Microglial inflammation in genome instability: A neurodegenerative perspective.

The maintenance of genome stability is crucial for cell homeostasis and tissue integrity. Numerous human neuropathologies display chronic inflammation in the central nervous system, set against a backdrop of genome instability, implying a close interplay between the DNA damage and immune responses in the context of neurological disease. Dissecting the molecular mechanisms of this crosstalk is essential for holistic understanding of neuroinflammatory pathways in genome instability disorders. Non-neuronal cell types, specifically microglia, are major drivers of neuroinflammation in the central nervous system with neuro-protective and -toxic capabilities. Here, we discuss how persistent DNA damage affects microglial homeostasis, zooming in on the cytosolic DNA sensing cGAS-STING pathway and the downstream inflammatory response, which can drive neurotoxic outcomes in the context of genome instability.

cGAS-STING signalling regulates microglial chemotaxis in genome instability.

Defective DNA damage signalling and repair is a hallmark of age-related and genetic neurodegenerative disease. One mechanism implicated in disease progression is DNA damage-driven neuroinflammation, which is largely mediated by tissue-resident immune cells, microglia. Here, we utilise human microglia-like cell models of persistent DNA damage and ATM kinase deficiency to investigate how genome instability shapes microglial function. We demonstrate that upon DNA damage the cytosolic DNA sensing cGAS-STING axis drives chronic inflammation and a robust chemokine response, exemplified by production of CCL5 and CXCL10. Transcriptomic analyses revealed that cell migratory pathways were highly enriched upon IFN-ß treatment of human iPSC-derived microglia, indicating that the chemokine response to DNA damage mirrors type I interferon signalling. Furthermore, we find that STING deletion leads to a defect in microglial chemotaxis under basal conditions and upon ATM kinase loss. Overall, this work provides mechanistic insights into cGAS-STING-dependent neuroinflammatory mechanisms and consequences of genome instability in the central nervous system.

Persistent DNA damage associated with ATM kinase deficiency promotes microglial dysfunction.

The autosomal recessive genome instability disorder Ataxia-telangiectasia, caused by mutations in ATM kinase, is characterized by the progressive loss of cerebellar neurons. We find that DNA damage associated with ATM loss results in dysfunctional behaviour of human microglia, immune cells of the central nervous system. Microglial dysfunction is mediated by the pro-inflammatory RELB/p52 non-canonical NF-κB transcriptional pathway and leads to excessive phagocytic clearance of neuronal material. Activation of the RELB/p52 pathway in ATM-deficient microglia is driven by persistent DNA damage and is dependent on the NIK kinase. Activation of non-canonical NF-κB signalling is also observed in cerebellar microglia of individuals with Ataxia-telangiectasia. These results provide insights into the underlying mechanisms of aberrant microglial behaviour in ATM deficiency, potentially contributing to neurodegeneration in Ataxia-telangiectasia.

A Feasibility Cluster Randomized Controlled Trial of Individual Placement and Support (IPS) for Patients With Offending Histories.

Objective: To examine the feasibility of conducting a fully powered randomized controlled trial (RCT) of Individual Placement and Support (IPS). IPS is a form of supported employment which aims to put people into open employment quickly and in accordance with their preferences. It is delivered by employment specialists collocated within clinical teams, and provides time unlimited support for the individual and their employer, along with welfare benefits counselling. Method: A feasibility cluster RCT of treatment as usual (TAU) plus IPS versus TAU alone was conducted over 12 months among patients with offending histories in a community forensic setting in the UK. The feasibility criteria were to achieve 50% recruitment rate; 50% completion rate for IPS; 50% completion rate of all outcome measures; and 80% acceptability rating for IPS. The primary efficacy outcome was the proportion of people in open employment at 12 months. The secondary outcomes were other vocational and educational activities; Brief Psychiatric Rating Scale; Rosenberg's Self-esteem Scale; Client Service Receipt Inventory; quality of life using the SF12-v2 and EQ5-D3; Social Functioning Questionnaire; Work Limitation Questionnaire; and reoffending. Results: Participants' mean age was 39.2 years. The majority were male (88.9), White British (72.2), and single (72.2%). Over 72% had no higher qualification beyond secondary education; mean years in education was 10.4. Over one third had schizophrenia, one fifth had depression, and the rest had personality disorder as their primary diagnosis. Participants had a lifetime average of 7.5 convictions for 15.5 offences. The recruitment rate of all referrals was 38.3% (IPS n = 11; TAU n = 7). Completion rate for IPS was 54.5, with 45.5% acceptability rating. Completion rates for outcome measures for the groups at baseline and 12 months ranged from 22.2 to 100%. The proportion of people in open employment at 12 months were 9.1 and 0% for IPS and TAU respectively. Conclusion: It is not feasible to conduct a full RCT of IPS in community forensic settings in the UK owing to recruitment and retention difficulties. Conducting a trial of this kind requires a large pool of patients from multiple sites and longer IPS implementation and recruitment periods than those of this study. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02442193.

Characteristics and Pathways of Long-Stay Patients in High and Medium Secure Settings in England; A Secondary Publication From a Large Mixed-Methods Study.

Background: Many patients experience extended stays within forensic care, but the characteristics of long-stay patients are poorly understood. Aims: To describe the characteristics of long-stay patients in high and medium secure settings in England. Method: Detailed file reviews provided clinical, offending and risk data for a large representative sample of 401 forensic patients from 2 of the 3 high secure settings and from 23 of the 57 medium secure settings in England on 1 April 2013. The threshold for long-stay status was defined as 5 years in medium secure care or 10 years in high secure care, or 15 years in a combination of high and medium secure settings. Results: 22% of patients in high security and 18% in medium security met the definition for "long-stay," with 20% staying longer than 20 years. Of the long-stay sample, 58% were violent offenders (22% both sexual and violent), 27% had been convicted for violent or sexual offences whilst in an institutional setting, and 26% had committed a serious assault on staff in the last 5 years. The most prevalent diagnosis was schizophrenia (60%) followed by personality disorder (47%, predominantly antisocial and borderline types); 16% were categorised as having an intellectual disability. Overall, 7% of the long-stay sample had never been convicted of any offence, and 16.5% had no index offence prompting admission. Although some significant differences were found between the high and medium secure samples, there were more similarities than contrasts between these two levels of security. The treatment pathways of these long-stay patients involved multiple moves between settings. An unsuccessful referral to a setting of lower security was recorded over the last 5 years for 33% of the sample. Conclusions: Long-stay patients accounted for one fifth of the forensic inpatient population in England in this representative sample. A significant proportion of this group remain unsettled. High levels of personality pathology and the risk of assaults on staff and others within the care setting are likely to impact on treatment and management. Further research into the treatment pathways of longer stay patients is warranted to understand the complex trajectories of this group.

The development of an in vitro Pig-a assay in L5178Y cells.

A recent flow cytometry-based in vivo mutagenicity assay involves the hemizygous phosphatidylinositol class A (Pig-a) gene. Pig-a forms the catalytic subunit of N-acetylglucosaminyltransferase required for glycophosphatidylinositol (GPI) anchor biosynthesis. Mutations in Pig-a prevent GPI-anchor synthesis resulting in loss of cell-surface GPI-linked proteins. The aim of the current study was to develop and validate an in vitro Pig-a assay in L5178Y mouse lymphoma cells. Ethyl methanesulfonate (EMS)-treated cells (186.24-558.72 µg/ml; 24 h) were used for method development and antibodies against GPI-linked CD90.2 and stably expressed CD45 were used to determine GPI-status by flow cytometry. Antibody concentration and incubation times were optimised (0.18 µg/ml, 30 min, 4 °C) and Zombie Violet™ (viability marker; 0.5%, 30 min, RT) was included. The optimum phenotypic expression period was 8 days. The low background mutation frequency of GPI-deficiency [GPI(-)] in L5178Y cells (0.1%) constitutes a rare event, thus flow cytometry acquisition parameters were optimised; 104 cells were measured at medium flow rate to ensure a CV ≤ 30%. Spiking known numbers of GPI(-) cells into a wild-type population gave high correlation between measured and spiked numbers (R2 0.999). We applied the in vitro Pig-a assay to a selection of well-validated genotoxic and non-genotoxic compounds. EMS, N-ethyl-N-nitrosourea and 4-nitroquinoline-N-oxide dose dependently increased numbers of GPI(-) cells, while etoposide, mitomycin C, and a bacterial-specific mutagen did not. Cycloheximide and sodium chloride were negative. Sanger sequencing revealed Pig-a mutations in the GPI(-) clones. In conclusion, this in vitro Pig-a assay could complement the in vivo version, and follow up weak Ames positives and late-stage human metabolites or impurities.

Effectiveness of work skills programmes for offenders with mental disorders: A systematic review.

BACKGROUND: Academic literature and government initiatives have emphasised the importance of work as a means of improving health and reducing reoffending among offenders with mental disorders. Whilst a number of work skills programmes have shown promise for offenders more generally, evaluation of evidence for their effectiveness for those with a mental disorder is lacking, particularly in relation to improving employment outcomes. AIMS: To assess the evidence on the effectiveness of work skills programmes for mentally disordered offenders. METHOD: A systematic review of the literature was conducted by searching the following databases: PsycINFO, CINAHL, Cochrane Library (Trials Register), Embase and Medline, using search terms which included Work Skills Programme*, Offend* and Mental*. Any empirical comparison study of work skills programmes was included in this review. The primary outcome was employment. Secondary outcomes included employment outcomes, reoffending, education, mental state, substance misuse, global functioning, quality of life, acceptability, leaving the study early and cost effectiveness or other economic outcomes. RESULTS: Six articles met the inclusion criteria. Collectively they provided limited evidence that work skills programmes increase the likelihood of people with mental disorder who are offenders obtaining employment in the short term, but there are insufficient studies to determine the long-term impact of work skills programmes. CONCLUSIONS: There is modest evidence to support inclusion of specific work skills programmes in the treatment of offenders with mental disorder. Future studies should be of theoretically driven programmes, such as Individual Placement Support (IPS), and use a standard set of relevant outcome measures and long enough follow-up for testing the effectiveness of any programme on engagement in competitive, paid employment as, even if skilled, offenders with mental disorder must constitute a hard to place group. Copyright © 2015 John Wiley & Sons, Ltd.

Experience-dependent plasticity in the mushroom bodies of the solitary bee Osmia lignaria (Megachilidae).

All members of the solitary bee species Osmia lignaria (the orchard bee) forage upon emergence from their natal nest cell. Conversely, in the honey bee, days-to-weeks of socially regulated behavioral development precede the onset of foraging. The social honey bee's behavioral transition to foraging is accompanied by neuroanatomical changes in the mushroom bodies, a region of the insect brain implicated in learning. If these changes were general adaptations to foraging, they should also occur in the solitary orchard bee. Using unbiased stereological methods, we estimated the volume of the major compartments of the mushroom bodies, the neuropil and Kenyon cell body region, in adult orchard bees. We compared the mushroom bodies of recently emerged bees with mature bees that had extensive foraging experience. To separate effects of general maturation from field foraging, some orchard bees were confined to a cage indoors. The mushroom body neuropil of experienced field foragers was significantly greater than that of both recently emerged and mature caged orchard bees, suggesting that, like the honey bee, this increase is driven by outdoor foraging experience. Unlike the honey bee, where increases in the ratio of neuropil to Kenyon cell region occur in the worker after emerging from the hive cell, the orchard bee emerged from the natal nest cell with a ratio that did not change with maturation and was comparable to honey-bee foragers. These results suggest that a common developmental endpoint may be reached via different development paths in social and solitary species of foraging bees.

Encephalitis in children: a clinical neuropsychology perspective.

Encephalitis is an inflammation of brain tissue that can result from a number of viruses and can be contracted at any age, with prevalence in children exceeding adult incidence. In order to illustrate specific cognitive, behavioural and service provision issues related to post-encephalitis rehabilitation of children, this paper examines the pattern of referrals to a specialist regional paediatric neuropsychology service in the United Kingdom. Three case vignettes are presented to demonstrate the wide range of presentations encountered in our service ranging from mild (10%) to moderate (65%) and severe (25%) impairment with 80% of referrals relating to behaviour and educational concerns. On average 13 new referrals are received annually resulting in a cumulative case-load due to the need for serial assessment. The implications for patient care are discussed.