Differential gene expression in multiple neurological, inflammatory and connective tissue pathways in a spontaneous model of human small vessel stroke

Aims: Cerebral small vessel disease (SVD) causes a fifth of all strokes plus diffuse brain damage leading to cognitive decline, physical disabilities and dementia. The aetiology and pathogenesis of SVD are unknown, but largely attributed to hypertension or microatheroma. Methods: We used the spontaneously hypertensive stroke-prone rat (SHRSP), the closest spontaneous experimental model of human SVD, and age-matched control rats kept under identical, non-salt-loaded conditions, to perform a blinded analysis of mRNA microarray, qRT-PCRand pathway analysis in two brain regions (frontal and midcoronal) commonly affected by SVD in the SHRSP at age five, 16 and 21 weeks. Results: We found gene expression abnormalities, with fold changes ranging from 2.5 to 59 for the 10 most differentially expressed genes, related to endothelial tight junctions (reduced), nitric oxide bioavailability (reduced), myelination (impaired), glial and microglial activity (increased), matrix proteins (impaired), vascular reactivity (impaired) and albumin (reduced), consistent with protein expression defects in the same rats. All were present at age 5 weeks thus pre-dating blood pressure elevation. ‘Neurological’ and ‘inflammatory’ pathways were more affected than ‘vascular’ functional pathways. Conclusions: This set of defects, although individually modest, when acting in combination could explain the SHRSP's susceptibility to microvascular and brain injury, compared with control rats. Similar combined, individually modest, but multiple neurovascular unit defects, could explain susceptibility to spontaneous human SVD

Severe mental illness and mortality and coronary revascularisation following a myocardial infarction:a retrospective cohort study

Background: Severe mental illness (SMI), comprising schizophrenia, bipolar disorder and major depression, is associated with higher myocardial infarction (MI) mortality but lower coronary revascularisation rates. Previous studies have largely focused on schizophrenia, with limited information on bipolar disorder and major depression, long-term mortality or the effects of either sociodemographic factors or year of MI. We investigated the associations between SMI and MI prognosis and how these differed by age at MI, sex and year of MI. Methods: We conducted a national retrospective cohort study, including adults with a hospitalised MI in Scotland between 1991 and 2014. We ascertained previous history of schizophrenia, bipolar disorder and major depression from psychiatric and general hospital admission records. We used logistic regression to obtain odds ratios adjusted for sociodemographic factors for 30-day, 1-year and 5-year mortality, comparing people with each SMI to a comparison group without a prior hospital record for any mental health condition. We used Cox regression to analyse coronary revascularisation within 30 days, risk of further MI and further vascular events (MI or stroke). We investigated associations for interaction with age at MI, sex and year of MI. Results: Among 235,310 people with MI, 923 (0.4%) had schizophrenia, 642 (0.3%) had bipolar disorder and 6239 (2.7%) had major depression. SMI was associated with higher 30-day, 1-year and 5-year mortality and risk of further MI and stroke. Thirty-day mortality was higher for schizophrenia (OR 1.95, 95% CI 1.64–2.30), bipolar disorder (OR 1.53, 95% CI 1.26–1.86) and major depression (OR 1.31, 95% CI 1.23–1.40). Odds ratios for 1-year and 5-year mortality were larger for all three conditions. Revascularisation rates were lower in schizophrenia (HR 0.57, 95% CI 0.48–0.67), bipolar disorder (HR 0.69, 95% CI 0.56–0.85) and major depression (HR 0.78, 95% CI 0.73–0.83). Mortality and revascularisation disparities persisted from 1991 to 2014, with absolute mortality disparities more apparent for MIs that occurred around 70 years of age, the overall mean age of MI. Women with major depression had a greater reduction in revascularisation than men with major depression. Conclusions: There are sustained SMI disparities in MI intervention and prognosis. There is an urgent need to understand and tackle the reasons for these disparities

Conducting public involvement in dementia research:The contribution of the European Working Group of People with Dementia to the ROADMAP project

Background Dementia outcomes include memory loss, language impairment, reduced quality of life and personality changes. Research suggests that outcomes selected for dementia clinical trials might not be the most important to people affected. Objective One of the goals of the ‘Real world Outcomes across the Alzheimer's Disease spectrum for better care: Multi‐modal data Access Platform’ (ROADMAP) project was to identify important outcomes from the perspective of people with dementia and their caregivers. We review how ROADMAP's Public Involvement shaped the programme, impacted the research process and gave voice to people affected by dementia. Design The European Working Group of People with Dementia (EWGPWD) were invited to participate. In‐person consultations were held with people with dementia and caregivers, with advance information provided on ROADMAP activities. Constructive criticism of survey content, layout and accessibility was sought, as were views and perspectives on terminology and key concepts around disease progression. Results The working group provided significant improvements to survey accessibility and acceptability. They promoted better understanding of concepts around disease progression and how researchers might approach measuring and interpreting findings. They effectively expressed difficult concepts through real‐world examples. Conclusions The role of the EWGPWD in ROADMAP was crucial, and its impact was highly influential. Involvement from the design stage helped shape the ethos of the programme and ultimately its meaningfulness. Public contribution People with dementia and their carers were involved through structured consultations and invited to provide feedback on project materials, methods and insight into terminology and relevant concepts

The Edinburgh CT and genetic diagnostic criteria for lobar intracerebral haemorrhage with cerebral amyloid angiopathy: model development and diagnostic test accuracy study

BACKGROUND: Identification of lobar spontaneous intracerebral haemorrhage associated with cerebral amyloid angiopathy (CAA) is important because it is associated with a higher risk of recurrent intracerebral haemorrhage than arteriolosclerosis-associated intracerebral haemorrhage. We aimed to develop a prediction model for the identification of CAA-associated lobar intracerebral haemorrhage using CT features and genotype.METHODS: We identified adults with first-ever intracerebral haemorrhage diagnosed by CT, who died and underwent research autopsy as part of the Lothian IntraCerebral Haemorrhage, Pathology, Imaging and Neurological Outcome (LINCHPIN) study, a prospective, population-based, inception cohort. We determined APOE genotype and radiologists rated CT imaging appearances. Radiologists were not aware of clinical, genetic, and histopathological features. A neuropathologist rated brain tissue for small vessel diseases, including CAA, and was masked to clinical, radiographic, and genetic features. We used CT and APOE genotype data in a logistic regression model, which we internally validated using bootstrapping, to predict the risk of CAA-associated lobar intracerebral haemorrhage, derive diagnostic criteria, and estimate diagnostic accuracy.FINDINGS: Among 110 adults (median age 83 years [IQR 76-87], 49 [45%] men) included in the LINCHPIN study between June 1, 2010 and Feb 10, 2016, intracerebral haemorrhage was lobar in 62 (56%) participants, deep in 41 (37%), and infratentorial in seven (6%). Of the 62 participants with lobar intracerebral haemorrhage, 36 (58%) were associated with moderate or severe CAA compared with 26 (42%) that were associated with absent or mild CAA, and were independently associated with subarachnoid haemorrhage (32 [89%] of 36 vs 11 [42%] of 26; p=0·014), intracerebral haemorrhage with finger-like projections (14 [39%] of 36 vs 0; p=0·043), and APOE ɛ4 possession (18 [50%] of 36 vs 2 [8%] of 26; p=0·0020). A prediction model for CAA-associated lobar intracerebral haemorrhage using these three variables had excellent discrimination (c statistic 0·92, 95% CI 0·86-0·98), confirmed by internal validation. For the rule-out criteria, neither subarachnoid haemorrhage nor APOE ɛ4 possession had 100% sensitivity (95% CI 88-100). For the rule-in criteria, subarachnoid haemorrhage and either APOE ɛ4 possession or finger-like projections had 96% specificity (95% CI 78-100).INTERPRETATION: The CT and APOE genotype prediction model for CAA-associated lobar intracerebral haemorrhage shows excellent discrimination in this cohort, but requires external validation. The Edinburgh rule-in and rule-out diagnostic criteria might inform prognostic and therapeutic decisions that depend on identification of CAA-associated lobar intracerebral haemorrhage.FUNDING: UK Medical Research Council, The Stroke Association, and The Wellcome Trust.</p

The Formation of Brown Dwarfs as Ejected Stellar Embryos

We conjecture that brown dwarfs are substellar objects because they have been ejected from small newborn multiple systems which have decayed in dynamical interactions. In this view, brown dwarfs are stellar embryos for which the star formation process was aborted before the hydrostatic cores could build up enough mass to eventually start hydrogen burning. The disintegration of a small multiple system is a stochastic process, which can be described only in terms of the half-life of the decay. A stellar embryo competes with its siblings in order to accrete infalling matter, and the one that grows slowest is most likely to be ejected. With better luck, a brown dwarf would therefore have become a normal star. This interpretation of brown dwarfs readily explains the rarity of brown dwarfs as companions to normal stars (aka the ``brown dwarf desert''), the absence of wide brown dwarf binaries, and the flattening of the low mass end of the initial mass function. Possible observational tests of this scenario include statistics of brown dwarfs near Class 0 sources, and the kinematics of brown dwarfs in star forming regions while they still retain a kinematic signature of their expulsion. Because the ejection process limits the amount of gas brought along in a disk, it is predicted that substellar equivalents to the classical T Tauri stars should be very rare.Comment: 8 pages, 1 figure, Accepted by the Astronomical Journa

Low-Dose Nitric Oxide as Targeted Anti-biofilm Adjunctive Therapy to Treat Chronic Pseudomonas aeruginosa Infection in Cystic Fibrosis

© 2017 The Authors Despite aggressive antibiotic therapy, bronchopulmonary colonization by Pseudomonas aeruginosa causes persistent morbidity and mortality in cystic fibrosis (CF). Chronic P. aeruginosa infection in the CF lung is associated with structured, antibiotic-tolerant bacterial aggregates known as biofilms. We have demonstrated the effects of non-bactericidal, low-dose nitric oxide (NO), a signaling molecule that induces biofilm dispersal, as a novel adjunctive therapy for P. aeruginosa biofilm infection in CF in an ex vivo model and a proof-of-concept double-blind clinical trial. Submicromolar NO concentrations alone caused disruption of biofilms within ex vivo CF sputum and a statistically significant decrease in ex vivo biofilm tolerance to tobramycin and tobramycin combined with ceftazidime. In the 12-patient randomized clinical trial, 10 ppm NO inhalation caused significant reduction in P. aeruginosa biofilm aggregates compared with placebo across 7 days of treatment. Our results suggest a benefit of using low-dose NO as adjunctive therapy to enhance the efficacy of antibiotics used to treat acute P. aeruginosa exacerbations in CF. Strategies to induce the disruption of biofilms have the potential to overcome biofilm-associated antibiotic tolerance in CF and other biofilm-related diseases

The REstart or STop Antithrombotics Randomised Trial (RESTART) after stroke due to intracerebral haemorrhage: study protocol for a randomised controlled trial

Background For adults surviving stroke due to spontaneous (non-traumatic) intracerebral haemorrhage (ICH) who had taken an antithrombotic (i.e. anticoagulant or antiplatelet) drug for the prevention of vaso-occlusive disease before the ICH, it is unclear whether starting antiplatelet drugs results in an increase in the risk of recurrent ICH or a beneficial net reduction of all serious vascular events compared to avoiding antiplatelet drugs. Methods/design The REstart or STop Antithrombotics Randomised Trial (RESTART) is an investigator-led, randomised, open, assessor-blind, parallel-group, randomised trial comparing starting versus avoiding antiplatelet drugs for adults surviving antithrombotic-associated ICH at 122 hospital sites in the United Kingdom. RESTART uses a central, web-based randomisation system using a minimisation algorithm, with 1:1 treatment allocation to which central research staff are masked. Central follow-up includes annual postal or telephone questionnaires to participants and their general (family) practitioners, with local provision of information about adverse events and outcome events. The primary outcome is recurrent symptomatic ICH. The secondary outcomes are: symptomatic haemorrhagic events; symptomatic vaso-occlusive events; symptomatic stroke of uncertain type; other fatal events; modified Rankin Scale score; adherence to antiplatelet drug(s). The magnetic resonance imaging (MRI) sub-study involves the conduct of brain MRI according to a standardised imaging protocol before randomisation to investigate heterogeneity of treatment effect according to the presence of brain microbleeds. Recruitment began on 22 May 2013. The target sample size is at least 720 participants in the main trial (at least 550 in the MRI sub-study). Discussion Final results of RESTART will be analysed and disseminated in 2019. Trial registration ISRCTN71907627 (www.isrctn.com/ISRCTN71907627). Prospectively registered on 25 April 2013

Comparison of Two Quantitative Methods of Discerning Airspace Enlargement in Smoke-Exposed Mice

In this work, we compare two methods for evaluating and quantifying pulmonary airspace enlargement in a mouse model of chronic cigarette smoke exposure. Standard stereological sample preparation, sectioning, and imaging of mouse lung tissues were performed for semi-automated acquisition of mean linear intercept (Lm) data. After completion of the Lm measurements, D2, a metric of airspace enlargement, was measured in a blinded manner on the same lung images using a fully automated technique developed in-house. An analysis of variance (ANOVA) shows that although Lm was able to separate the smoke-exposed and control groups with statistical significance (p = 0.034), D2 was better able to differentiate the groups (p<0.001) and did so without any overlap between the control and smoke-exposed individual animal data. In addition, the fully automated implementation of D2 represented a time savings of at least 24x over semi-automated Lm measurements. Although D2 does not provide 3D stereological metrics of airspace dimensions as Lm does, results show that it has higher sensitivity and specificity for detecting the subtle airspace enlargement one would expect to find in mild or early stage emphysema. Therefore, D2 may serve as a more accurate screening measure for detecting early lung disease than Lm