprived areas on standardised measures of core language, receptive vocabulary, articulation, information conveyed and grammar. Of the total sample, 26% had difficulty in at least one area of language. While most children with speech and language difficulty had generally low performance in all areas, around one in 10 displayed more uneven language abilities. For example, some children had generally good speech and language ability, but had specific difficulty with grammar. In such cases their difficulty is masked somewhat by good overall performance on language tests but they could still benefit from intervention in a specific area. The analysis also identified a number of typically achieving children who were identified as having borderline speech and language difficulty and should be closely monitored

The influence of mobility on mental health status in young people: The role of area-level deprivation

Residential mobility during childhood has been previously associated with poor mental health; however, this association could be mediated by several aspects of moving. This paper investigated the impact of mobility across different levels of area deprivation on the individual’s mental health status in Northern Ireland. Mobility towards deprived areas was associated with an elevated risk of reporting poor mental health in both house owners and renters. However, the number of residential moves appeared to be moderating the effect of area change on the individual’s mental health. Further exploration of this relationship is warranted through the use of more in-depth mental health measures

The quality of parenting of individuals who had failed to thrive as children

Parenting behaviour is determined by a range of factors including personality, psychopathology, values, social support, child characteristics and socio-cultural influences. It has also been suggested that an individual's style of child-rearing is influenced by the style of parenting that they experienced as children. The relationships between children who fail-to-thrive and their parents are often characterized by interactional difficulties. Previous research using retrospective accounts suggested that mothers of children who fail-to-thrive for non-organic reasons themselves showed high levels of abuse, neglect, and deprivation during their childhoods. However, to date no one has investigated prospectively what kinds of parents failure-to-thrive individuals become. This paper examines the parenting experiences of individuals who had received psychosocial intervention for their non-organic failure-to-thrive as children over 20 years ago. Results suggest that where initial intervention failed to bring about long-term changes in family interactional patterns, there was a greater incidence of failure-to-thrive in the next generation. These families were characterized by dissatisfaction with the child, high levels of stress associated with the parenting role, and low levels of social support. However, where the family environment in the original study had changed substantially, the former clients' outcomes were more positive with their own children. These parents tended to find interaction with their children more rewarding, had good support networks and low levels of stress. The characteristics of particular cases are discussed in detail to illustrate differences between these two groups of individuals.

Higher incidence of childhood-onset type 1 diabetes mellitus in remote areas: a UK regional small-area analysis

Aims/hypothesis: We investigated the association between the incidence of type 1 diabetes mellitus and remoteness (a proxy measure for exposure to infections) using recently developed techniques for statistical analysis of small-area data.

Subjects, materials and methods: New cases in children aged 0 to 14 years in Northern Ireland were prospectively registered from 1989 to 2003. Ecological analysis was conducted using small geographical units (582 electoral wards) and area characteristics including remoteness, deprivation and child population density. Analysis was conducted using Poisson regression models and Bayesian
hierarchical models to allow for spatially correlated risks that were potentially caused by unmeasured explanatory variables.

Results: In Northern Ireland between 1989 and 2003, there were 1,433 new cases of type 1 diabetes, giving a directly standardised incidence rate of 24.7 per 100,000 personyears. Areas in the most remote fifth of all areas had a significantly (p=0.0006) higher incidence of type 1 diabetes mellitus (incidence rate ratio=1.27 [95% CI 1.07, 1.50]) than those in the most accessible fifth of all areas. There was also a higher incidence rate in areas that were less deprived (p<0.0001) and less densely populated (p=0.002). After adjustment for deprivation and additional adjustment for child population density the association between diabetes and remoteness remained significant (p=0.01 and p=0.03, respectively).

Conclusions/interpretation: In Northern Ireland, there is evidence that remote areas experience higher rates of type 1 diabetes mellitus. This could reflect a reduced or delayed exposure to infections, particularly early in life, in these areas.

An Investigation into the Link between UK Credit Union Characterisitics, Location and their Success

The unique characteristics of credit unions reduces the information asymmetry that is prevalent in credit making decisions, enabling them to provide loans where other financial institutions cannot. This makes them a potential tool in the fight against financial exclusion. Yet, the UK credit union movement is not regarded as being successful, even though there is evidence of much financial exclusion. This study is cross sectional in form, and evaluates characteristics that may contribute to the success of the UK credit union movement at national and regional level, in 2000. The findings are used to consider the impact of recent regulatory changes on the movement. The key findings are that there is a significant relationship between the success of a credit union, its size and the deprivation of the ward from which it sources its members. More specifically, larger credit unions and those located in more affluent wards, are more successful. Affiliation to the Irish League of Credit Unions and having a common bond of occupation, are also found to be contributing factors to credit union success. These results are taken as providing support for the recent changes implemented by the Financial Services Authority (FSA), which is likely to result in the emergence of larger credit unions (through mergers), run by appropriately qualified persons, serving a more mixed-income membership base. It is, however, noted that the history of the UK movement is one of missed opportunities and only time will tell whether credit unions have the wherewithal to accept current opportunities.

Auditory sensory memory and working memory processes in children with normal hearing and cochlear implants.

There can be wide variation in the level of oral/aural language ability that prelingually hearing-impaired children develop after cochlear implantation. Automatic perceptual processing mechanisms have come under increasing scrutiny in attempts to explain this variation. Using mismatch negativity methods, this study explored associations between auditory sensory memory mechanisms and verbal working memory function in children with cochlear implants and a group of hearing controls of similar age. Whilst clear relationships were observed in the hearing children between mismatch activation and working memory measures, this association appeared to be disrupted in the implant children. These findings would fit with the proposal that early auditory deprivation and a degraded auditory signal can cause changes in the processes underpinning the development of oral/aural language skills in prelingually hearing-impaired children with cochlear implants and thus alter their developmental trajectory

Failure to Achieve PSA Level ≤I ng/ml Following Neo-Adjuvant LHRHa Therapy Predicts for a Lower Biochemical Control Rate and Overall Survival in Localized Prostate Cancer Treated with Radiotherapy

PURPOSE: To investigate whether failure to suppress the prostate-specific antigen (PSA) level to /=2 months of neoadjuvant luteinizing hormone-releasing hormone agonist therapy in patients scheduled to undergo external beam radiotherapy for localized prostate carcinoma is associated with reduced biochemical failure-free survival. METHODS AND MATERIALS: A retrospective case note review of consecutive patients with intermediate- or high-risk localized prostate cancer treated between January 2001 and December 2002 with neoadjuvant hormonal deprivation therapy, followed by concurrent hormonal therapy and radiotherapy was performed. Patient data were divided for analysis according to whether the PSA level in Week 1 of radiotherapy was 1 ng/mL in 52. At a median follow-up of 49 months, the 4-year actuarial biochemical failure-free survival rate was 84% vs. 60% (p = 0.0016) in favor of the patients with a PSA level after neoadjuvant hormonal deprivation therapy of 1 ng/mL at the beginning of external beam radiotherapy after >/=2 months of neoadjuvant luteinizing hormone-releasing hormone agonist therapy have a significantly greater rate of biochemical failure and lower survival rate compared with those with a PSA level of

Neuroprotective actions of a histidine analogue in models of ischemic stroke.

Histidine is a naturally occurring amino acid with antioxidant properties, which is present in low amounts in tissues throughout the body. We recently synthesized and characterized histidine analogues related to the natural dipeptide carnosine, which selectively scavenge the toxic lipid peroxidation product 4-hydroxynonenal (HNE). We now report that the histidine analogue histidyl hydrazide is effective in reducing brain damage and improving functional outcome in a mouse model of focal ischemic stroke when administered intravenously at a dose of 20 mg/kg, either 30 min before or 60 min and 3 h after the onset of middle cerebral artery occlusion. The histidine analogue also protected cultured rat primary neurons against death induced by HNE, chemical hypoxia, glucose deprivation, and combined oxygen and glucose deprivation. The histidine analogue prevented neuronal apoptosis as indicated by decreased production of cleaved caspase-3 protein. These findings suggest a therapeutic potential for HNE-scavenging histidine analogues in the treatment of stroke and related neurodegenerative conditions.

Chronic child abuse and domestic violence: Children and families with long-term and complex needs

It is estimated that up to one million children may have been exposed to domestic violence in the UK, with significant consequences for their social and emotional development in childhood and later life. At a time when the central and devolved administrations in the UK have developed strategies to tackle domestic violence, this paper reports the findings from a study conducted on children in the child protection system with long-term and complex needs as a result of experiencing domestic violence. The research identifies the characteristics of the children and their families and tracks their careers through the child protection system. The findings indicate that professionals have an awareness of domestic violence, and that younger children with younger parents are most likely to experience prolonged periods in the child protection system. Domestic violence in this context typically co-exists in families experiencing other difficulties such as substance misuse and socio-economic deprivation. In conclusion, the paper argues that Government policy and professional practice should primarily be concerned with assessing the risk that men present, rather than the risk that children are at. By reframing professional interventions, men are more likely to be challenged to accept responsibility for their behaviour and the consequences for their families.

Conflict, Regulation and Marginalisation in the North of Ireland: The Experiences of Children and Young People

Based on primary research and consultations conducted over the last four years in the north of Ireland, this article considers the lives and experiences of children and young people in communities where the legacy of conflict and economic deprivation are most marked. It explores the reality of differential policing in communities where paramilitaries filled the policing deficit during the Conflict through informal 'justice' and punishment beatings. Finally, it considers the potential for change in a climate increasingly hostile towards children and young people, and the realisation of their rights.

Predictable Pathways? Negotiating Risk in the Context of Marginalisation and Social Exclusion

This article is based on ethnographic research with young people living in an area of multiple deprivation in the North-east of England. The young people in this study experience many risk factors associated with social exclusion and future offending. Through in-depth examination of crime within the context of their lives, it will be argued that recent theorisations of youth crime and criminal careers do not fully capture the nature of their offending, the contextual circumstances surrounding it and the differential impact of similar risk factors on their lives. The article concludes by suggesting that not only do such theories detract from the situations of poverty and social exclusion in which young people live but that youth policies informed by them potentially add to their experiences of exclusion and marginalisation.

The Impact of Disrespect on Prisoners’ Aggression: Outcomes of Experimentally Inducing Violence Supportive Cognitions

Self-report research suggests that much violence is triggered by perceived insults and disrespect. This may be particularly true in the context of a prison or another environment of acute deprivation, whereby individuals have little other recourse to means of reputation enhancement. This paper presents the findings of two studies conducted with prisoner volunteers inside a Category C (minimum security) prison in England. In the first study, the authors randomly assigned a sample of 89 prisoners to one of two conditions: the experimental group were asked to discuss times they have been disrespected by authority figures inside and outside the prison; the control group were asked more neutral questions. Both groups then completed several measures of cognitive beliefs, distortions, and hostile attribution biases. None of the measures differed across the two groups except the measure of excuse and justification acceptance. Controlling for other factors, the experimental group endorsed these rationalisations at a significantly higher rate than the control group. This finding suggests that raising the salience of disrespect - reminding prisoners of times they have been made to feel unworthy of consideration - may raise the risk that prisoners will engage in violence by providing prisoners with justifications or excuses for actions they might not otherwise endorse. These findings received some additional validation in the second study, a qualitative analysis of offender accounts of violence and aggression within the prison. Implications for reducing violence within prisons are discussed.