NIHR Biomedical Research Unit

Nottingham, United Kingdom

NIHR Biomedical Research Unit

Nottingham, United Kingdom
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News Article | July 17, 2017

Specific signatures of the immune mechanisms that lead to serious organ failure are evident in the hours immediately following injury, according to a study by Joanna Shepherd of Queen Mary University of London, UK, and colleagues, publishing in PLOS Medicine. Multiple Organ Dysfunction Syndrome (MODS) is a condition that involves failure of organ systems including lung, heart, kidney, and liver and is thought to be a result of an excessive immune response after traumatic injury. While the precise immune mechanisms leading to MODS are not fully understood, the hyperacute window after injury is thought to be a critical period for understanding these mechanisms and for potential intervention. In a cohort of 70 critically injured patients at Royal Hospital London, Shepherd and colleagues investigated the early immune response signatures in whole blood samples obtained within 2 hours of injury, and at 24 hours and 72 hours following injury. The researchers characterized circulating immune cell populations, and analyzed expression of 29,385 immune cell genes (available for 36 critically injured patients). When comparing patients who developed MODS to patients who did not develop MODS, they found 363 genes that were different at admission, but by 24 hours postinjury, only 33 genes differed between the groups. Further analysis of this hyperacute timeline demonstrated enrichment of gene pathways associated with cell death in patients with MODS and implicated downregulation of neutrophils and upregulation of natural killer immune cells. While the authors note that this study is limited by its small sample size, and that larger cohorts will be able to investigate the drivers of the hyperacute response and different MODS phenotypes in more detail, the finding of a specific early response that developed into widespread activation could eventually lead to improvement in treatment of severe injury: "The findings suggest multiple new directions for discovery research and hold opportunities for translation in diagnostics, clinical trial design, precision medicine, and novel therapeutic and management approaches." CPC, DW, and MRB were funded by the National Institute for Health Research (NIHR) as part of the portfolio of translational research of the NIHR Biomedical Research Unit at Barts and The London School of Medicine and Dentistry. This project was enabled through access to the MRC eMedLab Medical Bioinformatics infrastructure, supported by the Medical Research Council [grant number MR/L016311/1]. JM was funded in part by the NIHR [academic clinical fellowship]. JMS is funded by the Wellcome Trust and Department of Health [grant numbers 101012/Z/13/Z and HICFR7405]. HDT was funded by grants from Barts and The London Charity and the Royal College of Surgeons of England. MBP is funded by an MRC-DTP PhD fellowship in Translational Immunology [grant number 1797139]. The Centre for Trauma Sciences received funding from Barts Charity [grant number 753/1722]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. KB is a member of the Editorial Board of PLOS Medicine and served as guest editor on PLOS Medicine's Special Issue on Trauma. Cabrera CP, Manson J, Shepherd JM, Torrance HD, Watson D, Longhi MP, et al. (2017) Signatures of inflammation and impending multiple organ dysfunction in the hyperacute phase of trauma: A prospective cohort study. PLoS Med 14(7): e1002352. https:/ Centre for Translational Bioinformatics, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom Centre for Trauma Sciences, The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom Centre for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom Heart Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom Department of Genetics, Evolution & Environment, University College London, London, United Kingdom Centre for Microvascular Research, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, United Kingdom IN YOUR COVERAGE PLEASE USE THIS URL TO PROVIDE ACCESS TO THE FREELY AVAILABLE PAPER:

Gyawali C.P.,University of Washington | Conklin J.L.,Cedars Sinai Medical Center | Fox M.,NIHR Biomedical Research Unit | Pandolfino J.E.,Northwestern University | And 4 more authors.
Neurogastroenterology and Motility | Year: 2013

Esophageal motor function is highly coordinated between central and enteric nervous systems and the esophageal musculature, which consists of proximal skeletal and distal smooth muscle in three functional regions, the upper and lower esophageal sphincters, and the esophageal body. While upper endoscopy is useful in evaluating for structural disorders of the esophagus, barium esophagography, radionuclide transit studies, and esophageal intraluminal impedance evaluate esophageal transit and partially assess motor function. However, esophageal manometry is the test of choice for the evaluation of esophageal motor function. In recent years, high-resolution manometry (HRM) has streamlined the process of acquisition and display of esophageal pressure data, while uncovering hitherto unrecognized esophageal physiologic mechanisms and pathophysiologic patterns. New algorithms have been devised for analysis and reporting of esophageal pressure topography from HRM. The clinical value of HRM extends to the pediatric population, and complements preoperative evaluation prior to foregut surgery. Provocative maneuvers during HRM may add to the assessment of esophageal motor function. The addition of impedance to HRM provides bolus transit data, but impact on clinical management remains unclear. Emerging techniques such as 3-D HRM and impedance planimetry show promise in the assessment of esophageal sphincter function and esophageal biomechanics. © 2013 Blackwell Publishing Ltd.

Fox M.,NIHR Biomedical Research Unit
Neurogastroenterology and Motility | Year: 2012

Background Weak and absent esophageal peristalsis are frequently encountered esophageal motility disorders, which may be associated with dysphagia and which may contribute to gastroesophageal reflux disease. Recently, rapid developments in the diagnostic armamentarium have taken place, in particular, in high-resolution manometry with or without concurrent intraluminal impedance monitoring. Purpose This article aims to review the current insights in the terminology, pathology, pathophysiology, clinical manifestations, diagnostic work-up,and management of weak and absent peristalsis. © 2012 Blackwell Publishing Ltd.

Fox M.,NIHR Biomedical Research Unit | Sweis R.,Guys And St Thomas Hospital Nhs Foundation Trust
Neurogastroenterology and Motility | Year: 2012

Background Symptom based diagnosis is not reliable in patients with swallowing problems, heartburn, and other dyspeptic complaints. The aim of investigation is to provide clinically relevant measurements of gastrointestinal structure and function that explain the cause of symptoms, identify pathology, and guide effective management. Current practice rarely meets these ideals. Purpose This review considers recent advances in technology such as high-resolution manometry (HRM) with esophageal pressure topography (EPT), HRM with impedance, high frequency ultrasound, and endoscopic functional luminal impedance planimetry (Endo-FLIP) that provide new opportunities to identify the pathophysiologic basis of esophageal symptoms and disease. As experience with these new devices increases researchers are developing new methodologies that maximize their utility in clinical practice. For example, application of HRM to assess motility and function during and after a test meal can identify the causes of swallowing problems, reflux and other postprandial symptoms and intra-operative application of Endo-FLIP may help surgeons perform antireflux surgery. These examples illustrate the potential of physiologic measurement to direct rational and effective clinical management for individual patients. © 2012 Blackwell Publishing Ltd.

Mattesini A.,NIHR Biomedical Research Unit | Secco G.G.,NIHR Biomedical Research Unit | Secco G.G.,University of Piemonte Orientale | Dall'Ara G.,NIHR Biomedical Research Unit | And 11 more authors.
JACC: Cardiovascular Interventions | Year: 2014

Objectives The aim of this study was to compare the acute performance of the PLLA ABSORB bioresorbable vascular scaffold (BVS) (Abbott Vascular, Santa Clara, California) with second-generation metal drug-eluting stents (DES) in complex coronary artery lesions. Background Thick polymer-based BVS have different mechanical properties than thin second-generation DES. Data on the acute performance of BVS are limited to simple coronary lesions treated in trials with strict inclusion criteria. Methods Fifty complex coronary lesions (all type American College of Cardiology/American Heart Association B2-C) treated with a BVS undergoing a final optical coherence tomography (OCT) examination were compared with an equal number of matched lesions treated with second-generation DES. The following stent performance indexes were assessed with OCT: mean and minimal area, residual area stenosis (RAS), incomplete strut apposition (ISA), tissue prolapse, eccentricity index, symmetry index, strut fracture, and edge dissection. Results One hundred lesions from 73 patients were analyzed. A higher balloon diameter/reference vessel diameter ratio was used for predilation in the BVS group (p < 0.01). Most of the BVS and DES were post-dilated with short noncompliant (NC) balloons of similar diameter. OCT showed in the BVS group a higher tissue prolapse area (p = 0.08) and greater incidence of ISA at the proximal edge (p = 0.04) with no difference in the overall ISA. The RAS was 20.2% in the BVS group and 21.7% in the DES group (p = 0.32). There was no difference in the eccentricity index. The minimal and mean lumen areas were similar in the 2 groups. Two cases of strut fractures occurred after the BVS, whereas none was observed in the DES. Conclusions Based on OCT, the BVS showed similar post-procedure area stenosis, minimal lumen area, and eccentricity index as second-generation DES. The different approach for lesion preparation and routine use of OCT guidance during BVS expansion may have contributed to these results. © 2014 by the American College of Cardiology Foundation.

Sweis R.,Guys and St Thomas NHS Foundation Trust | Anggiansah A.,Guys and St Thomas NHS Foundation Trust | Wong T.,Guys and St Thomas NHS Foundation Trust | Brady G.,Guys and St Thomas NHS Foundation Trust | And 2 more authors.
Neurogastroenterology and Motility | Year: 2014

Background: In the absence of major dysmotility, esophageal manometry with water swallows rarely explains the causes of esophageal symptoms and disease. This methodology development study assessed esophageal function and symptoms during a test meal in patients with reflux symptoms and asymptomatic controls. The impact of this approach on manometric diagnosis and clinical outcome was reviewed. Methods: 18 patients with reflux symptoms and 10 healthy volunteers underwent high resolution manometry (HRM) with 5 mL water swallows, 200 mL water drink, and standardized solid test meal followed by 10 min postprandial observation. The number of symptoms associated with esophageal dysfunction (SAD) divided by total symptoms (dysfunction symptom index [D-SI]) was calculated. Ambulatory reflux pH-monitoring was performed. Final diagnosis and clinical outcome were documented at 2 years. Key Results: Meal intake took longer in patients than controls (552 vs 339 s) and this was associated with a higher number of ineffective swallows in this group (51% vs 28%; p < 0.001). No swallowing problems occurred with water swallows but 12/18 (66%) patients had SAD during either the meal or postprandial observations with D-SI >50% in 9/12 (75%). Compared with water swallows, manometric classification was altered in 12/18 (67%) and clinical diagnosis was altered in 7/18 (39%) patients due to test meal observations. Conclusions & Inferences: A novel methodology for the detection of symptomatic dysmotility during a test meal and postprandial observation is presented. This technique increased the diagnostic yield of esophageal dysfunction in patients presenting with reflux symptoms. Long-term follow-up indicated that these observations can guide effective clinical management. © 2013 John Wiley & Sons Ltd.

Background/Objectives:Children with Crohn’s disease often demonstrate nutritional recovery during primary therapy at diagnosis, but long-term nutritional support is sometimes necessary. Evidence to inform best nutritional practice including energy and micronutrient requirements is limited. The principal objective of this study was to determine how energy expenditure and physical activity vary with disease activity over the first year following diagnosis.Subjects/Methods:Twenty children were studied at diagnosis with Crohn’s disease and were followed up over 1 year while receiving treatment according to national guidelines. The majority of children (13) were treated with exclusive enteral nutrition. At study visits, height, weight, bioelectrical impedance, resting energy expenditure by indirect calorimetry, tri-axial accelerometer and blood investigations were performed alongside clinical assessment.Results:There was no significant effect of disease activity on resting energy expenditure (REE). Physical activity was greater after primary therapy (Z=3.31, P<0.01). Median wPCDAI fell from 58 at diagnosis to 7.5 after primary therapy and was 7.5 at 1 year. Weight s.d.s increased from −1.67 to −0.86 and lean index s.d.s increased from −2.93 to −1.64, although the increase was mostly in the first 2 months. Median height s.d.s was unchanged throughout this study. There was a significant association between dietary intake and weight gain (r=0.8 P<0.01) but not height gain. Persistent micronutrient deficits beyond diagnosis were seen for both iron and vitamin D.Conclusions:This study has demonstrated that REE does not change significantly through different phases of disease activity, but physical activity is low at diagnosis. Children with Crohn's disease should be screened for deficiencies of iron and vitamin D.European Journal of Clinical Nutrition advance online publication, 22 June 2016; doi:10.1038/ejcn.2016.107. © 2016 Macmillan Publishers Limited

Chung K.F.,Imperial College London | Chung K.F.,NIHR Biomedical Research Unit
Drugs | Year: 2014

Asthma is a common disease with a complex pathophysiology. It can present in various clinical forms and with different levels of severity. Unbiased cluster analytic methods have unravelled several phenotypes in cohorts representative of the whole spectrum of severity. Clusters of severe asthma include those on high-dose corticosteroid treatment, often with both inhaled and oral treatment, usually associated with severe airflow obstruction. Phenotypes with concordance between symptoms and sputum eosinophilia have been reported, including an eosinophilic inflammation-predominant group with few symptoms and late-onset disease who have a high prevalence of rhinosinusitis, aspirin sensitivity, and exacerbations. Sputum eosinophilia is also a biomarker that can predict therapeutic responses to antibody-based treatments to block the effects of the T-helper (Th)-2 cytokine, interleukin (IL)-5. Low Th2-expression has been predictive of poor therapeutic response to inhaled corticosteroid therapy. Current asthma schedules emphasise a step-up approach to treating asthma in relation to increasing severity, but, in more severe disease, phenotyping or endotyping of asthma will be necessary to determine new treatment strategies as severe asthma is recognized as being a particularly heterogeneous disease. Much less is known about 'non-eosinophilic' asthma. Phenotypic characterisation of corticosteroid insensitivity and chronic airflow obstruction of severe asthma is also needed. Phenotype-driven treatment of asthma will be further boosted by the advent of transcriptomic and proteomic technologies, with the application of systems biology or medicine approaches to defining phenotypes and biomarkers of disease and therapeutic response. This will pave the way towards personalized medicine and healthcare for asthma. © 2014 Springer International Publishing Switzerland.

Monaghan T.M.,NIHR Biomedical Research Unit | Cockayne A.,University of Nottingham | Mahida Y.R.,NIHR Biomedical Research Unit
Inflammatory Bowel Diseases | Year: 2015

Colonization with toxigenic Clostridium difficile may be associated with a wide spectrum of clinical presentation ranging from asymptomatic carriage to mild diarrhea to life-threatening colitis. Over the last 15 years, there has been a marked increase in the incidence of C. difficile infection, which predominantly affects elderly patients on antibiotics. More recently, there has been significant interest in the association between inflammatory bowel disease (IBD) and C. difficile infection. This review article discusses in some detail current knowledge of the mechanisms by which C. difficile toxins may mediate mucosal inflammation, together with the role of cell wall components of the microorganism in disease pathogenesis. Innate and adaptive host responses to C. difficile toxins and other components are described and include consideration of the potential role of known mucosal changes in IBD that may lead to an enhanced inflammatory response in the presence of C. difficile infection. Recent studies, which have characterized resident microbiota that may mediate protection against colonization by C. difficile, including their mechanisms of action, are also discussed. This includes the role of bile acids and 7α-dehydroxylase-expressing bacteria, such as Clostridium scindens. Recent studies suggest a higher carriage rate of C. difficile in patients with IBD. It is anticipated that future studies will determine the role of dysbiosis in IBD in predisposing to colonization with C. difficile. Copyright © 2015 Crohn's & Colitis Foundation of America, Inc.

Spiller R.,NIHR Biomedical Research Unit
Digestive Diseases | Year: 2012

Symptomatic diverticular disease (SYMP-DD) and irritable bowel syndrome (IBS) share many features. Both are characterised by recurrent episodes of abdominal pain which may be slightly more frequent in IBS than SYMP-DD. They may also both exhibit an erratic bowel habit with diarrhoea, constipation and alternating types. It is important to assess anxiety, depression and somatisation since this can be increased in both types of patients and may be associated with visceral hypersensitivity. There are also significant differences between IBS and SYMP-DD. In particular, SYMP-DD patients are older, lack the female predominance seen in IBS and may often have fever with prolonged episodes of pain. For them, abnormalities of the gut are probably more important than cerebral factors, while for IBS the reverse is true. Treatments should be directed at the predominant abnormality which will vary in every patient. Copyright © 2012 S. Karger AG, Basel.

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