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Sanders R.D.,Intensive Care and Pain Medicine and Leucocyte Biology | Manning H.J.,Intensive Care and Pain Medicine | Robertson N.J.,Medical Research Council Clinical science Center | Ma D.,Imperial College London | And 4 more authors.
Anesthesiology | Year: 2010

Perinatal hypoxic-ischemic encephalopathy can be a devastating complication of childbirth. Herein, the authors review the pathophysiology of hypoxic-ischemic encephalopathy and the current status of neuroprotective strategies to ameliorate the injury centering on four themes: (1) monitoring in the perinatal period, (2) rapid identification of affected neonates to allow timely institution of therapy, (3) preconditioning therapy (a therapeutic that reduces the brain vulnerability) before hypoxic-ischemic encephalopathy, and (4) prompt institution of postinsult therapies to ameliorate the evolving injury. Recent clinical trials have demonstrated the significant benefit for hypothermic therapy in the postnatal period; furthermore, there is accumulating preclinical evidence that adjunctive therapies can enhance hypothermic neuroprotection. Advances in the understanding of preconditioning may lead to the administration of neuroprotective agents earlier during childbirth. Although most of these neuroprotective strategies have not yet entered clinical practice, there is a significant hope that further developments will enhance hypothermic neuroprotection. Copyright © 2010, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins.


McGinnity C.J.,Imperial College London | McGinnity C.J.,Medical Research Council Clinical science Center | McGinnity C.J.,King's College London | Koepp M.J.,University College London | And 20 more authors.
Journal of Neurology, Neurosurgery and Psychiatry | Year: 2015

Objective: To demonstrate altered N-methyl-D-aspartate (NMDA) receptor availability in patients with focal epilepsies using positron emission tomography (PET) and [18 F]GE-179, a ligand that selectively binds to the open NMDA receptor ion channel, which is thought to be overactive in epilepsy. Methods: Eleven patients (median age 33 years, 6 males) with known frequent interictal epileptiform discharges had an [18F]GE-179 PET scan, in a crosssectional study. MRI showed a focal lesion but discordant EEG changes in two, was non-localising with multifocal EEG abnormalities in two, and was normal in the remaining seven patients who all had multifocal EEG changes. Individual patient [18F]GE-179 volume-of distribution (VT) images were compared between individual patients and a group of 10 healthy controls (47 years, 7 males) using Statistical Parametric Mapping. Results: Individual analyses revealed a single cluster of focal VT increase in four patients; one with a single and one with multifocal MRI lesions, and two with normal MRIs. Post hoc analysis revealed that, relative to controls, patients not taking antidepressants had globally increased [18F]GE-179 VT (+28%; p<0.002), and the three patients taking an antidepressant drug had globally reduced [18F]GE-179 VT (-29%; p<0.002). There were no focal abnormalities common to the epilepsy group. Conclusions: In patients with focal epilepsies, we detected primarily global increases of [18F]GE-179 VT consistent with increased NMDA channel activation, but reduced availability in those taking antidepressant drugs, consistent with a possible mode of action of this class of drugs. [18F]GE-179 PET showed focal accentuations of NMDA binding in 4 out of 11 patients, with difficult to localise and treat focal epilepsy.


Van Breevoort D.,Sanquin AMC Landsteiner Laboratory | Snijders A.P.,Medical Research Council Clinical science Center | Hellen N.,UK National Institute for Medical Research | Hellen N.,Imperial College London | And 14 more authors.
Blood | Year: 2014

Vascular endothelial cells contain unique rod-shaped secretory organelles, called Weibel-Palade bodies (WPBs), which contain the hemostatic protein von Willebrand factor (VWF) and a cocktail of angiogenic and inflammatory mediators. We have shown that the Rab27A effector synaptotagmin-like protein 4-a (Slp4-a) plays a critical role in regulating hormoneevoked WPB exocytosis. Using a nonbiased proteomic screen for targets for Slp4-a, we now identify syntaxin-binding protein 1 (STXBP1) and syntaxin-2 and -3 as endogenous Slp4-a binding partners in endothelial cells. Coimmunoprecipitations showed that STXBP1 interacts with syntaxin-2 and -3, but not with syntaxin-4. Small interfering RNA-mediated silencing of STXBP1 expression impaired histamine- and forskolin-induced VWF secretion. To further substantiate the role of STXBP1, we isolated blood outgrowth endothelial cells (BOECs) from an early infantile epileptic encephalopathy type 4 (EIEE4) patient carrying a de novo mutation in STXBP1. STXBP1-haploin sufficient EIEE4 BOECs contained similar numbers of morphologically normal WPBs compared with control BOECs of healthy donors; however, EIEE4 BOECs displayed significantly impaired histamine- and forskolin-stimulated VWF secretion. Based on these findings, we propose that the Rab27A-Slp4- a complex on WPB promotes exocytosis through an interaction with STXBP1, thereby controlling the release of vaso-active substances in the vasculature. © 2014 by The American Society of Hematology.


Rimoldi O.,Medical Research Council Clinical science Center | Rimoldi O.,Imperial College London | Rimoldi O.,CNR Institute of Molecular Bioimaging and Physiology | Rosen S.D.,Imperial College London | And 3 more authors.
Journal of Hypertension | Year: 2014

Background: Hypertensive patients show a blunted coronary flow reserve (CFR) that, in the absence of epicardial disease, is an index of microvascular dysfunction. We aimed at assessing subendocardial and subepicardial myocardial blood flow (MBF) and CFR using high-resolution PET and determine the influence of haemodynamic load and ventricular mass in patients with arterial hypertension and left ventricular hypertrophy. Methods: We measured MBF (ml/min per g) using PET with oxygen-15 labelled water. Thirty patients (56 ± 8 years, 21 men) with stage 1-2 hypertension in therapy wash-out, except for thiazides, and 10 healthy volunteers were studied at baseline and during dipyridamole-induced hyperaemia (0.56 mg/kg over 4 min). Data are mean ± SD. Results: In patients, left ventricular mass index was 144 ± 40 g/m2 and septal thickness 14.8 ± 1.9mm. Baseline MBF was similar in patients and healthy volunteers in subendocardial (ENDO) (P = 0.08) and subepicardial (EPI) (P = 0.5), but patients had significantly lower hyperaemic MBF-EPI and MBF-ENDO (P < 0.001) and significantly lower CFR (EPI P < 0.001; ENDO P = 0.003). In patients, the degree of impairment of CFR-EPI (R = 0.52, P = 0.003) and CFR-ENDO (R = 0.51, P = 0.004) was inversely related to SBP, but not to left ventricular mass index. Conclusion: In patients with stage 1-2 hypertension and left ventricular hypertrophy, CFR is transmurally blunted due to a reduced hyperaemic response to stress, which is inversely related to SBP. In the absence of coronary stenosis, this phenomenon is most likely the expression of severe coronary microvascular dysfunction. Copyright © Lippincott Williams & Wilkins.


Cuhlmann S.,National Science Foundation | Cuhlmann S.,Biological Imaging Center | Van Der Heiden K.,National Science Foundation | Saliba D.,Kennedy Institute of Rheumatology | And 12 more authors.
Circulation Research | Year: 2011

Rationale: The nuclear factor (NF)-κB pathway is involved in arterial inflammation. Although the signaling pathways that regulate transcriptional activation of NF-κB are defined, the mechanisms that regulate the expression levels of NF-κB transcription factors are uncertain. Objective: We studied the signaling mechanisms that regulate RelA NF-κB subunit expression in endothelial cells (ECs) and their role in arterial inflammation. Methods and Results: Gene silencing and chromatin immunoprecipitation revealed that RelA expression was positively regulated by c-Jun N-terminal kinase (JNK) and the downstream transcription factor ATF2 in ECs. We concluded that this pathway promotes focal arterial inflammation as genetic deletion of JNK1 reduced NF-κB expression and macrophage accumulation at an atherosusceptible site. We hypothesized that JNK signaling to NF-κB may be controlled by mechanical forces because atherosusceptibility is associated with exposure to disturbed blood flow. This was assessed by positron emission tomography imaging of carotid arteries modified with a constrictive cuff, a method that was developed to study the effects of disturbed flow on vascular physiology in vivo. This approach coupled to en face staining revealed that disturbed flow elevates NF-κB expression and inflammation in murine carotid arteries via JNK1. Conclusions: We demonstrate that disturbed blood flow promotes arterial inflammation by inducing NF-κB expression in endothelial cells via JNK-ATF2 signaling. Thus, our findings illuminate a novel form of JNK-NF-κB crosstalk that may determine the focal nature of arterial inflammation and atherosclerosis. © 2011 American Heart Association, Inc.


Rinne J.O.,Clinical Research Services Turku | Brooks D.J.,Medical Research Council Clinical science Center | Rossor M.N.,University College London | Fox N.C.,University College London | And 13 more authors.
The Lancet Neurology | Year: 2010

Background: Carbon-11-labelled Pittsburgh compound B (11C-PiB) PET is a marker of cortical fibrillar amyloid-β load in vivo. We used 11C-PiB PET to investigate whether bapineuzumab, a humanised anti-amyloid-β monoclonal antibody, would reduce cortical fibrillar amyloid-β load in patients with Alzheimer's disease. Methods: Patients with mild-to-moderate Alzheimer's disease were randomly assigned to receive intravenous bapineuzumab or placebo in a ratio of seven to three in three ascending dose groups (0·5, 1·0, or 2·0 mg/kg). Each dose group was enrolled after safety review of the previous group. Randomisation was by interactive voice response system; masking was achieved with numbered kit allocation. Patients, investigators, study site personnel, sponsor staff, and carers were masked to treatment. Patients received up to six infusions, 13 weeks apart, and had 11C-PiB PET scans at baseline and at weeks 20, 45, and 78. The primary outcome was the difference between the pooled bapineuzumab group and the pooled placebo group in mean change from screening to week 78 in 11C-PiB cortical to cerebellar retention ratio averaged across six cortical regions of interest. Analysis was by modified intention to treat. This study is registered with EudraCT, number 2004-004120-12; ISRCTN17517446. Findings: 28 patients were assigned to bapineuzumab (n=20) or placebo (n=8). 19 patients in the bapineuzumab group and seven in the placebo group were included in the modified intention-to-treat analysis. Estimated mean 11C-PiB retention ratio change from baseline to week 78 was -0·09 (95% CI -0·16 to -0·02; p=0·014) in the bapineuzumab group and 0·15 (95% CI 0·02 to 0·28; p=0·022) in the placebo group. Estimated mean difference in 11C-PiB retention ratio change from baseline to week 78 between the bapineuzumab group and the placebo group was -0·24 (95% CI -0·39 to -0·09; p=0·003). Differences between the bapineuzumab group and the placebo group in the individual regions of interest were similar to the overall mean difference. Adverse events were typically mild to moderate in severity and transient. Two patients in the 2·0 mg/kg bapineuzumab group had transient cerebral vasogenic oedema. Interpretation: Treatment with bapineuzumab for 78 weeks reduced cortical 11C-PiB retention compared with both baseline and placebo. 11C-PiB PET seems to be useful in assessing the effects of potential Alzheimer's disease treatments on cortical fibrillar amyloid-β load in vivo. Funding: Elan Pharmaceuticals and Wyeth Research. © 2010 Elsevier Ltd. All rights reserved.


Mahalingam S.,East Surrey Hospital | Gao L.,55 Fruit Street | Nageshwaran S.,Medical Research Council Clinical science Center | Vickers C.,Watford General Hospital | And 2 more authors.
Journal of Wound Care | Year: 2014

Objective: Pressure ulcers (PUs) cost the National Health Service (NHS) up to 4% of its health care expenditure. Arising from this are also clinical negligence claims, where inadequate risk assessment has been cited as one of the principal drawbacks in the prevention of PUs. This two-cycle audit aims to examine the consistency and accuracy of risk assessment of patients, and demonstrates how simple focused interventions can improve the quality of care provided.Method: The Waterlow pressure ulcer risk assessment tool was employed to assess inpatients during a 6-month period at a London teaching hospital. Patients were risk assessed, and examined to detect PUs and to determine the type of mattress. We compared our findings with clinical (nursing and medical) documentation. Interventions were made through questionnaires given to staff, educational sessions, presentations and posters addressing where improvements could be made in risk stratifying patients. A repeat audit was carried out 24 months later and the results from both cycles were compared. Statistical analysis was carried out using Fisher's exact and the Student's T-test.Results: In total 100 in-patients were assessed in each cycle with a mean age of 71.4 years in cycle 1 and 70.1 years in cycle 2. A nursing Waterlow score was recorded for 81% of patients in cycle 1 and 100% in cycle 2 (p<0.05). In cycle 1, the average nursing score was significantly lower than that from the study (mean 13.7 versus 17.1, median 14.0 versus 18.0; p<0.05), but after intervention this had reduced to a minimal difference (mean 8.5 versus 9.0, median 8.0 versus 9.0, p=0.08).Conclusion: Nursing scores recorded in the notes were lower than the study scores in cycle 1, primarily from a failure to appropriately assess certain categories of the Waterlow scale. These differences reduced after focused education of staff. Our results suggest that targeted interventions tailored towards nursing and medical staff can result in improvements in the risk assessment for prevention and subsequent management of PUs. However, it also highlights the need for increased input from the entire multidisciplinary team in order to reduce the morbidity caused by PUs.Declaration of interest: The authors have no conflict of interest. No funding was received for this study. © 2014 MA HEALTHCARE LTD.


Kim E.,Seoul National University | Howes O.D.,Institute of Psychiatry | Howes O.D.,Medical Research Council Clinical science Center | Howes O.D.,Imperial College London | And 7 more authors.
Clinical Pharmacokinetics | Year: 2016

Background and objective: Escitalopram is one of the most commonly prescribed selective serotonin reuptake inhibitors (SSRIs). It is thought to act by blocking the serotonin transporter (SERT). However, its dose–SERT occupancy relationship is not well known, so it is not clear what level of SERT blockade is achieved by currently approved doses. Methods: To determine the dose–occupancy relationship, we measured serial SERT occupancy using [11C]DASB [3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile] positron emission tomography (PET) and plasma drug concentrations after the administration of escitalopram in 12 healthy volunteers. We then built a pharmacokinetic–pharmacodynamic model to characterize the dose–occupancy relationship in the putamen and the dorsal raphe nucleus. Results: Escitalopram at approved doses occupied less SERT than expected and the SERT occupancy showed regional effects [occupancy was higher in the dorsal raphe nucleus than in the putamen (p < 0.001)]. The drug concentration when 50 % of receptors are occupied (EC50) value and Hill coefficient were significantly different between the putamen (EC50 4.30, Hill coefficient 0.459) and the dorsal raphe nucleus (EC50 2.89, Hill coefficient 0.817). Conclusions: Higher doses of escitalopram than 20 mg are needed to achieve 80 % or greater SERT occupancy. Higher occupancy by escitalopram in the dorsal raphe nucleus relative to the striatum may explain the delayed onset of action of SSRIs by modulating autoreceptor function. The prevention of the 5-HT1A autoreceptor-mediated negative feedback could be a strategy for accelerating the clinical antidepressant effects. © 2016 Springer International Publishing Switzerland


Guillemette B.,Imperial College London | Guillemette B.,University of Montréal | Drogaris P.,University of Montréal | Lin H.-H.S.,Imperial College London | And 8 more authors.
PLoS Genetics | Year: 2011

Methylation of histone H3 lysine 4 (H3K4me) is an evolutionarily conserved modification whose role in the regulation of gene expression has been extensively studied. In contrast, the function of H3K4 acetylation (H3K4ac) has received little attention because of a lack of tools to separate its function from that of H3K4me. Here we show that, in addition to being methylated, H3K4 is also acetylated in budding yeast. Genetic studies reveal that the histone acetyltransferases (HATs) Gcn5 and Rtt109 contribute to H3K4 acetylation in vivo. Whilst removal of H3K4ac from euchromatin mainly requires the histone deacetylase (HDAC) Hst1, Sir2 is needed for H3K4 deacetylation in heterochomatin. Using genome-wide chromatin immunoprecipitation (ChIP), we show that H3K4ac is enriched at promoters of actively transcribed genes and located just upstream of H3K4 tri-methylation (H3K4me3), a pattern that has been conserved in human cells. We find that the Set1-containing complex (COMPASS), which promotes H3K4me2 and -me3, also serves to limit the abundance of H3K4ac at gene promoters. In addition, we identify a group of genes that have high levels of H3K4ac in their promoters and are inadequately expressed in H3-K4R, but not in set1Δ mutant strains, suggesting that H3K4ac plays a positive role in transcription. Our results reveal a novel regulatory feature of promoter-proximal chromatin, involving mutually exclusive histone modifications of the same histone residue (H3K4ac and H3K4me). © 2011 Guillemette et al.

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