Caunt C.J.,University of Bath |
Keyse S.M.,Ninewells Hospital
FEBS Journal | Year: 2013
Dual-specificity MAP kinase phosphatases (MKPs) provide a complex negative regulatory network that acts to shape the duration, magnitude and spatiotemporal profile of MAP kinase activities in response to both physiological and pathological stimuli. Individual MKPs may exhibit either exquisite specificity towards a single mitogen-activated protein kinase (MAPK) isoform or be able to regulate multiple MAPK pathways in a single cell or tissue. They can act as negative feedback regulators of MAPK activity, but can also provide mechanisms of crosstalk between distinct MAPK pathways and between MAPK signalling and other intracellular signalling modules. In this review, we explore the current state of knowledge with respect to the regulation of MKP expression levels and activities, the mechanisms by which individual MKPs recognize and interact with different MAPK isoforms and their role in the spatiotemporal regulation of MAPK signalling. © 2012 The Authors Journal compilation © 2012 FEBS.
Welte T.,Klinik fur Pneumologie |
Torres A.,University of Barcelona |
Nathwani D.,Ninewells Hospital
Thorax | Year: 2012
It is difficult to determine the impact of community-acquired pneumonia (CAP) in Europe, because precise data are scarce. Mortality attributable to CAP varies widely between European countries and with the site of patient management. This review analysed the clinical and economic burden, aetiology and resistance patterns of CAP in European adults. All primary articles reporting studies in Europe published from January 1990 to December 2007 addressing the clinical and economic burden of CAP in adults were included. A total of 2606 records were used to identify primary studies. CAP incidence varied by country, age and gender, and was higher in individuals aged ≥65 years and in men. Streptococcus pneumoniae was the most common agent isolated. Mortality varied from <1% to 48% and was associated with advanced age, co-morbid conditions and CAP severity. Antibiotic resistance was seen in all pathogens associated with CAP. There was an increase in antibiotic-resistant strains, but resistance was not related to mortality. CAP was associated with high rates of hospitalisation and length of hospital stay. The review showed that the clinical and economic burden of CAP in Europe is high. CAP has considerable long-term effects on quality of life, and long-term prognosis is worse in patients with pneumococcal pneumonia.
Belch J.J.F.,Ninewells Hospital |
Dormandy J.,St Georges Hospital
Journal of Vascular Surgery | Year: 2010
Objective: Dual antiplatelet therapy with clopidogrel plus acetylsalicylic acid (ASA) is superior to ASA alone in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention. We sought to determine whether clopidogrel plus ASA conferred benefit on limb outcomes over ASA alone in patients undergoing below-knee bypass grafting. Methods: Patients undergoing unilateral, below-knee bypass graft for atherosclerotic peripheral arterial disease (PAD) were enrolled 2 to 4 days after surgery and were randomly assigned to clopidogrel 75 mg/day plus ASA 75 to 100 mg/day or placebo plus ASA 75 to 100 mg/day for 6 to 24 months. The primary efficacy endpoint was a composite of index-graft occlusion or revascularization, above-ankle amputation of the affected limb, or death. The primary safety endpoint was severe bleeding (Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries [GUSTO] classification). Results: In the overall population, the primary endpoint occurred in 149 of 425 patients in the clopidogrel group vs 151 of 426 patients in the placebo (plus ASA) group (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.78-1.23). In a prespecified subgroup analysis, the primary endpoint was significantly reduced by clopidogrel in prosthetic graft patients (HR, 0.65; 95% CI, 0.45-0.95; P = .025) but not in venous graft patients (HR, 1.25; 95% CI, 0.94-1.67, not significant [NS]). A significant statistical interaction between treatment effect and graft type was observed (Pinteraction = .008). Although total bleeds were more frequent with clopidogrel, there was no significant difference between the rates of severe bleeding in the clopidogrel and placebo (plus ASA) groups (2.1% vs 1.2%). Conclusion: The combination of clopidogrel plus ASA did not improve limb or systemic outcomes in the overall population of PAD patients requiring below-knee bypass grafting. Subgroup analysis suggests that clopidogrel plus ASA confers benefit in patients receiving prosthetic grafts without significantly increasing major bleeding risk. © 2010 Society for Vascular Surgery.
Gifford A.M.,Ninewells Hospital |
Chalmers J.D.,University of Dundee
Current Opinion in Hematology | Year: 2014
PURPOSE OF REVIEW: Neutrophils are known to dominate the pulmonary inflammatory process observed in cystic fibrosis (CF). An enduring paradox is how these large numbers of neutrophils fail to eradicate colonizing bacteria. Major advances in our understanding of neutrophil dysfunction in CF and its effect on the innate immune system are leading to advances in our understanding of the pathophysiology and leading directly to new therapies. RECENT FINDINGS: New mechanisms of neutrophil dysfunction have been described in CF including disabled cystic fibrosis transmembrane conductance regulator recruitment to phagosomes and novel mechanisms of protease-induced neutrophil dysfunction. Neutrophil elastase has been shown to be present in the airway very early in life in CF patients, and appears a biomarker of disease progression, predicting lung function decline and bronchiectasis. Elastase has also been shown to induce a pro-inflammatory state of senescence in bronchial epithelial cells in vitro and potentially in vivo. Inhibitors of neutrophil elastase are now entering clinical trials with promising results. New avenues of CF therapeutics are being explored including novel macrolides, CXCR2 antagonists and exogenous opsonins. SUMMARY: This article reviews the past 12 months of research that contributes to our understanding of the role of neutrophils and immune dysfunction in CF. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Kerr A.,Ninewells Hospital
Photodermatology, photoimmunology & photomedicine | Year: 2010
BACKGROUND: Photoallergic contact dermatitis (PACD) presents in patients after certain exogenous agents come into contact with the skin in the presence of ultraviolet and/or visible light. The best method currently available for investigating PACD is photopatch testing. However, photopatch testing as an investigation is under-used by clinicians, and therefore PACD may go undetected in many patients. PURPOSE: To highlight the importance of PACD and photopatch testing when investigating patients with a photo-exposed site dermatosis. METHOD: A comprehensive review of the available literature relating to PACD and photopatch testing. RESULTS: Experimental evidence suggests that PACD is a delayed type hypersensitivity reaction. Various agents have been historically shown to cause PACD, but currently the most common photosensitizers are sunscreens and topical non-steroidal anti-inflammatory drugs. Photopatch testing has in the past been subject to differing methodologies; however, a European consensus methodology now exists and should allow a greater comparison of results across centres. As chemical, pharmaceutical, and cosmetic industries produce new agents, photopatch testing of such agents in humans before release in the marketplace may prevent widespread contact with potent photosensitizers. It will also be important for ongoing multi-centre studies of existing agents to be conducted in order to keep the photopatch test batteries used by clinicians investigating PACD up to date.
Kerr A.C.,Ninewells Hospital
Clinical and Experimental Dermatology | Year: 2011
The frequency, and thus availability to patients, of ultraviolet (UV) filters contained within sunscreens changes over time. Obtaining current data on filter availability is necessary when considering which agents to include in sunscreen series for patch and photopatch testing of patients. A survey of sunscreen products was undertaken in Dundee, UK, in 2010. In total, 337 products were identified, with a median sun-protection factor of 30 (range 2-50+). In these products, 19 UV filters were identified, of which the most common was butyl methoxydibenzoylmethane. Compared with data from 2005, most filters had an increase in frequency of inclusion, with a trend towards broader spectrum protection. This information should be of use to clinicians considering investigation of contact and photocontact allergy. It also aids determination of the allergenic potential of these filters when reports of allergy and photocontact allergy arise in the literature. © The Author(s). CED © 2011 British Association of Dermatologists.
Bonner J.C.,Ninewells Hospital |
McClymont W.,Ninewells Hospital
Anaesthesia | Year: 2012
Remifentanil patient-controlled analgesia is well established in many centres and provides satisfactory pain relief for many women in labour. We describe a patient using remifentanil patient-controlled analgesia who suffered a respiratory arrest requiring a brief period of ventilation. In our institution, remifentanil patient-controlled analgesia has been offered to women in labour since 2009. Up to this point, we had not observed any critical incidents in over 130 patients using this mode of analgesia in our labour suite. Anaesthesia © 2012 The Association of Anaesthetists of Great Britain and Ireland.
Morrison I.,Ninewells Hospital
Sleep medicine reviews | Year: 2014
This review is aimed at summarizing the current state of knowledge regarding parasomnias, which have been implicated in medicolegal cases as well as providing guidance to those working within common-law jurisdictions regarding the technical aspects of the law. Sleepwalking and sexsomnia as a defence are being raised more frequently in criminal cases and there has been public debate on their validity. Unfortunately, expert evidence on forensic sleep disorders continues to be heavily opinion-based with the potential for miscarriages of justice seen in recent highly publicized cases. There is an apparent inertia in research into violent sleep disorders. We review the current state of forensic sleep science in the United Kingdom (UK) and abroad and discuss the need to formulate guidelines based on available evidence. We also highlight the pressing necessity for more research in this area as well as the need to reform the law, which is the subject of a recent Criminal Law Commission report in the United Kingdom. In time, this will facilitate the efficient, proportionate, and just disposal of violence arising from sleep, thus benefitting both society and the individual sufferer. Copyright © 2013 Elsevier Ltd. All rights reserved.
Hiom K.,Ninewells Hospital
DNA Repair | Year: 2010
The FANCJ protein (also known as BACH1 and BRIP1) is a DNA helicase that is required to preserve the genetic and structural integrity of the genome in complex eukaryotes. In humans, mutations in FANCJ are associated with the chromosome instability disorder Fanconi's anemia and also with the inherited predisposition early-onset breast cancer. Here I will discuss the contribution of FANCJ to human disease, its role in maintenance of genome stability and some current thoughts on the mechanisms through which this is achieved. © 2010 Elsevier B.V. All rights reserved.
Eljamel S.,Ninewells Hospital
Photodiagnosis and Photodynamic Therapy | Year: 2010
Introduction: GBM is the comment glioma. GBM-outcome had not changed much over two decades despite leaps in medical technology. Fewer than 25% survive 2 years. There is no jacket that fits all GBMs. This paper reviews the evidence for PDT in GBMs. Rationale: Maximum safe resection is supported by level-II evidence. PDT-technology (PDTT) provides means to maximize safe resection. PDTT paints GBM red in contrast to brain because of selective uptake and retention of photosensitizers. Exposure to specific light wave produces cytotoxic singlet oxygen. PDT-applications: (1)Fluorescence image guided biopsy to sample high grade components of what looks like low grade glioma on MRI, 89% sensitive.(2)Fluorescence image guided surgery for maximum safe surgical resection is >84% sensitive, achieves complete resection in >65% and prolongs tumor free survival (1 observational and 2 RCT, p < 0.001).(3)Photodynamic treatment supported by several observational studies with combined total of >1000 patients and 3 RCT used PDT in GBMs. PDT was highly selective, safe, significantly improved good quality survival, and delayed tumor relapse (p < 0.001). Safety: PDT had a very high safety track record, thromboemolism 2%, brain-oedema 1.3%, and skin photosensitivity complications 1-3%. Conclusion: PDT in GBMs is safe, selective, and sensitive and leads to significant prolongation of good quality survival, delay in tumor relapse and significant reduction of further interventions. It would be impractical, impossible and probably unethical to randomize patients between PDT and placebo, in the same way it would be unethical to carry out a RCT to prove that the parachute saves lives. © 2010 Elsevier B.V. All rights reserved.