an experimental approach with a trauma film paradigm

Background Intrusive memories of traumatic events are a core feature of post- traumatic stress disorder but little is known about the neurobiological formation of intrusions. The aim of this study was to determine whether the activity of the noradrenergic system during an intrusion-inducing stressor would influence subsequent intrusive memories. Method We conducted an experimental, double-blind, placebo-controlled study in 118 healthy women. Participants received a single dose of either 10 mg yohimbine, stimulating noradrenergic activity, or 0.15 mg clonidine, inhibiting noradrenergic activity, or placebo. Subsequently, they watched an established trauma film which induced intrusions. The number of consecutive intrusions resulting from the trauma film, the vividness of the intrusions, and the degree of distress evoked by the intrusions were assessed during the following 4 days. Salivary cortisol and α-amylase were collected before and after the trauma film. Results A significant time × treatment interaction for the number of intrusions and the vividness of intrusions indicated a different time course of intrusions depending on treatment. Post-hoc tests revealed a delayed decrease of intrusions and a delayed decrease of intrusion vividness after the trauma film in the yohimbine group compared with the clonidine and placebo groups. Furthermore, after yohimbine administration, a significant increase in salivary cortisol levels was observed during the trauma film. Conclusions Our findings indicate that pharmacological activation of the noradrenergic system during an emotionally negative event makes an impact on consecutive intrusive memories and their vividness in healthy women. The noradrenergic system seems to be involved in the formation of intrusive memories

East Midlands Research into Ageing Network (EMRAN) Discussion Paper Series

Academic geriatric medicine in Leicester . There has never been a better time to consider joining us. We have recently appointed a Professor in Geriatric Medicine, alongside Tom Robinson in stroke and Victoria Haunton, who has just joined as a Senior Lecturer in Geriatric Medicine. We have fantastic opportunities to support students in their academic pursuits through a well-established intercalated BSc programme, and routes on through such as ACF posts, and a successful track-record in delivering higher degrees leading to ACL post. We collaborate strongly with Health Sciences, including academic primary care. See below for more detail on our existing academic set-up. Leicester Academy for the Study of Ageing We are also collaborating on a grander scale, through a joint academic venture focusing on ageing, the ‘Leicester Academy for the Study of Ageing’ (LASA), which involves the local health service providers (acute and community), De Montfort University; University of Leicester; Leicester City Council; Leicestershire County Council and Leicester Age UK. Professors Jayne Brown and Simon Conroy jointly Chair LASA and have recently been joined by two further Chairs, Professors Kay de Vries and Bertha Ochieng. Karen Harrison Dening has also recently been appointed an Honorary Chair. LASA aims to improve outcomes for older people and those that care for them that takes a person-centred, whole system perspective. Our research will take a global perspective, but will seek to maximise benefits for the people of Leicester, Leicestershire and Rutland, including building capacity. We are undertaking applied, translational, interdisciplinary research, focused on older people, which will deliver research outcomes that address domains from: physical/medical; functional ability, cognitive/psychological; social or environmental factors. LASA also seeks to support commissioners and providers alike for advice on how to improve care for older people, whether by research, education or service delivery. Examples of recent research projects include: ‘Local History Café’ project specifically undertaking an evaluation on loneliness and social isolation; ‘Better Visits’ project focused on improving visiting for family members of people with dementia resident in care homes; and a study on health issues for older LGBT people in Leicester. Clinical Geriatric Medicine in Leicester We have developed a service which recognises the complexity of managing frail older people at the interface (acute care, emergency care and links with community services). There are presently 17 consultant geriatricians supported by existing multidisciplinary teams, including the largest complement of Advance Nurse Practitioners in the country. Together we deliver Comprehensive Geriatric Assessment to frail older people with urgent care needs in acute and community settings. The acute and emergency frailty units – Leicester Royal Infirmary This development aims at delivering Comprehensive Geriatric Assessment to frail older people in the acute setting. Patients are screened for frailty in the Emergency Department and then undergo a multidisciplinary assessment including a consultant geriatrician, before being triaged to the most appropriate setting. This might include admission to in-patient care in the acute or community setting, intermediate care (residential or home based), or occasionally other specialist care (e.g. cardiorespiratory). Our new emergency department is the county’s first frail friendly build and includes fantastic facilities aimed at promoting early recovering and reducing the risk of hospital associated harms. There is also a daily liaison service jointly run with the psychogeriatricians (FOPAL); we have been examining geriatric outreach to oncology and surgery as part of an NIHR funded study. We are home to the Acute Frailty Network, and those interested in service developments at the national scale would be welcome to get involved. Orthogeriatrics There are now dedicated hip fracture wards and joint care with anaesthetists, orthopaedic surgeons and geriatricians. There are also consultants in metabolic bone disease that run clinics. Community work Community work will consist of reviewing patients in clinic who have been triaged to return to the community setting following an acute assessment described above. Additionally, primary care colleagues refer to outpatients for sub-acute reviews. You will work closely with local GPs with support from consultants to deliver post-acute, subacute, intermediate and rehabilitation care services. Stroke Medicine 24/7 thrombolysis and TIA services. The latter is considered one of the best in the UK and along with the high standard of vascular surgery locally means one of the best performances regarding carotid intervention

The Interferon Response Inhibits HIV Particle Production by Induction of TRIM22

Treatment of human cells with Type 1 interferons restricts HIV replication. Here we report that the tripartite motif protein TRIM22 is a key mediator. We used transcriptional profiling to identify cellular genes that were induced by interferon treatment and identified TRIM22 as one of the most strongly up-regulated genes. We confirmed, as in previous studies, that TRIM22 over-expression inhibited HIV replication. To assess the role of TRIM22 expressed under natural inducing conditions, we compared the effects of interferon in cells depleted for TRIM22 using RNAi and found that HIV particle release was significantly increased in the knockdown, implying that TRIM22 acts as a natural antiviral effector. Further studies showed that TRIM22 inhibited budding of virus-like particles containing Gag only, indicating that Gag was the target of TRIM22. TRIM22 did not block the release of MLV or EIAV Gag particles. Inhibition was associated with diffuse cytoplasmic staining of HIV Gag rather than accumulation at the plasma membrane, suggesting TRIM22 disrupts proper trafficking. Mutational analyses of TRIM22 showed that the catalytic amino acids Cys15 and Cys18 of the RING domain are required for TRIM22 antiviral activity. These data disclose a pathway by which Type 1 interferons obstruct HIV replication

T Cell-Dependence of Lassa Fever Pathogenesis

Lassa virus (LASV), the causative agent of Lassa fever (LF), is endemic in West Africa, accounting for substantial morbidity and mortality. In spite of ongoing research efforts, LF pathogenesis and mechanisms of LASV immune control remain poorly understood. While normal laboratory mice are resistant to LASV, we report that mice expressing humanized instead of murine MHC class I (MHC-I) failed to control LASV infection and develop severe LF. Infection of MHC-I knockout mice confirmed a key role for MHC-I-restricted T cell responses in controlling LASV. Intriguingly we found that T cell depletion in LASV-infected HHD mice prevented disease, irrespective of high-level viremia. Widespread activation of monocyte/macrophage lineage cells, manifest through inducible NO synthase expression, and elevated IL-12p40 serum levels indicated a systemic inflammatory condition. The absence of extensive monocyte/macrophage activation in T cell-depleted mice suggested that T cell responses contribute to deleterious innate inflammatory reactions and LF pathogenesis. Our observations in mice indicate a dual role for T cells, not only protecting from LASV, but also enhancing LF pathogenesis. The possibility of T cell-driven enhancement and immunopathogenesis should be given consideration in future LF vaccine development

Inferior frontal sulcal hyperintensities on brain MRI are associated with amyloid positivity beyond Age—results from the multicentre observational DELCODE study

Inferior frontal sulcal hyperintensities (IFSHs) on fluid-attenuated inversion recovery (FLAIR) sequences have been proposed to be indicative of glymphatic dysfunction. Replication studies in large and diverse samples are nonetheless needed to confirm them as an imaging biomarker. We investigated whether IFSHs were tied to Alzheimer’s disease (AD) pathology and cognitive performance. We used data from 361 participants along the AD continuum, who were enrolled in the multicentre DELCODE study. The IFSHs were rated visually based on FLAIR magnetic resonance imaging. We performed ordinal regression to examine the relationship between the IFSHs and cerebrospinal fluid-derived amyloid positivity and tau positivity (Aβ42/40 ratio ≤ 0.08; pTau181 ≥ 73.65 pg/mL) and linear regression to examine the relationship between cognitive performance (i.e., Mini-Mental State Examination and global cognitive and domain-specific performance) and the IFSHs. We controlled the models for age, sex, years of education, and history of hypertension. The IFSH scores were higher in those participants with amyloid positivity (OR: 1.95, 95% CI: 1.05–3.59) but not tau positivity (OR: 1.12, 95% CI: 0.57–2.18). The IFSH scores were higher in older participants (OR: 1.05, 95% CI: 1.00–1.10) and lower in males compared to females (OR: 0.44, 95% CI: 0.26–0.76). We did not find sufficient evidence linking the IFSH scores with cognitive performance after correcting for demographics and AD biomarker positivity. IFSHs may reflect the aberrant accumulation of amyloid β beyond age