Salford, United Kingdom
Salford, United Kingdom

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Di Napoli M.,San Camillo Of Lellis General Hospital | Di Napoli M.,Center for Cardiovascular Medicine and Cerebrovascular Disease Prevention | Godoy D.A.,Neurocritical Care Unit | Campi V.,Central Laboratory | And 10 more authors.
Neurology | Year: 2012

Objectives: We examined the C-reactive protein (CRP) response after spontaneous intracerebral hemorrhage (sICH) and its relationship to outcome. We additionally characterized early brain localization of CRP. Methods: In this prospective, multicenter, international, collaborative, longitudinal study with cross-sectional immunohistochemical analysis of brain tissue, 223 patients (M/F: 132/91) were recruited during the 2010 calendar year. CRP was evaluated at admission (median 93 minutes from symptom onset), 24 hours, 48 hours, and 72 hours after sICH. Brains of 5 subjects with sICH were compared to brains of 2 aged controls without evidence of brain pathology and 7 patients with ischemic stroke. Plasma CRP was measured over 72 hours following sICH and its relationship to 30-day mortality and functional outcome at 30 days (Glasgow Outcome Scale) was determined. CRP immunostaining patterns were analyzed in samples of sICH autopsy brains. Results: Plasma CRP increased over the 48 hours from admission and was significantly (p < 0.001) related to hematoma volume at later time points. The predictive utility of CRP for morbidity and mortality were maintained when adjusted for other risk factors and improved at 48 hours and 72 hours when compared with admission values. Although an early CRP localization was present in both ischemic and hemorrhagic lesions, an intense and diffuse neuropil staining was only present in sICH patients and particularly evident proximal to the hemorrhagic areas. Conclusions: Plasma CRP production increases markedly over the 48 hours to 72 hours period following sICH and is related to outcome. CRP is also present in large amounts around the hemorrhagic lesion and within neurons and glia of patients who died within 12 hours of sICH. Copyright © 2012 by AAN Enterprises, Inc.


Galea J.,Brain Injury Research Group | Cruickshank G.,University of Birmingham | Teeling J.L.,University of Southampton | Boche D.,University of Southampton | And 4 more authors.
Journal of Neurochemistry | Year: 2012

Delayed cerebral ischemia resulting from extracellular hemoglobin is an important determinant of outcome in subarachnoid hemorrhage. Hemoglobin is scavenged by the CD163-haptoglobin system in the circulation, but little is known about this scavenging pathway in the human CNS. The components of this system were analyzed in normal cerebrospinal fluid and after subarachnoid hemorrhage. The intrathecal presence of the CD163-haptoglobin-hemoglobin scavenging system was unequivocally demonstrated. The resting capacity of the CD163-haptoglobin-hemoglobin system in the normal CNS was 50 000-fold lower than that of the circulation. After subarachnoid hemorrhage, the intrathecal CD163-haptoglobin-hemoglobin system was saturated, as shown by the presence of extracellular hemoglobin despite detectable haptoglobin. Hemoglobin efflux from the CNS was evident, enabling rescue hemoglobin scavenging by the systemic circulation. Therefore, the CNS is not capable of dealing with significant intrathecal hemolysis. Potential therapeutic options to prevent delayed cerebral ischemia ought to concentrate on augmenting the capacity of the intrathecal CD163-haptoglobin-hemoglobin scavenging system and strategies to encourage hemoglobin efflux from the brain. This study was performed to examine the CD163-haptoglobin-hemoglobin system in the healthy human CNS and after subarachnoid hemorrhage. Compared with the circulation, the healthy human CNS has a very limited hemoglobin-scavenging capacity, which is clearly overwhelmed in subarachnoid hemorrhage. Results identify two potential therapeutic strategies to prevent delayed cerebral ischemia: inhibition of CD163 shedding and augmentation of Hb efflux from the brain. © 2011 The Authors.


Karim S.,University of Manchester | Hopkins S.,Brain Injury Research Group | Purandare N.,University of Exeter | Crowther J.,University of Liverpool | And 3 more authors.
International Journal of Geriatric Psychiatry | Year: 2014

Objective To prospectively monitor plasma inflammatory marker concentrations in peripheral blood, over 12 months, in subjects with amnestic mild cognitive impairment (MCI), and to determine the relationship between peripheral inflammatory markers and cognitive decline. Methods Seventy patients with amnestic MCI were recruited from two sites providing specialist memory assessment services in Manchester. The baseline assessment included physical examination, neuro-psychological testing and venous blood samples for C-reactive protein (CRP) and interleukin 6 (IL-6) concentrations. Sixty two participants were followed up after 12 months and the assessments were repeated. Results Data analysis revealed a significant rise in CRP, but not IL-6 concentrations over 12 months, which was not confounded by demographic variables. The neuro-psychological test scores had no association with CRP or IL-6 concentrations at baseline or 12 months follow-up. Conclusion This study adopted the unique approach of prospectively investigating peripheral inflammatory markers in a cohort with amnestic MCI. A significant rise in CRP concentrations over 12 months, but lack of significant association with cognition, provide no evidence for a relationship between systemic inflammation and cognitive decline in amnestic MCI. © 2013 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons, Ltd. © 2013 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons, Ltd.


Boutin H.,University of Manchester | Prenant C.,University of Manchester | Maroy R.,Service Hospitalier Frederic Joliot Commissariat a lEnergie Atomique | Galea J.,University of Manchester | And 12 more authors.
PLoS ONE | Year: 2013

Purpose: Neuroinflammation is involved in several brain disorders and can be monitored through expression of the translocator protein 18 kDa (TSPO) on activated microglia. In recent years, several new PET radioligands for TSPO have been evaluated in disease models. [18F]DPA-714 is a TSPO radiotracer with great promise; however results vary between different experimental models of neuroinflammation. To further examine the potential of [18F]DPA-714, it was compared directly to [11C]PK11195 in experimental cerebral ischaemia in rats. Methods: Under anaesthesia, the middle cerebral artery of adult rats was occluded for 60 min using the filament model. Rats were allowed recovery for 5 to 7 days before one hour dynamic PET scans with [11C]PK11195 and/or [18F]DPA-714 under anaesthesia. Results: Uptake of [11C]PK11195 vs [18F]DPA-714 in the ischemic lesion was similar (core/contralateral ratio: 2.84±0.67 vs 2.28±0.34 respectively), but severity of the brain ischemia and hence ligand uptake in the lesion appeared to vary greatly between animals scanned with [11C]PK11195 or with [18F]DPA-714. To solve this issue of inter-individual variability, we performed a direct comparison of [11C]PK11195 and [18F]DPA-714 by scanning the same animals sequentially with both tracers within 24 h. In this direct comparison, the core/contralateral ratio (3.35±1.21 vs 4.66±2.50 for [11C]PK11195 vs [18F]DPA-714 respectively) showed a significantly better signal-to-noise ratio (1.6 (1.3-1.9, 95%CI) fold by linear regression) for [18F]DPA-714. Conclusions: In a clinically relevant model of neuroinflammation, uptake for both radiotracers appeared to be similar at first, but a high variability was observed in our model. Therefore, to truly compare tracers in such models, we performed scans with both tracers in the same animals. By doing so, our result demonstrated that [18F]DPA-714 displayed a higher signal-to-noise ratio than [11C]PK11195. Our results suggest that, with the longer half-life of [18F] which facilitates distribution of the tracer across PET centre, [18F]DPA-714 is a good alternative for TSPO imaging. © 2013 Boutin et al.


Galea J.,Brain Injury Research Group | Galea J.,University of Manchester | Ogungbenro K.,University of Manchester | Hulme S.,Brain Injury Research Group | And 9 more authors.
Journal of Cerebral Blood Flow and Metabolism | Year: 2011

The naturally occurring antagonist of interleukin-1, IL-1RA, is highly neuroprotective experimentally, shows few adverse effects, and inhibits the systemic acute phase response to stroke. A single regime pilot study showed slow penetration into cerebrospinal fluid (CSF) at experimentally therapeutic concentrations. Twenty-five patients with subarachnoid hemorrhage (SAH) and external ventricular drains were sequentially allocated to five administration regimes, using intravenous bolus doses of 100 to 500 mg and 4 hours intravenous infusions of IL-1RA ranging from 1 to 10 mg per kg per hour. Choice of regimes and timing of plasma and CSF sampling was informed by pharmacometric analysis of pilot study data. Data were analyzed using nonlinear mixed effects modeling. Plasma and CSF concentrations of IL-1RA in all regimes were within the predicted intervals. A 500-mg bolus followed by an intravenous infusion of IL-1RA at 10 mg per kg per hour achieved experimentally therapeutic CSF concentrations of IL-1RA within 45 minutes. Experimentally, neuroprotective CSF concentrations in patients with SAH can be safely achieved within a therapeutic time window. Pharmacokinetic analysis suggests that IL-1RA transport across the blood-CSF barrier in SAH is passive. Identification of the practicality of this delivery regime allows further studies of efficacy of IL-1RA in acute cerebrovascular disease. © 2011 ISCBFM All rights reserved.


Emsley H.C.A.,Royal Preston Hospital | Hopkins S.J.,Brain Injury Research Group
Infectious Disorders - Drug Targets | Year: 2010

Infections occur commonly following stroke and adversely influence outcome. Dysphagia, greater stroke severity and increasing age are associated with post-stroke infection, but post-stroke immunodepression is now recognised as an independent factor associated with increased susceptibility. Counter-regulatory responses, triggered by the proinflammatory response to stroke, appear to effect systemic immunodepression via suppression of both innate and adaptive immune responses. Experimental and clinical studies have identified a range of anti-inflammatory and immunosuppressive changes, including reduced mononuclear phagocyte and natural killer cell function, induction of antiinflammatory cytokines, apoptotic lymphocyte loss and altered T lymphocyte activity. A range of mechanisms has been proposed, including hypothalamo-pituitary-adrenal axis (HPAA) and sympathetic nervous system (SNS) activation. The post-stroke balance of pro- and anti-inflammatory mechanisms may be aimed at restricting the extent of inflammation and contributing to the restoration of immune homeostasis. However, severe inflammation in the brain may trigger major systemic, counter-inflammatory responses that ultimately compromise immune mechanisms required to combat pathogens. Although key pathways have been identified, the extent to which the various elements of post-stroke immunodepression are clinically relevant remains to be discovered. The identification of markers of immunodepression in the early post-stroke phase may prove useful for identifying patients that may have increased susceptibility to infection. It also seems likely that post-stroke immunodepression will need to be taken into account where stroke treatments impact upon inflammatory and immune pathways. © 2010 Bentham Science Publishers Ltd.


Kitchen W.J.,Brain Injury Research Group | Kitchen W.J.,Greater Manchester Neuroscience Center | Singh N.,Brain Injury Research Group | Singh N.,Greater Manchester Neuroscience Center | And 7 more authors.
British Journal of Neurosurgery | Year: 2011

Introduction.The placement of external ventricular drain (EVD) is a common neurosurgical procedure to drain cerebrospinal fluid (CSF) in many acute neurosurgical conditions that disrupt the normal CSF absorption pathway. Infection is the primary complication with infection rates ranging between 0% and 45%, and this is associated with significant morbidity and mortality, prolonged hospital stay and increased hospital costs.This article compares and discusses the differences in rates of EVD CSF infection between clinical neurosurgical practice and the infection rates in a group of research patients where EVDs were sampled frequently as part of the study. Materials and methods.Patients who had EVD placed were identified by review of theatre logs from 20052008. A retrospective case-note review was performed with the primary end point being those patients treated with intrathecal antibiotics. Patients within the research group were identified from established data and the same primary endpoint was used. A standard silicone catheter was the EVD used in both cohorts. Patients were excluded if the EVD was placed for diagnoses other than hydrocephalus associated with aneurysmal subarachnoid haemorrhage (SAH). Results.Ninety-four patients had 156 EVDs placed within the clinical group, 49 patients were treated giving an infection rate within this group of 52.1% per patient and 31.4% per EVD. Thirty-nine patients had 39 EVDs placed within the research group, four patients were treated, the infection rate within this group was 10.3% per EVD, p = 0.0001. Conclusion.Sampling or irrigating ventricular drainage systems does not increase the risk of CNS infection providing the operator has appropriate experience and has used theatre standard aseptic technique. © 2011 The Neurosurgical Foundation.


Kirkman M.A.,Brain Injury Research Group
British Journal of Neurosurgery | Year: 2011

Intracerebral haemorrhage is a devastating condition lacking effective therapies, with an uncertain role for surgery in many. Early research described an ischaemic penumbra around the haematoma, representing an area of potential therapeutic intervention. This article discusses the evidence for and against the existence of an ischaemic penumbra in ICH, with particular reference to recent imaging studies. © 2011 The Neurosurgical Foundation.


Hoadley M.E.,Brain Injury Research Group | Scarth S.,Brain Injury Research Group | Hopkins S.J.,Brain Injury Research Group
Cytokine | Year: 2012

We observed significant discrepancies between immunoassay results when using different internally prepared reference preparations for interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) from the National Institute for Biological Standards and Control (NIBSC). To evaluate the reasons for this we prepared the chemokines using diluents that incorporated protein at different steps. This showed that even brief addition of water to these preparations, in the absence of additional protein, resulted in loss of immunoreactivity in assays. The data obtained emphasise the importance of adding protein at an early stage of preparation to avoid loss of material and potential loss of activity. © 2012 Elsevier Ltd.


Hoadley M.E.,Brain Injury Research Group | Hopkins S.J.,Brain Injury Research Group
Journal of Immunological Methods | Year: 2013

Failure to match assay matrices with samples in immunoassays can result in incorrect sample values being reported. For multiplex assays this presents particular problems, due to the need to find a matrix suitable for all the analytes. Here, we describe strategies adopted to overcome matrix problems identified in establishing a cytokine multiplex assay in human plasma.Standard analytes were diluted in plasma samples to identify representative plasma for assay development. Horse sera were screened to evaluate potential interference before using to adjust a matrix to match plasma samples. Suitability of the matrix match was confirmed by evaluating recovery of known concentrations of analytes from plasma.Individual plasmas modified the assay signal for some analytes to a variable extent, particularly for IL-1α and IL-1β. Addition of horse serum to assay buffer improved matching to plasma samples, although endogenous MCP-1 activity was apparent in one sample. Matching of plasma and assay matrices allowed recoveries within 10% to 20% of the expected values, unless the samples contained atypical interfering activity.Attention to choice of samples and diluent used for assay development is particularly important for measurement of sample analytes in cytokine multiplex assays. © 2013 Elsevier B.V.

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