News Article | March 1, 2017
University of Leicester leads study into cause of airway narrowing in cases of asthma Improved treatments for people with severe asthma are a 'step closer' after a research team led by the University of Leicester identified a breakthrough in the cause of airway narrowing. Scientists have, for the first time, discovered that an active form of a key protein, HMGB1, is increased and related to narrowing of the airway in people with severe asthma. The finding will now enable drug makers to specifically target the protein in future treatment for non-allergy related asthma. The study, published in the Journal of Allergy and Clinical Immunology, was carried out on mucous and airway muscle samples gathered from people with mild to moderate asthma, severe asthma and healthy volunteers recruited from Leicester's Glenfield Hospital. Dr Ruth Saunders, lead author of the study from the University of Leicester Department of Infection, Immunity & Inflammation, said: "For a number of people with asthma, particularly severe asthma, treatment is not 100 per cent effective. Although a number of new therapies are under investigation for allergy-related asthma, there is still a need for new therapies for asthma that is not related to allergies. "We have shown that the amount of HMGB1, a protein that can be released in the airways by cells involved in inflammation or by damaged cells, is increased in the mucous from the airways of people with severe asthma. "To our knowledge, this is the first study to show a direct effect of HMGB1 on enhancing airway muscle contraction in response to stimuli. The findings of this research bring us a step closer to improved treatments for people with severe asthma." Asthma is a long-term condition that affects the airways. When a person with asthma comes into contact with something that irritates their sensitive airways it causes the body to react in several ways which can include wheezing, coughing and can make breathing more difficult. The study was part funded by the NIHR Leicester Respiratory Biomedical Unit (BRU), the BBSRC studentship and in part by Airway Disease Predicting Outcomes through Patient Specific Computational Modelling (AirPROM) project (funded through an FP7 EU grant), Wellcome Senior Fellowship (CEB), and the EAACI Research Fellowship. The NIHR Leicester Respiratory Biomedical Research Unit - a partnership between the University of Leicester and Leicester's Hospitals - focuses on promoting the development of new and effective therapies for the treatment of respiratory diseases including severe asthma and chronic obstructive pulmonary disease (COPD).
News Article | February 24, 2017
An approved international test to check whether people need open heart surgery could be sending twice as many people under the knife unnecessarily, at a cost of nearly £75m, research by the University of Leicester has suggested. Since 2012 doctors have been using exercise testing on people with a condition called aortic stenosis (AS) to determine whether they need an operation to save their life. However, a study, led by Gerry McCann, Professor of Cardiac Imaging and Honorary Consultant Cardiologist from the University of Leicester Department of Cardiovascular Sciences, who conducted the research as part of a NIHR Fellowship, has shown the current approach is "highly inaccurate" and if followed may send thousands of patients to surgery before it is needed. The exercise test, which involves cycling on a stationary bike, is used to determine whether surgery is needed for people with the condition - but it only has a 60 per cent accuracy rate, the study found. AS, which is the narrowing of the aortic heart valve, affects predominantly older people and affects up to three per cent of people over 75 years of age. Symptoms, such as chest pain, breathlessness and feeling faint, can take years to develop. However, when they do it means the person is seriously ill and could die from heart failure or sudden death. If exercise test participants become breathless, they are recommended to have valve replacement therapy. About 10,000 aortic valve replacements are performed every year at a cost of up to £15,000. Hospital recuperation then takes between seven and 10 days. Professor McCann, who is also a consultant cardiologist from the NIHR Leicester Cardiovascular Biomedical Research Unit (BRU), said: "There is no doubt that valve replacement therapy is highly effective for patients with symptoms, however there are risks involved. It's a major operation and there's a one per cent chance of people dying or having a stroke during or after. There's also the chance they could develop an infection. "It can often take six months to recover, but if they survive they tend to do very well afterwards. However, if we know a patient has AS and no symptoms and we do nothing there's also a one per cent chance they will die so there's a fine line between whether we should intervene or not. "Our findings showed that this exercise test, which has been approved by the American Heart Association/American College of Cardiology and the European Society of Cardiology, was highly inaccurate as almost twice the number of people who became breathless during the test did not develop symptoms within a year." The findings have been published in the world-leading European Heart Journal1, which showcases work often considered in future guidelines. Professor McCann now wants to conduct further research to find a more accurate way to determine whether doctors should wait for symptoms to develop or to intervene beforehand. Ultimately a clinical study comparing early surgery versus waiting for symptoms to develop is needed. The study was funded by the NIHR and most of the research was carried out at the NIHR Leicester Cardiovascular BRU. The NIHR BRUs are focused on translational clinical research, taking new ideas from the laboratory bench to the patient's bedside to improve health. The NIHR Leicester Cardiovascular BRU at Glenfield Hospital harnesses the power of experimental science to explore and develop ways to help prevent and treat cardiovascular conditions. The BRU is one of 20 units around England funded by the NIHR, the research arm of the NHS.
Evans R.A.,Glenfield Hospital |
Morgan M.D.L.,Glenfield Hospital
Clinics in Chest Medicine | Year: 2014
The systemic effects and comorbidities of chronic respiratory disease such as COPD contribute substantially to its burden. Symptoms in COPD do not solely arise from the degree of airflow obstruction as exercise limitation is compounded by the specific secondary manifestations of the disease including skeletal muscle impairment, osteoporosis, mood disturbance, anemia, and hormonal imbalance. Pulmonary rehabilitation targets the systemic manifestations of COPD, the causes of which include inactivity, systemic inflammation, hypoxia and corticosteroid treatment. Comorbidities are common, including cardiac disease, obesity, and metabolic syndrome and should not preclude pulmonary rehabilitation as they may also benefit from similar approaches. © 2014 Elsevier Inc.
Nicolaou G.,Glenfield Hospital |
Goodall A.H.,Glenfield Hospital |
Erridge C.,Glenfield Hospital
Journal of Atherosclerosis and Thrombosis | Year: 2012
Aim: Atherosclerotic lesions contain DNA signatures from a wide variety of bacteria, although little is known of how exposure to these organisms may modulate the accumulation of lipids in macrophages. Methods: To address this, a panel of nine bacteria representing those most frequently reported to be present in human atheroma were examined for their potential to promote lipid accumulation in human primary monocytes and murine J774 macrophages. Results: All bacteria examined, and defined stimulants of Toll-like receptors (TLRs) 2, 3, 4, 5 and 9, induced lipid body formation and cholesterol ester accumulation in a dose-dependent manner. The mechanisms of bacteria-mediated foam cell formation were found to be dependent on TLR2 and/or TLR4 signalling, but independent of lipoprotein oxidation pathways, since lipid accumulation was significantly inhibited by the TLR4 inhibitors polymyxin-B and TAK-242, or the TLR2 and TLR4 inhibitor oxidised palmitoyl-arachidonyl-phosphatidyl-choline, but not by the scavenger receptor blocker polyinosinic acid or the antioxidant butylated hydroxytoluene. A number of genes involved in lipid body biosynthesis, including perilipin-A, stearoyl-coenzyme-A desaturase 1, fatty acid synthase and HMG-CoA reductase were upregulated in response to TLR4 stimulation. Conclusions: The bacterial debris observed in human atheroma, which is currently considered to be harmless, may have potential to contribute to disease progression via TLR-dependent lipid body formation in macrophages.
Medford A.R.L.,Glenfield Hospital
Journal of Clinical Ultrasound | Year: 2010
Video-assisted thoracoscopy under local anesthesia (VAT-LA) is a key investigation in the diagnosis and management of suspected malignant pleural effusion. Two problems encountered at VAT-LA are accessing the pleural space and fibrinous intrapleural septa. Thoracic sonography (TUS) is known to facilitate thoracocentesis after dry tap but has not been studied in detail before VAT-LA. We report a case of lateral decubitus pre-VAT TUS that helped locate the optimal access to the pleural space and demonstrated fibrinous intrapleural septation, thereby affecting the decision to avoid thoracoscopic pleurodesis. © 2009 Wiley Periodicals, Inc.
Brack K.E.,University of Leicester |
Brack K.E.,Glenfield Hospital
Experimental Physiology | Year: 2015
Heart disease is a primary cause of mortality in the developed world, and it is well recognized that neural mechanisms play an important role in many cardiac pathologies. The role of extrinsic autonomic nerves has traditionally attracted the most attention. However, there is a rich intrinsic innervation of the heart, including numerous cardiac ganglia (ganglionic plexuses), that has the potential to affect cardiac function independently as well as to influence the actions of the extrinsic nerves. To investigate this, an isolated, perfused, innervated rabbit Langendorff heart preparation was considered the best option. Although ganglionic plexuses have been well described for several species, there was no full description of the anatomy and histochemistry of rabbit hearts. To this end, rabbit intrinsic ganglia were located using acetylcholinesterase histology (n = 33 hearts). This revealed six generalized ganglionic regions, defined as a left neuronal complex above the left pulmonary vein, a right neuronal complex around the base of right cranial vein, three scattered in the dorsal right atrium and a region containing numerous ventricular ganglia located on the conus arteriosus. Using immunohistochemistry, neurons were found to contain choline acetyltransferase or tyrosine hydroxylase and/or neuronal nitric oxide synthase in differing amounts (choline acetyltransferase > tyrosine hydroxylase > neuronal nitric oxide synthase). The function of rabbit intrinsic ganglia was investigated using a bolus application of nicotine or electrical stimulation at each of the above sites whilst measuring heart rate and atrioventricular conduction. Nicotine applied to different ganglionic plexuses caused a bradycardia, a tachycardia or a mixture of the two, with the right atrial plexus producing the largest chronotropic responses. Electrical stimulation at these sites induced only a bradycardia. Atrioventricular conduction was modestly changed by nicotine, the main response being a prolongation. Electrical stimulation produced significant prolongation of atrioventricular conduction, particularly when the right neuronal complex was stimulated. These studies show that the intrinsic plexuses of the heart are important and could be crucial for understanding impairments of cardiac function. Additionally, they provide a strong basis from which to progress using the isolated, innervated rabbit heart preparation. © 2014 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.
Pavord I.D.,Glenfield Hospital
Annals of the American Thoracic Society | Year: 2013
Our understanding of the clinical implications of eosinophilic airway in flammation has increased signi ficantly over the last 20 years, aided by the development of noninvasive means to assess it. This pattern of airway in flammation can occur in a diverse range of airway diseases. It is associated with a positive response to corticosteroids and a high risk of preventable exacerbations. Our new understanding of the role of eosinophilic airway inflammation has paved the way for the clinical development of a number of more speci fic inhibitors that may become new treatment options. Different defi nitions, ideas of disease, and adoption of biomarkers that are not well known are necessary to fully realize the potential of these treatments. Copyright © 2013 by the American Thoracic Society.
Ng G.A.,University of Leicester |
Ng G.A.,Glenfield Hospital
Experimental Physiology | Year: 2014
New findings: What is the topic of this review? This article addresses the relationship between vagus nerve activity and malignant ventricular arrhythmias. It focuses on the clinical association of an impaired vagal tone in cardiac disease states with high mortality from sudden cardiac death and the potential underlying mechanisms. What advances does it highlight? The article summarizes the mounting evidence that vagal innervation in the cardiac ventricle plays a key direct role in the prevention of the initiation of ventricular fibrillation. Data are presented on the role that nitric oxide plays in mediating the effects of vagal protection against ventricular fibrillation, supporting the notion that a separate non-muscarinic, nitrergic population of vagal neurons is responsible for this protection. Sudden cardiac death remains a significant unresolved clinical problem, with many of the deaths being due to malignant ventricular arrhythmias. Markers of abnormal autonomic function have been shown to be strong prognostic predictors, highlighting the important relationship between reduced vagal tone and malignant ventricular arrhythmias, such as ventricular fibrillation, in cardiac patients. Exploring the mechanisms underlying the autonomic modulation of ventricular fibrillation, my group has shown that vagus nerve stimulation protects against ventricular fibrillation in the innervated isolated heart preparation. We have provided direct evidence that nitric oxide is released in the ventricle with cervical vagus nerve stimulation and NO mediates the antifibrillatory actions of vagus nerve stimulation in the ventricle. Classical physiology teaches that vagal postganglionic nerves modulate the heart via acetylcholine acting at muscarinic receptors and, dogmatically, that there is little vagal effect in the ventricle, as innervation was believed to be sparse. Mounting evidence from many species now supports the presence of a rich vagal innervation in the ventricle. Data from my group showing that the protective actions of vagus nerve stimulation against ventricular fibrillation and NO release are preserved in the presence of muscarinic block support the notion that a population of nitrergic neurons could be responsible. This potentially exploitable downstream pathway together with the availability of vagus nerve stimulators make it an exciting time to investigate the development of an effective strategy of vagal protection against ventricular fibrillation in the clinical setting. © 2013 The Author. Experimental Physiology © 2013 The Physiological Society.
Corno A.F.,Glenfield Hospital
Interactive Cardiovascular and Thoracic Surgery | Year: 2016
To attract the interest of all people potentially involved in humanitarian activities in the emerging economies, in particular giving attention to the basic requirements of the organization of paediatric cardiac surgery activities, the requirements for a successful partnership with the local existing organizations and the basic elements of a patient-centred multidisciplinary integrated approach. Unfortunately, for many years, the interventions in the low and middle income countries were largely limited to short-term medical missions, not inappropriately nicknamed 'surgical safari', because of negative general and specific characteristics. The negative aspects and the limits of the short-term medical missions can be overcome only by long-term educational programmes. The most suitable and consistent models of long-term educational programmes have been combined and implemented with the personal experience to offer a proposal for a long-term educational project, with the following steps: (i) site selection; (ii) demographic research; (iii) site assessment; (iv) organization of surgical educational teams; (v) regular frequency of surgical educational missions; (vi) programme evolution and maturation; (vii) educational outreach and interactive support. Potential limits of a long-term educational surgical programme are: (i) financial affordability; (ii) basic legal needs; (iii) legal support; (iv) non-profit indemnification. The success should not be measured by the number of successful operations of any given mission, but by the successful operations that our colleagues perform after we leave. Considering that the children in need outnumber by far the people able to provide care, in this humanitarian medicine there should be plenty of room for cooperation rather than competition. The main goal should be to provide teaching to local staff and implement methods and techniques to support the improvement of the care of the patients in the long run. This review focuses on the organization of paediatric cardiac activities in the emerging economies, but 'the less privileged parts of the world' can be anywhere, not necessarily limited to economic constraints. Lack of diversity because of social, intellectual, educational and professional growth, the last consisting in cultural stagnation, is responsible for the lack of scientific progress and development. © 2016 The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
Nakas A.,Glenfield Hospital |
Waller D.,Glenfield Hospital
European Journal of Cardio-thoracic Surgery | Year: 2014
Objectives: The aim of radical surgery for malignant pleural mesothelioma (MPM) is to achieve greater survival than from chemotherapy alone. Although adverse overall prognostic factors have already been determined, our aim was to identify the most important factors affecting long-term survival arbitrarily defined as >24 months. Methods: We retrospectively reviewed the records of 252 patients (35 females; 193 epithelioid and 59 biphasic; 112 extrapleural pneumonectomy (EPP); 140 extended pleurectomy decortication (EPD)) who survived for at least 90 postoperative days. We tested for factors affecting overall cancer-related mortality and specific clinical factors predicting the 24-month survival. Results: The overall median survival was 18.2 (SE 1.3, 95% CI 15.8-20.7 months). There was no difference in survival between EPP and EPD (P = 0.92). One hundred and twenty-eight patients received induction, adjuvant or palliative chemotherapy. Seventy-seven (30.6%) patients survived for >24 months. On univariate analysis, age at operation over 60 years (P = 0.044), pT4 stage (P = 0.041), any lymph node metastases (P = 0.002), biphasic cell type (P = 0.00) and no administration of chemotherapy (P = 0.00) were associated with decreased survival. On multivariate analysis, age <60 (P = 0.018, OR = 0.7), epithelioid disease (P = 0.001, OR = 0.56) and negative nodes (P = 0.009, OR = 0.67) were associated with increased survival and no administration of chemotherapy (P = 0.00, OR = 1.9) with decreased survival. Factors predicting survival over 24 months included: age at operation under 60 (P = 0.014), epithelioid histology (P ≤ 0.00), negative nodes (P = 0.002) and chemotherapy (P = 0.022). Conclusions: These results support a policy of accurate preoperative tissue diagnosis, nodal staging and induction chemotherapy prior to radical surgery for MPM, which can result in long-term survival. Trials investigating the role of surgery should be focused on confirming and refining these selection criteria. © The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.