Familial and Bullying Victimisation: The Impact of Early Adversity Within the Home and Peer Settings on Late Adolescence and Adult Psychopathology.

Background: Awareness of adverse childhood experiences and their impact on adult psychopathology primarily focuses on adversities within the home. There is limited insight into the impact of adversities across peer environments. Objective: This study investigates 19 items related to adverse experiences across the home, school and peer environments and their relationship to 12-month and lifetime psychopathology. Data: Secondary analysis of the Ulster University Student Well-being Study. The dataset included completed responses across all selected variables for 729 participants. Method and Results: Latent profile analysis identified a low adversity profile, bullying adversity profile and higher prevalence adversity profile. Regression analysis of the three profiles and demographics variables indicated their impact on adult psychopathology lifetime and 12-month prevalence rates. Conclusion: Schools and HE institutions should acknowledge the impact of childhood adversities. In doing so, it is important to consider the deeper impact of bullying due to its links with psychopathology across the lifespan. Educational institutions should take appropriate steps to mitigate continued exposure as students' progress through the education system.

Chatbots to Support Mental Wellbeing of People Living in Rural Areas: Can User Groups Contribute to Co-design?

Digital technologies such as chatbots can be used in the field of mental health. In particular, chatbots can be used to support citizens living in sparsely populated areas who face problems such as poor access to mental health services, lack of 24/7 support, barriers to engagement, lack of age appropriate support and reductions in health budgets. The aim of this study was to establish if user groups can design content for a chatbot to support the mental wellbeing of individuals in rural areas. University students and staff, mental health professionals and mental health service users (N = 78 total) were recruited to workshops across Northern Ireland, Ireland, Scotland, Finland and Sweden. The findings revealed that participants wanted a positive chatbot that was able to listen, support, inform and build a rapport with users. Gamification could be used within the chatbot to increase user engagement and retention. Content within the chatbot could include validated mental health scales and appropriate response triggers, such as signposting to external resources should the user disclose potentially harmful information or suicidal intent. Overall, the workshop participants identified user needs which can be transformed into chatbot requirements. Responsible design of mental healthcare chatbots should consider what users want or need, but also what chatbot features artificial intelligence can competently facilitate and which features mental health professionals would endorse.

Emergency department and hospital care prior to suicide: A population based case control study.

BACKGROUND: High proportions of those who die by suicide in Northern Ireland (NI) are not known to mental health services, making it important to understand contact with the wider health services. Previous research has not examined the patterns of emergency department (ED) attendance and hospital admissions amongst those who have died by suicide in NI. OBJECTIVES: The study objectives are to examine the relationships between ED attendances, hospital admissions, and death by suicide. METHODS: A case control methodology was used, drawing on routinely collected administrative data on all deaths by suicide in Northern Ireland between 1/1/2012 and 31/12/2015. Each death was matched to 5 live controls, based on age and gender (n = 6630). RESULTS: Death by suicide is associated with a recent ED attendance, with the highest odds for those who attended within the past three months (odds = 3.2, 95% CI = 2.5-4.2). Death by suicide is also associated with recent hospital admission, with the highest odds of death for admission within the past three months (odds = 6.6, 95% CI = 5.2-8.3). The odds of suicide are also higher for those living in a more deprived or urban area. LIMITATIONS: The study is limited to administrative data. CONCLUSIONS: Staff in EDs and hospitals may have a role in suicide prevention. These findings again support the importance of addressing economic deprivation and other area level factors, such as contagion in suicide prevention strategies.

Prescribed pain and mental health medication prior to suicide: A population based case control study.

BACKGROUND: Information about prescription medications prior to death by suicide may help us understand the role of medications, illness and service contact in suicide. AIMS: Through the use of a novel dataset, this study aims to provide an improved understanding of the relationships between pain medication and mental health medication, suicide and area level deprivation. METHODS: Data was included on all deaths by suicide in NI (Northern Ireland) between 1/1/2012 and 31/12/2015. Each death was matched to 5 live controls, based on age (the closest match within 2 years) and gender, resulting in a dataset consisting of 6630 individuals. Four data sources were linked to obtain the final dataset. RESULTS: Suicide linked with and deprivation, with a heightened risk of suicide for 9 months after last prescription of pain medication and for up to two years after last prescription of mental health medication. Odds ratios for death by suicide were strongest among those with the most recent prescriptions (within 0-3 months) (OR for death by suicide = 12.20 amongst those with mental health prescription medication; OR for death by suicide = 3.69 amongst those with pain medication). These figures support the associations between suicide and pain related conditions, and physical health difficulties. Recent prescriptions are particularly important. LIMITATIONS: Received medication prescriptions may not have been taken as recommended. CONCLUSIONS: Contact with a clinician to obtain a prescription may present opportunities for intervention. Suicide assessment (and evidence-based suicide specific treatments) may be important for people who are receiving prescribed medication, particularly for a mental illness.

Factors Associated with Suicide in Four Age Groups: A Population Based Study.

Life events and circumstances leading to death change throughout the life course. In this study, 4 age groups within those who have died by suicide are compared in terms method of suicide, sex, occupation, mental disorders, prior suicide attempts, and life events prior to death. Analyses were based on a database of deaths by suicide and undetermined intent based on data in the Northern Ireland (NI) coronial files from 2005-2011 (N = 1667). Research determined that hanging is very prominent as a method of death within the under-20 age group. Women who die by suicide are more likely to have a known mental disorder than men, and the proportions increase with age group. Relationship difficulties are associated with many of these deaths and particularly for males aged under 40 years. Physical health and life events were more relevant than mental illness per se, in males aged over 61 years. For a sizeable proportion of the cases included in the current database there was no information on the life events prior to death. Understanding the factors associated with suicide across age groups is essential to informing suicide prevention strategy and programs and the development of more nuanced and effective interventions.

Choline on the Move: Perspectives on the Molecular Physiology and Pharmacology of the Presynaptic Choline Transporter.

Genetic, biochemical, physiological, and pharmacological approaches have advanced our understanding of cholinergic biology for over 100 years. High-affinity choline uptake (HACU) was one of the last features of cholinergic signaling to be defined at a molecular level, achieved through the cloning of the choline transporter (CHT, SLC5A7). In retrospect, the molecular era of CHT studies initiated with the identification of hemicholinium-3 (HC-3), a potent, competitive CHT antagonist, though it would take another 30 years before HC-3, in radiolabeled form, was used by Joseph Coyle's laboratory to identify and monitor the dynamics of CHT proteins. Though HC-3 studies provided important insights into CHT distribution and regulation, another 15 years would pass before the structure of CHT genes and proteins were identified, a full decade after the cloning of most other neurotransmitter-associated transporters. The availability of CHT gene and protein probes propelled the development of cell and animal models as well as efforts to gain insights into how human CHT gene variation affects the risk for brain and neuromuscular disorders. Most recently, our group has pursued a broadening of CHT pharmacology, elucidating novel chemical structures that may serve to advance cholinergic diagnostics and medication development. Here we provide a short review of the transformation that has occurred in HACU research and how such advances may promote the development of novel therapeutics.

Isolation and characterization of cell lines with genetically distinct mutations downstream of protein kinase C that result in defective activation-dependent regulation of T cell integrin function.

beta 1-integrins expressed on resting T cells support only minimal adhesion to integrin ligands. T cell activation through multiple stimuli, including phorbol ester treatment and Ab cross-linking of the CD3/TCR complex, results in a rapid and transient switch in integrin function from low to high avidity binding. The exact nature of the intracellular signals involved in this avidity switch remain poorly defined, but the ability of phorbol esters to induce such up-regulation implicates a role for protein kinase C (PKC). We have used a genetic approach to identify factors other than PKC that regulate activation-dependent beta 1-integrin function on T cells. We isolated mutants of the Jurkat T cell line that express beta 1- and beta 2-integrins but do not exhibit increased integrin activity in response to PMA stimulation or CD3 cross-linking. PKC activity appears to be normal in the mutants. One mutation is associated with an altered form of the mitogen-activated protein kinase ERK1 and an inability to produce IL-2. Another mutant with defective integrin function has IL-2 production intact. Complementation analysis verified that these two types of mutants are genetically distinct. Thus, two mutations downstream of PKC have been identified that alter the process of integrin regulation without affecting T cell viability or proliferative capacity. These mutants represent novel reagents for the identification of integrin regulatory factors and indicate possible sites of pharmacologic intervention that could prevent integrin-dependent migration and localization in the process of inflammation, while leaving other T cell functions intact.

Differential activation-dependent regulation of integrin function in cultured human T-leukemic cell lines.

T lymphocytes isolated from human peripheral blood express beta 1 (VLA) and LFA-1 integrins, but strong binding to integrin ligands occurs only after the delivery of an activation stimulus to the T cell. To gain further insight into activation-dependent regulation of integrin function, we have analyzed integrin activity on three different T-leukemic cell lines: Jurkat, CEM, and H9. This analysis shows important mechanistic differences in integrin regulation. First, phorbol ester treatment results in increased beta 1 integrin-dependent adhesion of both Jurkat and CEM cells to fibronectin, but decreased adhesion of H9 cells. Second, certain activation stimuli that upregulate beta 1 integrin activity in peripheral T cells are nonfunctional in these T-cell lines. Third, analysis of a panel of Jurkat mutants lacking surface expression of CD2 and/or CD3 shows that CD2-mediated upregulation of beta 1 integrin activity is dependent on expression of CD3, whereas CD28-mediated upregulation is not dependent on either CD2 or CD3 expression. Fourth, all T-cell lines tested show an inability to adhere to purified ICAM-1 via LFA-1. The selective alterations in integrin regulation in these cell lines relative to peripheral blood T cells provide important insights into the intracellular processes involved in integrin activation.

Very late antigen 4-dependent adhesion and costimulation of resting human T cells by the bacterial beta 1 integrin ligand invasin.

Bacteria and viruses often use the normal biological properties of host adhesion molecules to infect relevant host cells. The outer membrane bacterial protein invasin mediates the attachment of Yersinia pseudotuberculosis to human cells. In vitro studies have shown that four members of the very late antigen (VLA) integrin family of adhesion molecules, VLA-3, VLA-4, VLA-5, and VLA-6, can bind to invasin. Since CD4+ T cells express and use these integrins, we have investigated the interaction of CD4+ T cells with purified invasin. Although VLA integrin-mediated adhesion of T cells to other ligands such as fibronectin does not occur at high levels unless the T cells are activated, resting T cells bind strongly to purified invasin. The binding of resting T cells to invasin requires metabolic activity and an intact cytoskeleton. Although CD4+ T cells express VLA-3, VLA-4, VLA-5, and VLA-6, monoclonal antibody (mAb) blocking studies implicate only VLA-4 as a T cell invasin receptor. Like other integrin ligands, invasin can facilitate T cell proliferative responses induced by a CD3-specific mAb. These results suggest that the nature of the integrin ligand is a critical additional factor that regulates T cell integrin activity, and that direct interactions of T cells with bacterial pathogens such as Yersinia may be relevant to host immune responses to bacterial infection.

Crosslinking of the T cell-specific accessory molecules CD7 and CD28 modulates T cell adhesion.

Regulated adhesion enables T cells to migrate through tissue and transiently interact with an endless succession of cells. Monoclonal antibody (mAb) engagement of the CD3/T cell receptor (TCR) complex results in a rapid and transient augmentation of the adhesion function of LFA-1 and VLA integrin molecules on human T cells. We show in this study that mAb crosslinking of the T cell-specific accessory molecules CD7 and CD28, or treatment with the Ca2+ ionophore A23187, results in the rapid induction of integrin-mediated adhesion to three distinct ligands: the extracellular matrix protein fibronectin, and the cell surface molecules ICAM-1 and VCAM-1. Like CD3 crosslinking, increased adhesion via CD7 and CD28 crosslinking appears to involve both protein kinase C (PKC) and cAMP-dependent protein kinases. In contrast, A23187 induction of adhesion is unaffected by PKC inhibitors. CD7 is preferentially expressed on naive T cells and is unique in being a potent inducer of naive T cell adhesion. Enhanced expression/function of adhesion-inducing molecules thus overcomes relative deficits in adhesion receptor expression.

Analysis of T cell stimulation by superantigen plus major histocompatibility complex class II molecules or by CD3 monoclonal antibody: costimulation by purified adhesion ligands VCAM-1, ICAM-1, but not ELAM-1.

Many ligands of adhesion molecules mediate costimulation of T cell activation. The generality of this emerging concept is best determined by using model systems which exploit physiologically relevant ligands. We developed such an "antigen-specific" model system for stimulation of resting CD4+ human T cells using the following purified ligands: (a) major histocompatibility complex class II plus the superantigen Staphylococcus enterotoxin A, to engage the T cell receptor (TCR); (b) adhesion proteins vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and endothelial leukocyte adhesion molecule 1 (ELAM-1), to provide potential cell surface costimulatory signals; and (c) recombinant interleukin 1 beta (rIL-1 beta)/rIL-6 as costimulatory cytokines. In this biochemically defined system, we find that resting CD4+ T cells require costimulation in order to respond to TCR engagement. This costimulation can be provided by VCAM-1 or ICAM-1; however adhesion alone is not sufficient since ELAM-1 mediates adhesion but not costimulation. The cytokines IL-1 beta and IL-6 by themselves cannot mediate costimulation, but augment the adhesion ligand-mediated costimulation. Direct comparison with the model of TCR/CD3 engagement by CD3 monoclonal antibody demonstrated comparable costimulatory requirements in both systems, thereby authenticating the commonly used CD3 model. The costimulation mediated by the activation-dependent interaction of the VLA-4 and LFA-1 integrins with their respective ligands VCAM-1 and ICAM-1 leads to increased IL-2R alpha (CD25) expression and proliferation in both CD45RA+ CD4+ and CD45RO+ CD4+ T cells. The integrins also regulate the secretion of IL-2, IL-4, and granulocyte/macrophage colony-stimulating factor. In contrast the activation-independent adhesion of CD4+ T cell to ELAM-1 molecules does not lead to T cell stimulation as measured by proliferation, IL-2R alpha expression, or cytokine release. These findings imply that adhesion per se is not sufficient for costimulation, but rather that the costimulation conferred by the VLA-4/VCAM-1 and LFA-1/ICAM-1 interactions reflects specialized accessory functions of these integrin pathways. The new finding that VLA-4/VCAM-1 mediates costimulation adds significance to observations that VCAM-1 is expressed on a unique set of potential antigen-presenting cells in vivo.