382 results on '"Ken Donaldson"'
Search Results
2. Inhaled nanoparticles and lung cancer – what we can learn from conventional particle toxicology
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Ken Donaldson and Craig A. Poland
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Cancer ,genotoxicity ,inflammation ,nanoparticles ,nanotubes ,Oxidative stress ,Medicine - Abstract
Manufactured nanoparticles (MNP) represent a growth area in industry where their interesting and useful properties bestow advantage over conventional particles for many purposes. This review specifically addresses the potential for lung cancer in those who might be exposed to airborne MNP. There is no strong evidence that MNP are carcinogenic and MNP come in a wide spectrum of materials, sizes, shapes and compositions and it is likely that the hazard will vary across different MNP types dependent upon their intrinsic properties. Low toxicity low solubility (LTLS) MNP are unlikely to pose a substantial cancer risk as they are not very biologically active. Nanoparticles with a more reactive surface may undoubtedly generate inflammation more readily and inflammation could be sufficiently intense to lead to secondary carcinogenesis via the oxidants and mitogens produced during inflammation. There is some evidence in vitro that MNP can gain access to the nucleus and the genetic material if specifically designed to do so by surface modification and that nanoparticles such as carbon nanotubes (CNT) can cause genetic aberrations by a primary mechanism additional to the inflammation–mediated one; these potential mechanisms require further study. High aspect ratio nanoparticles (HARN) are MNP that are fibre-shaped and analogously to asbestos might pose a special cancer hazard to the lungs, pleural and peritoneal mesothelium. Recent research suggests that the existing fibre pathogenicity paradigm is adequate for describing the hazard of HARN and that making the HARN of a non-biopersistent material or restricting the length could, via benign-by-design principles, allow safe HARN to be produced.
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- 2012
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3. Diesel exhaust particle exposure in vitro alters monocyte differentiation and function.
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Nazia Chaudhuri, Hannah Jary, Simon Lea, Naimat Khan, Katie C Piddock, David H Dockrell, Ken Donaldson, Rodger Duffin, Dave Singh, Lisa C Parker, and Ian Sabroe
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Medicine ,Science - Abstract
Air pollution by diesel exhaust particles is associated with elevated mortality and increased hospital admissions in individuals with respiratory diseases such as asthma and chronic obstructive pulmonary disease. During active inflammation monocytes are recruited to the airways and can replace resident alveolar macrophages. We therefore investigated whether chronic fourteen day exposure to low concentrations of diesel exhaust particles can alter the phenotype and function of monocytes from healthy individuals and those with chronic obstructive pulmonary disease. Monocytes were purified from the blood of healthy individuals and people with a diagnosis of chronic obstructive pulmonary disease. Monocyte-derived macrophages were generated in the presence or absence of diesel exhaust particles and their phenotypes studied through investigation of their lifespan, cytokine generation in response to Toll like receptor agonists and heat killed bacteria, and expression of surface markers. Chronic fourteen day exposure of monocyte-derived macrophages to concentrations of diesel exhaust particles >10 µg/ml caused mitochondrial and lysosomal dysfunction, and a gradual loss of cells over time both in healthy and chronic obstructive pulmonary disease individuals. Chronic exposure to lower concentrations of diesel exhaust particles impaired CXCL8 cytokine responses to lipopolysaccharide and heat killed E. coli, and this phenotype was associated with a reduction in CD14 and CD11b expression. Chronic diesel exhaust particle exposure may therefore alter both numbers and function of lung macrophages differentiating from locally recruited monocytes in the lungs of healthy people and patients with chronic obstructive pulmonary disease.
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- 2012
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4. Richard Muir: Edinburgh-based pioneer biomedical scientist and medical artist
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Ken Donaldson and Christopher Henry
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History and Philosophy of Science ,Medicine (miscellaneous) ,humanities - Abstract
Richard Muir (1862—1931) began his career as a ‘lab boy’ in the Pathology Department of the University of Edinburgh in 1876 at the age of 13. This was a newly created category of worker that eventually became today's biomedical scientist Muir rapidly gained expertise in pathological and bacteriological techniques including staining and microscopy. Exceptionally, for someone non-medical and non-university-educated individual, he was elected a member of the Pathological Society of Great Britain and appointed Demonstrator in Pathology in the University of Edinburgh Pathology Department. He authored papers on staining techniques for bacteria and on the pathology of syphilis of the ear and became a recognised diagnostic histopathologist, despite having no medical qualifications. He especially excelled as an artist, depicting the microscopic world of pathology and microbiology and produced diagrams for hundreds of publications including his own book and also large wall hangings of the microscopic world for teaching purposes. This paper describes the unique contribution of Richard Muir to pathology in Edinburgh and beyond in the early 20th century.
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- 2022
5. The recognition of lung disease in coal workers: The role of Gough–Wentworth whole lung sections
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Ken, Donaldson, William A, Wallace, William, MacNee, Christopher, Henry, and Anthony, Seaton
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Emphysema ,Lung Diseases ,Coal ,Pulmonary Emphysema ,Humans ,Dust ,Quartz ,General Medicine ,Coal Mining ,Lung ,Education - Abstract
From the identification of a specific lung disease caused by coal dust exposure in miners in 1831 until the demonstration of the association of that exposure to risk of emphysema in 1984, there was continuous argument about the harmfulness of coal dust. Ill health in miners was attributed variously to tuberculosis, quartz exposure or cigarette smoking. An acceptance that coal dust was harmful only started with investigative radiology and pathology in the 1920s, and physiology in the 1950s. Most of the early investigations were in South Wales, the centre of the most important coal field in Great Britain. Among the investigators was Professor Jethro Gough who, with his technician James Wentworth, introduced a technique for making thick sections of whole, inflated lungs on paper backing. Here, we describe this method and its central role in understanding the relationships between coal dust exposure, pneumoconiosis, emphysema and lung dysfunction in miners.
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- 2022
6. Length-dependent pleural inflammation and parietal pleural responses after deposition of carbon nanotubes in the pulmonary airspaces of mice
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Ken Donaldson, Fiona Murphy, Rodger Duffin, and Craig A Poland
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Pathology ,medicine.medical_specialty ,Materials science ,Biomedical Engineering ,Inflammation ,Neutrophilic inflammation ,Toxicology ,Mice ,medicine ,Animals ,Mesothelioma ,Pleurisy ,Inhalation Exposure ,medicine.diagnostic_test ,Nanotubes, Carbon ,respiratory system ,Pleural cavity ,medicine.disease ,respiratory tract diseases ,Diaphragm (structural system) ,Bronchoalveolar lavage ,medicine.anatomical_structure ,Nanotoxicology ,Pleura ,Thickening ,medicine.symptom - Abstract
Background: Carbon nanotubes (CNT) are fibre-like nanomaterials whose structural similarity to asbestos has raised concerns that they may also pose a mesothelioma hazard. The objective of this study was to examine the inflammatory potential of three CNT samples of differing length on the lungs and pleural cavity following introduction into the airspaces of mice. ResultsAspiration of the two short/tangled and one long CNT sample into the lungs of mice resulted in a length-dependent inflammatory response at 1 week, i.e., only the long CNT sample caused acute neutrophilic inflammation in bronchoalveolar lavage at 1 week and progressive thickening of the alveolar septa. The authors also report length-dependent inflammatory responses in the pleural lavage after exposure only to the long CNT. The inflammatory response in the pleural cavity to long fibres and the appearance of lesions along the chest wall and diaphragm was not present at 1 week and only evident by 6 weeks post-exposure. Conclusion: Length-dependent pathogenicity is a feature of asbestos and the results presented in this study demonstrate similar length-dependent pathogenicity of CNT in the lungs and pleural space following airspace deposition. The data support the contention that long CNT reach the pleura from the airspaces, and that they are retained at the parietal pleura and cause inflammation and lesion development. The parietal pleura is the site of origin of mesothelioma and inflammation is considered to be a process involved in asbestos carcinogenesis and so the data support the contention that CNT may pose an asbestos-like mesothelioma hazard.
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- 2023
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7. Dr Robert Knox and his book on fishing in Scotland: A window into his mind
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Ken Donaldson and Christopher Henry
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Male ,Scotland ,Humans ,Hunting ,History, 19th Century ,General Medicine ,Homicide ,Education - Abstract
Robert Knox was publicly vilified for his suspected complicity in the 16 murders committed by Burke and Hare, although he had no involvement in them. Along with several books on anatomy Knox also wrote a book on angling in Lowland Scotland. In ‘Fish and Fishing in the Lone Glens of Scotland’ Knox’s deep love for nature and for fishing emerges. Most interesting however is that although generally focussed on fish and fishing, the book abounds with asides on Knox’s other preoccupations and passions. These provide rare insights into the character of the great anatomist, whose personality has otherwise retained its opacity over the years. In the book, Knox writes in passing and in a relatively unguarded fashion, about such topics as transcendental anatomy, Scottish Independence, empiricism, race and Edinburgh medical figures. In so-doing, we contend that he affords the reader some insight into the mind of the real Dr Robert Knox.
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- 2022
8. John Goodsir and Local Opposition to Rudolf Virchow'S Election to Fellowship of the Royal Society of Edinburgh in 1868
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Christopher Henry and Ken Donaldson
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Male ,Cellular pathology ,Opposition (planets) ,Cell theory ,Philosophy ,History, 19th Century ,General Medicine ,English language ,Dissent and Disputes ,Brother ,Education ,Death ,03 medical and health sciences ,0302 clinical medicine ,Humans ,030212 general & internal medicine ,Fellowships and Scholarships ,Societies ,Classics - Abstract
In 1869 Rudolf Virchow, the distinguished Prussian pathologist who pioneered the modern concept of cellular pathology, was offered an honorary Fellowship of The Royal Society of Edinburgh (RSE). However, the Rev. Joseph T Goodsir, Fellow of the Royal Society of Edinburgh (FRSE), the brother of Professor John Goodsir FRSE, the famed Edinburgh anatomist who had died two years previously, mounted a campaign to stop the award. As part of this he published a pamphlet entitled Grounds of Objection to the Admission of Professor Virchow as an Honorary Fellow of the Royal Society of Edinburgh. The disagreement centred on John Goodsir's pioneering research and writings on cell theory. These had in fact been recognised by Virchow, who dedicated the English language edition of his most famous publication Cellular Pathology to John Goodsir. Joseph Goodsir was not, however, satisfied by this and the basis of his objection was that Virchow had plagiarised from his brother. We describe the background and outcome of this dispute.
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- 2020
9. John Goodsir: discovering Sarcina ventriculi and diagnosing Darwin’s dyspepsia
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Ken Donaldson and Christopher Henry
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business.industry ,Watery fluid ,General Medicine ,Ancient history ,Every Morning ,03 medical and health sciences ,0302 clinical medicine ,Charles darwin ,Male patient ,Darwin (ADL) ,Medicine ,030211 gastroenterology & hepatology ,030212 general & internal medicine ,Sarcina ventriculi ,business - Abstract
In 1842, when John Goodsir was Conservator to the Museum of the RCSEd, he saw a 19-year-old male patient who vomited a large volume of acidic, fermented-smelling, watery fluid every morning. Under his microscope, Goodsir found the vomitus to be populated with a micro-organism he named Sarcina ventriculi, which he considered to be causative. In so-doing, Goodsir became one of the first people to link a specific micro-organism with a disease. Goodsir recommended small doses of creosote as an antiseptic and claimed that the boy was eventually cured of the vomiting condition. In August of 1863 Charles Darwin was hugely celebrated by the scientific community and the public, but he had suffered from severe stomach problems all his adult life and at this point, he was vomiting daily. He read Goodsir’s paper and contacted him and asked if he could send some vomitus samples to Edinburgh in the hope that Goodsir might find Sarcina in it and solve the mystery of his debilitating stomach symptoms and perhaps cure them with creosote. Goodsir examined samples in his microscope, but failed to find Sarcina. Sadly, Darwin went on to suffer constantly from severe stomach problems, recently attributed to lactose intolerance, until he died in 1882, some 20 years later.
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- 2020
10. Black Lungs in the General Population: A New Look at An Old Dispute
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Ken Donaldson, Christopher Henry, Anthony Seaton, and William A Wallace
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lcsh:R5-920 ,Anthracosis ,education.field_of_study ,History ,anthracosis ,carbon ,air pollution ,Population ,History, 19th Century ,Pigments, Biological ,General Medicine ,History, 20th Century ,Ancient history ,History, 18th Century ,Coal Mining ,Education ,Soot ,Humans ,centrilobular region ,lcsh:Medicine (General) ,education ,Black spot - Abstract
Almost from the time that autopsies were first routinely carried out, darkening of lungs with increasing age was described. Different explanations for the origin of the accumulating black pigment arose and by the early nineteenth century three hypotheses had emerged: 1) soot inhaled into the lungs from the air; 2) carbon accumulating in the lungs from abnormal pulmonary carbon dioxide metabolism; and, 3) pigment derived from the blood. In 1813 the English physician and chemist George Pearson published a paper in which he described the recovery of the black pigment from lungs and its chemical analysis. Pearson declared the black pigment to be airborne carbon/soot from the burning of coal and wood. He described these particles depositing in ‘black spots’ in the terminal airways and accumulating in the peribronchial lymph nodes, forming ‘black glands'. Despite Pearson's prescient account, debate continued and the true explanation, given in that paper, was not fully accepted until the late nineteenth century.
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- 2019
11. Nanoscience fact versus fiction.
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Ken Donaldson and Vicki Stone
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- 2004
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12. P35 Delivering a community-based COVID-19 rehabilitation service using existing pulmonary rehabilitation teams is safe and feasible
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J Newsham, P Haslam, J Talbot, K Prior, N Turner, F Clarke, A Kinley, A Brenton, and Ken Donaldson
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Service (business) ,Rehabilitation ,Coronavirus disease 2019 (COVID-19) ,business.industry ,medicine.medical_treatment ,Psychological intervention ,medicine.disease ,Triage ,Integrated care ,medicine ,Virtual training ,Pulmonary rehabilitation ,Medical emergency ,business - Abstract
Background University Hospitals of Morecambe Bay NHS Trust, witnessed an early peak of COVID-19 with related hospital admissions in early 2020, this created a need for a coordinated approach to post COVID-19 rehabilitation needs across the area Objectives A three-armed COVID-19 rehabilitation pathway was devised in March 2020 with Arm 1 aiming to assess and address the immediate rehabilitation needs of those leaving hospital following an admission for respiratory complications of COVID-19 Methods Existing Pulmonary Rehabilitation teams were repurposed by integrated care network (MBRN) to be a new 'Virtual' rehabilitation service A register of patients discharged from hospital sites was remotely screened for pathway suitability Then, using a multi-professional template a holistic assessment needs was conducted using telephone and/or home visit consultations Clinical assessment tools were built into the assessment process Weekly 'acute-community' virtual in-service training sessions and multi-disciplinary case discussions supported the clinicians Results To date 207 patients have entered the service for virtual triage, 138 patients were deemed suitable for further assessment and interventions 427 direct clinician consultations were delivered to these 138 patients [122 initial telephone assessments;53 initial home visit assessments;168 follow-up telephone consultations;84 follow-up home visits] Two of the 138 patients assessed died, both were expected deaths No clinical incidents occurred and no staff contracted COVID-19 during this period Feedback from the services' staff survey was very positive highlighting the supportive value of virtual training and MDT and the enjoyment of being part of creating and delivering this new service to patients recovering from COVID-19 Conclusions Utilising the skills of pulmonary rehabilitation staff to deliver a holistic rehabilitation and treatment service to those discharged from hospital after suffering respiratory complications of COVID-19 was feasible, safe and well tolerated by staff and patients This service is now being used to address the needs of post-COVID-19 patients presenting with respiratory needs in the community We aim also to assess clinical outcome
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- 2021
13. The toxicology of ultrafine particles
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Ken Donaldson, William MacNee, and Vicki Stone
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Chemical engineering ,Chemistry ,Ultrafine particle - Published
- 2020
14. John Goodsir: discovering
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Ken, Donaldson and Charles, Darwin
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Causality ,Male ,Young Adult ,Vomiting ,Sarcina ,Stomach Diseases ,Humans ,History, 19th Century ,Dyspepsia ,Gram-Positive Bacterial Infections - Abstract
In 1842, when John Goodsir was Conservator to the Museum of the RCSEd, he saw a 19-year-old male patient who vomited a large volume of acidic, fermented-smelling, watery fluid every morning. Under his microscope, Goodsir found the vomitus to be populated with a micro-organism he named
- Published
- 2020
15. Induction of protein citrullination and auto-antibodies production in murine exposed to nickel nanomaterials
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Ken Donaldson, Anja Schinwald, Adriele Prina-Mello, Yuri Volkov, Ronan Ward, Steven G. Gray, Tatsiana Rakovich, Omar K. Mahfoud, Bashir M. Mohamed, Noreen T. Boyle, Kieran Crosbie-Staunton, and Bruno Murer
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0301 basic medicine ,Mesothelioma ,Hydrolases ,lcsh:Medicine ,Spleen ,medicine.disease_cause ,Kidney ,Protein citrullination ,Article ,Autoimmunity ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Nickel ,Cell Line, Tumor ,medicine ,Animals ,Humans ,lcsh:Science ,Autoantibodies ,A549 cell ,Multidisciplinary ,Chemistry ,Nanowires ,lcsh:R ,Kidney metabolism ,Citrullination ,Proteins ,3. Good health ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,A549 Cells ,030220 oncology & carcinogenesis ,Cancer cell ,Antibody Formation ,Cancer research ,Female ,lcsh:Q ,Lymph Nodes ,Carcinogenesis - Abstract
Citrullination, or the post-translational deimination of polypeptide-bound arginine, is involved in several pathological processes in the body, including autoimmunity and tumorigenesis. Recent studies have shown that nanomaterials can trigger protein citrullination, which might constitute a common pathogenic link to disease development. Here we demonstrated auto-antibody production in serum of nanomaterials-treated mice. Citrullination-associated phenomena and PAD levels were found to be elevated in nanomaterials -treated cell lines as well as in the spleen, kidneys and lymph nodes of mice, suggesting a systemic response to nanomaterials injection, and validated in human pleural and pericardial malignant mesothelioma (MM) samples. The observed systemic responses in mice exposed to nanomaterials support the evidence linking exposure to environmental factors with the development of autoimmunity responses and reinforces the need for comprehensive safety screening of nanomaterials. Furthermore, these nanomaterials induce pathological processes that mimic those observed in Pleural MM, and therefore require further investigations into their carcinogenicity.
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- 2018
16. James Craufurd Gregory, 19Th Century Scottish Physicians, and the Link between Occupation as a Coal Miner and Lung Disease
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T A Elliot, Ken Donaldson, William A Wallace, and Christopher Henry
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History ,Coal dust ,complex mixtures ,Education ,03 medical and health sciences ,0302 clinical medicine ,phthisis ,Occupational Exposure ,Physicians ,Economic history ,medicine ,Humans ,0601 history and archaeology ,Coal ,Occupations ,Industrial Revolution ,Lung ,lungs ,Anthracosis ,lcsh:R5-920 ,Coal mine dust ,business.industry ,Pneumoconiosis ,Coal mining ,Dust ,History, 19th Century ,06 humanities and the arts ,General Medicine ,respiratory system ,medicine.disease ,Coal Mining ,respiratory tract diseases ,Occupational Diseases ,Scotland ,030228 respiratory system ,060105 history of science, technology & medicine ,Lung disease ,melanoptysis ,pathology ,coal worker’s pneumoconiosis ,lcsh:Medicine (General) ,business - Abstract
By the mid-19th century about 200,000 miners were employed in a UK coalmining industry still growing with the advance of the Industrial revolution. Coalminers were long known to suffer poor health and a shortened lifespan but the link to inhaling dust in the coalmines had not been made. In 1813 George Pearson was the first to suggest that darkening of lungs seen in normal individuals as they aged was caused by inhaled soot from oil, candles and coal burning that were the common domestic source of heat and light. In a published case report in 1831 Dr James Craufurd Gregory of Edinburgh first described black pigmentation and disease in the lungs of a deceased coalminer and linked the two to pulmonary accumulation of coalmine dust. Gregory hypothesised that the black material seen at autopsy in the collier’s lungs was inhaled coal dust and this was confirmed by chemical analysis carried out by Professor Sir Robert Christison, the Edinburgh physician and toxicologist. Gregory suggested that the coal dust was the cause of the disease and warned physicians in mining areas to be vigilant for the disease in their patients. This first description of what came to be known as Coalworker’s Pneumoconiosis sparked a remarkable intellectual effort by physicians in Scotland, culminating in a large body of published work which led to the first understandings of this disease and its link to coal-blackened lungs. The present paper sets out the history of the role of Scottish physicians in gaining this understanding of Coalworker’s Pneumoconiosis in the 19th century. It also describes Gregory’s case and the lung on which Gregory based his landmark paper, which has recently been discovered in the pathology collection of the Surgeons Hall Museums, Edinburgh, where it has lain un-noticed for over 180 years.
- Published
- 2017
17. Risk profiling and control of spontaneous combustion for coal mine closure
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Basil Beamish, Ken Donaldson, and Brad Williams
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Risk analysis (engineering) ,Work (electrical) ,business.industry ,Computer science ,Coal mining ,Coal ,Closure (psychology) ,business ,Risk assessment ,Hazard ,Spontaneous combustion ,Risk management - Abstract
The Leigh Creek Coal Mine, located approximately 550 km north of Adelaide in South Australia, operated between 1944 and 2015. The coal, being a low rank sub-bituminous coal, is prone to self-heating and localised spontaneous combustion. Throughout the many decades of mining operation a significant body of knowledge was generated regarding the causal factors and more effective treatment strategies for spontaneous combustion. These strategies were effectively suited to an operational mine site, but not specifically designed, nor tested, for closure. A swift decision to close in June 2015, followed by a short mining operations shutdown period, presented significant operational, technical and regulatory challenges. The subsequent joint risk mapping process employed by Flinders Power and South Australian Mining Regulators was a unique example of obtaining realtime objective evidence through leading-edge science in order to inform the risk profile, determine the appropriate risk management strategies for closure and develop an appropriate mine closure plan. In developing the risk assessment for closure, the following three key assumptions needed to be tested. These assumptions were founded on operational experience and expert advice, however applicability to a rehabilitation phase had not been validated for the site. To address these uncertainties extensive laboratory test work and a unique field trial installation on an area of active combustion was conducted. The testing of these assumptions formed the basis of the rehabilitation specification, area-specific rehabilitation designs and subsequent completion criteria. The use of a risk and evidentiary-based approach to categorise spontaneous combustion hazard likelihood for developing an appropriate rehabilitation design across the vast 70 km2 open cut coal mine forms the basis for this paper.
- Published
- 2019
18. A demonstration of the cessation of spontaneous combustion in a coal overburden spoil pile
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Andrew Garvie, John Chapman, Brad Williams, and Ken Donaldson
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Total organic carbon ,Permeability (earth sciences) ,Overburden ,Mining engineering ,business.industry ,technology, industry, and agriculture ,Coal mining ,Environmental science ,Coal ,business ,Pile ,Combustion ,Spontaneous combustion - Abstract
Leigh Creek Coal Mine is located in South Australia approximately 550 km north of Adelaide and operated between 1944 and 2015. During operations, localised spontaneous combustion occurred on numerous occasions in the overburden spoil piles containing relatively small volumes of coal (about 0.8%). The majority of the overburden sequence consisted of sandstones and carbonaceous mudstones. Samples of overburden rocks had total sulfur and total organic carbon present at up to 2.2 and 14 wt% respectively. At the end of mining, localised surface temperatures of up to 200°C were measured. Laboratory testing demonstrated the potential for self-heating and spontaneous combustion of both coal and overburden material in the spoil piles. The management strategy selected for preventing spontaneous combustion in the post-closure period included: A trial of the management strategy was established in June 2017 in a location that was actively combusting. The batter slopes of the area were reduced, and an inert cover was placed over the area. Measurements of temperature, oxygen and carbon dioxide concentrations in the spoil pile over 20 months show that: Spoil pile conditions before and after the implementation of the management strategy are presented and an assessment of the effectiveness of the management strategy is provided.
- Published
- 2019
19. An Extended Phase Ib Study of Epertinib, an Orally Active Reversible Dual EGFR/HER2 Tyrosine Kinase Inhibitor, in Patients with Solid Tumours
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J Posner, Antoine Italiano, J Garcia-Corbacho, H-T. Arkenau, D Tosi, Richard H. Wilson, Antoine Adenis, Michael Flynn, S Deva, A Arimura, Gabriel Mak, Maud Toulmonde, Ken Donaldson, I Kawabata, Ruth Plummer, Richard D. Baird, Martin Forster, James Spicer, Institut Bergonié [Bordeaux], UNICANCER, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER, Université de Lille-UNICANCER, Baird, Richard [0000-0001-7071-6483], and Apollo - University of Cambridge Repository
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Loperamide ,medicine.drug_class ,EGFR ,Tyrosine kinase inhibitor ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Epertinib ,Gastroenterology ,Tyrosine-kinase inhibitor ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Pharmacokinetics ,Neoplasms ,Internal medicine ,HER2 ,Humans ,Medicine ,In patient ,030212 general & internal medicine ,Dosing ,Adverse effect ,skin and connective tissue diseases ,Protein Kinase Inhibitors ,Aged ,Aged, 80 and over ,business.industry ,Middle Aged ,medicine.disease ,3. Good health ,Treatment Outcome ,S-222611 ,Oncology ,Tolerability ,030220 oncology & carcinogenesis ,Quinazolines ,Female ,business ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,medicine.drug - Abstract
Background:\ud Dose-escalation of epertinib (S-222611), a new potent oral EGFR/HER2 inhibitor, has established a recommended daily dose of 800 mg in patients with solid tumours. In this study, we have recruited a larger number of patients to assess further the safety, tolerability, pharmacokinetics (PKs) and antitumour activity.\ud \ud Patients and Methods:\ud Patients with solid tumours expressing EGFR or HER2 received a single dose of epertinib at 800 mg on Day 1 to assess PK over 7 days, followed by continuous once-daily dosing from Day 8.\ud \ud Results:\ud We treated 76 patients with breast (n = 27), upper gastrointestinal (GI; n = 30), head and neck (n = 12) or renal cancers (n = 7). Epertinib was well-tolerated with mostly grade I and II adverse events (AEs). The most frequent AE was diarrhoea, which was generally manageable with loperamide. The objective response rate (ORR) in patients with heavily pretreated breast and upper GI cancers was 16.0% (4 PRs) and 8.3% (1CR, 1PR), respectively. All six responding patients had HER2-positive tumours; the ORR for HER2-positive breast and upper GI cancer populations was 19.0% and 20.0%. Partial response in the brain disease of one breast cancer patient lasted 7.5 months.\ud \ud Conclusion:\ud Once-daily dosing of epertinib at 800 mg was well-tolerated and demonstrated promising antitumour activity in patients with heavily pretreated HER2-positive breast and upper GI cancer, including those with brain metastases.\ud \ud EudraCT number:\ud 2009-017817-31.
- Published
- 2018
20. Factors influencing withdrawal from dialysis: a national registry study
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Graham A. Stewart, Ilona Shilliday, Robert K. Peel, Elaine Spalding, Wendy Metcalfe, Ken Donaldson, Jackie McDonald, Bruce Mackinnon, Jamie P. Traynor, Izhar U. H. Khan, Jonathan G. Fox, Arthur Doyle, and Mark Findlay
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Male ,medicine.medical_specialty ,medicine.medical_treatment ,030232 urology & nephrology ,03 medical and health sciences ,0302 clinical medicine ,Renal Dialysis ,Interquartile range ,Internal medicine ,Epidemiology ,Humans ,Medicine ,Registries ,030212 general & internal medicine ,Renal replacement therapy ,Intensive care medicine ,Dialysis ,Aged ,Cause of death ,Transplantation ,business.industry ,Incidence (epidemiology) ,medicine.disease ,Comorbidity ,Survival Rate ,Withholding Treatment ,Nephrology ,Kidney Failure, Chronic ,Female ,Hemodialysis ,business ,RC - Abstract
Background: \ud \ud Dialysis withdrawal is the third most common cause of death in patients receiving dialysis for established renal failure (ERF) in Scotland. We describe incidence, risk factors and themes influencing decision-making in a national renal registry.\ud \ud Methods: \ud \ud Details of deaths in those receiving renal replacement therapy (RRT) for ERF in Scotland are reported to the Scottish Renal Registry via a unique mortality report. We extracted patient demographics and comorbidity, cause and location of death, duration of RRT and pertinent free text comments from 1 January 2008 to 31 December 2014. Withdrawal incidence was calculated and logistic regression used to identify significantly influential variables. Themes emerging from clinician comments were tabulated for descriptive purposes.\ud \ud Results: \ud \ud There were 2596 deaths; median age at death was 68 [interquartile range (IQR) 58, 76] years, 41.5% were female. Median duration on RRT was 1110 (IQR 417, 2151) days. Dialysis withdrawal was the primary cause of death in 497 (19.1%) patients and withdrawal contributed to death in a further 442 cases (17.0%). The incidence was 41 episodes per 1000 patient-years. Regression analysis revealed increasing age, female sex and prior cerebrovascular disease were associated with dialysis withdrawal as a primary cause of death. Conversely, interstitial renal disease, angiographically proven ischaemic heart disease, valvular heart disease and malignancy were negatively associated. Analysis of free text comments revealed common themes, portraying an image of physical and psychological decline accelerated by acute illnesses.\ud \ud Conclusions: \ud \ud Death following dialysis withdrawal is common. Factors important to physical independence-prior cerebrovascular disease and increasing age-are associated with withdrawal. When combined with clinician comments this study provides an insight into the clinical decline affecting patients and the complexity of this decision. Early recognition of those likely to withdraw may improve end of life care.
- Published
- 2016
21. Death in the New Town: Edinburgh's hidden story of stonemasons' silicosis
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Ken Donaldson, Anthony Seaton, William A Wallace, and Christopher Henry
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Male ,History ,New Town ,Silicosis ,Edinburgh ,Ancient history ,History, 18th Century ,Town planning ,Education ,03 medical and health sciences ,0302 clinical medicine ,Dustiness ,medicine ,Humans ,030212 general & internal medicine ,Cities ,Epidemics ,Tuberculosis, Pulmonary ,Anecdotal evidence ,lcsh:R5-920 ,Prestige ,Construction Industry ,Dust ,History, 19th Century ,General Medicine ,medicine.disease ,030210 environmental & occupational health ,quartz ,tuberculosis ,Scotland ,silica ,stonemasons ,lcsh:Medicine (General) - Abstract
The building of the Edinburgh New Town, from the mid-18th to the mid-19th centuries, was a major advance in harmonious and elegant town planning. However, there is anecdotal evidence that it led to the occurrence of an epidemic of silicosis/tuberculosis among the stonemasons. We have reviewed contemporary accounts of the episode and early records of the understanding of silicosis. We have also studied the lung of a contemporary stonemason, preserved in the museum of the Royal College of Surgeons of Edinburgh, and confirmed the presence of silico-tuberculosis in it. The evidence shows that a major epidemic did occur, caused by a combination of factors. The size of the undertaking attracted many stonemasons to Edinburgh over a period of almost 100 years, intensively cutting and dressing stone. The principal stone worked was a very high-quartz sandstone, derived from the local Craigleith quarry, having properties that made it desirable for prestige buildings. However, even before the construction of the New Town, Craigleith sandstone was notorious for its dustiness and the Edinburgh stonemasons worked the stone in unventilated sheds. Stonemasons appeared to be aware of the risk of their trade, but little was known about preventive measures. It appears it was assumed that the risks to stonemasons disappeared after the Craigleith quarry closed, the employers emphasising (without evidence) the lack of health risks in other quarries, and the tragic episode appears to have been forgotten. However, we point to the continuing occurrence of silicosis among stonemasons to the present day; the importance of remembering such episodes is stressed lest the lessons of the past be forgotten.
- Published
- 2018
22. Assessment of the potential respiratory hazard of volcanic ash from future Icelandic eruptions: a study of archived basaltic to rhyolitic ash samples
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Claire J. Horwell, Ken Donaldson, Bice Fubini, David E. Damby, Thorvaldur Thordarson, G. Larsen, Maura Tomatis, Jarðvísindastofnun (HÍ), Institute of Earth Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Háskóli Íslands, and University of Iceland
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Aska ,Eldgos ,Heilsufar ,010504 meteorology & atmospheric sciences ,Health, Toxicology and Mutagenesis ,Áhættuþættir ,Geochemistry ,Iceland ,Air pollution ,Silicic ,Free radicals ,Volcanic Eruptions ,010502 geochemistry & geophysics ,Grímsvatnagos ,01 natural sciences ,Health hazard ,lcsh:RC963-969 ,Rhyolite ,Humans ,Particle Size ,0105 earth and related environmental sciences ,Basalt ,geography ,Air Pollutants ,geography.geographical_feature_category ,Eldgosið í Eyjafjallajökli ,lcsh:Public aspects of medicine ,Silicates ,Research ,Public Health, Environmental and Occupational Health ,Loftmengun ,Particle characterization ,Haemolysis ,lcsh:RA1-1270 ,Cristobalite ,Volcanic ash ,Particulate Matter ,Volcano ,13. Climate action ,lcsh:Industrial medicine. Industrial hygiene ,Environmental science ,Mafic - Abstract
Background The eruptions of Eyjafjallajökull (2010) and Grímsvötn (2011), Iceland, triggered immediate, international consideration of the respiratory health hazard of inhaling volcanic ash, and prompted the need to estimate the potential hazard posed by future eruptions of Iceland’s volcanoes to Icelandic and Northern European populations. Methods A physicochemical characterization and toxicological assessment was conducted on a suite of archived ash samples spanning the spectrum of past eruptions (basaltic to rhyolitic magmatic composition) of Icelandic volcanoes following a protocol specifically designed by the International Volcanic Health Hazard Network. Results Icelandic ash can be of a respirable size (up to 11.3 vol.% < 4 μm), but the samples did not display physicochemical characteristics of pathogenic particulate in terms of composition or morphology. Ash particles were generally angular, being composed of fragmented glass and crystals. Few fiber-like particles were observed, but those present comprised glass or sodium oxides, and are not related to pathogenic natural fibers, like asbestos or fibrous zeolites, thereby limiting concern of associated respiratory diseases. None of the samples contained cristobalite or tridymite, and only one sample contained quartz, minerals of interest due to the potential to cause silicosis. Sample surface areas are low, ranging from 0.4 to 1.6 m2 g−1, which aligns with analyses on ash from other eruptions worldwide. All samples generated a low level of hydroxyl radicals (HO•), a measure of surface reactivity, through the iron-catalyzed Fenton reaction compared to concurrently analyzed comparative samples. However, radical generation increased after ‘refreshing’ sample surfaces, indicating that newly erupted samples may display higher reactivity. A composition-dependent range of available surface iron was measured after a 7-day incubation, from 22.5 to 315.7 μmol m−2, with mafic samples releasing more iron than silicic samples. All samples were non-reactive in a test of red blood cell-membrane damage. Conclusions The primary particle-specific concern is the potential for future eruptions of Iceland’s volcanoes to generate fine, respirable material and, thus, to increase ambient PM concentrations. This particularly applies to highly explosive silicic eruptions, but can also hold true for explosive basaltic eruptions or discrete events associated with basaltic fissure eruptions., This work was funded under the UK Natural Environment Research Council (NERC) Knowledge Exchange (KE) Fellowship NE/J500525/1 granted to R.E. Holdsworth at Durham University. DED was additionally supported by the ERC Advanced Grant no. 247076 awarded to D.B. Dingwell at LMU Munich.
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- 2017
23. Contributors
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Harri Alenius, Don Beezhold, Enrico Bergamaschi, Diana Boraschi, Hans Bouwmeester, Luisa Campagnolo, Chunying Chen, Wim H. de Jong, Shareen H. Doak, Dominic Docter, Ken Donaldson, Rodger Duffin, Albert Duschl, Maria Dusinska, Vidana Epa, Bengt Fadeel, Francesca Larese Filon, Irina Guseva Canu, Maureen R. Gwinn, Akihiro Hirose, Karin S. Hougaard, Mark A. Jepson, Jun Kanno, Shirley K. Knauer, Robert Landsiedel, Tu C. Le, Ying Liu, Xuefei Lu, Andrea Magrini, Mats-Olof Mattsson, Agnieszka Mech, Nicholas L. Mills, Nancy A. Monteiro-Riviere, Antonio Pietroiusti, Craig A. Poland, Adriele Prina-Mello, Jennifer B. Raftis, Kirsten Rasmussen, Hubert Rauscher, Elise Rundén-Pran, Ursula G. Sauer, Kai Savolainen, Jürgen Schnekenburger, Galina V. Shurin, Michael R. Shurin, Anna A. Shvedova, Myrtill Simkó, Birgit Sokull-Klüttgen, Roland H. Stauber, Lang Tran, Dana Westmeier, Dave Winkler, Robert A. Yokel, Il Je Yu, Tao Zhu, and Yong Zhu
- Published
- 2017
24. Respiratory System, Part One: Basic Mechanisms
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Ken Donaldson and Craig A. Poland
- Subjects
Pathology ,medicine.medical_specialty ,Internal dose ,Engineered nanomaterials ,medicine ,Disease ,Occupational exposure ,Respiratory system ,Biology ,Pathogenicity ,Bioinformatics - Abstract
When considering the risks associated with nanomaterials, exposure is the key factor in defining risk with hazard being a key variable. With regards to the route of exposure, the lungs cause the greatest concern due to the sensitivity and ability to accumulate an internal dose. While the body is well adapted to constant exposure to particles from a variety of sources, with effective clearance and immunological defense mechanisms in place, exposure can also lead to disease and a real concern is the effect that new nanomaterials may have. In the present chapter, we describe the routes of exposure into the body via the lung and factors affecting this, as well as possible pathological reactions to nanomaterials ranging from inflammation and fibrosis to carcinogenicity. It is important to note that nanoparticles, like other particles, show differences and heterogeneity in their pathogenicity and a key area of research is the identification of physicochemical attributes, such as shape, size, etc. that contribute to or dictate toxicity.
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- 2017
25. Chronic kidney disease rather than illness severity predicts medium- to long-term mortality and renal outcome after acute kidney injury
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Ken Donaldson, Alison Almond, Sue Robertson, Chris Isles, Robert W. V. Flynn, and Mark Findlay
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,urologic and male genital diseases ,Severity of Illness Index ,Young Adult ,Internal medicine ,Severity of illness ,Odds Ratio ,medicine ,Humans ,Hospital Mortality ,Prospective Studies ,Renal replacement therapy ,Renal Insufficiency, Chronic ,Intensive care medicine ,Adverse effect ,Aged ,Aged, 80 and over ,Transplantation ,Kidney ,business.industry ,Acute kidney injury ,Odds ratio ,Acute Kidney Injury ,Middle Aged ,Prognosis ,medicine.disease ,female genital diseases and pregnancy complications ,Renal Replacement Therapy ,Survival Rate ,medicine.anatomical_structure ,Scotland ,Nephrology ,Breathing ,Female ,business ,Kidney disease - Abstract
Background. Acute kidney injury (AKI) requiring renal replacement therapy (RRT) continues to be associated with a hospital mortality of ∼50%. Longer-term outcomes have been less well studied. We sought to determine the influence of ventilation and of underlying chronic kidney disease (CKD) on medium and longterm mortality and renal outcomes. Methods. All patients requiring RRT for AKI in south west Scotland between 1 January 1994 and 31 December 2005 were followed prospectively. Survival of patients who were and were not ventilated and of those with and without underlying CKD was compared by odds ratio (OR), adjusting for age and sex. Renal outcomes were determined by interrogation of our biochemistry database. Results. Three hundred and ninety-six patients with AKI received RRT. One hundred and seventy-six (44%) were ventilated and 98 (25%) had underlying CKD. Patients who required ventilation had a significantly worse 90-day survival than those who did not (OR 2.10 for death; 95% CI 1.34, 3.29) whereas underlying CKD did not predict such an early adverse outcome (OR 1.49; 95% CI 0.89, 2.50). By 5 years, patients who had been ventilated during the acute illness were no longer at increased risk (OR 0.79; 95% CI 0.38, 1.62) whereas the adverse effect of underlying CKD was statistically significant (OR 6.05; 95% CI 2.23, 16.5). Underlying CKD was also a strong predictor of the need for RRT during follow-up. Conclusion. In an unselected series of patients with AKI requiring RRT, underlying CKD rather than illness severity predicted medium- to long-term mortality.
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- 2014
26. How safe is renal replacement therapy? A national study of mortality and adverse events contributing to the death of renal replacement therapy recipients
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Jennifer Boyd, Conal Daly, Bruce Mackinnon, Andrew Innes, Robert K. Peel, Jamie P. Traynor, Benjamin Bray, Graham A. Stewart, Wendy Metcalfe, Ilona Shilliday, Ken Donaldson, Izhar U. H. Khan, Jonathan G. Fox, Keith Simpson, and Arthur Doyle
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Adult ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Population ,urologic and male genital diseases ,Patient safety ,Renal Dialysis ,Risk Factors ,medicine ,Humans ,Renal replacement therapy ,Intensive care medicine ,Adverse effect ,education ,Aged ,Retrospective Studies ,Cause of death ,Aged, 80 and over ,Transplantation ,education.field_of_study ,business.industry ,Incidence ,Middle Aged ,Renal Replacement Therapy ,Survival Rate ,Nephrology ,Cohort ,Kidney Failure, Chronic ,Female ,Hemodialysis ,business - Abstract
Background Patients receiving treatment with renal replacement therapy (RRT) have high mortality, and ensuring patient safety in this population is difficult. We aimed to estimate the incidence and nature of medical adverse events contributing to the death of patients being treated with RRT. Methods This population registry-based retrospective case review study included all patients being treated with RRT for established renal failure in Scotland and who died between 1 January 2008 and 30 June 2011. Deaths were reviewed by consultant nephrologists using a structured questionnaire to identify factors contributing to death occurring in both the inpatient and outpatient setting. Reviewers were able to use any information source deemed relevant, including paper and electronic clinical records, mortality and morbidity meetings and procurator fiscal (Scottish coroner) investigations. Deaths occurring in 2008 and 2009 where avoidable factors were identified that may have or did lead to death of a patient were subject to further review and root cause analysis, in order to identify recurrent themes. Results Of 1551 deaths in the study period, 1357 were reviewed (87.5%). Cumulative RRT exposure in the cohort was 2.78 million person-days. RRT complications were the primary cause of death in 28 (2.1%). Health-care-associated infection had contributed to 9.6% of all deaths. In 3.5% of deaths, factors were identified which may have or did contribute to death. These were both organizational and human error related and were largely due to five main causes: management of hyperkalaemia, prescribing, out of hours care, infection and haemodialysis vascular access. Conclusions Adverse events contributing to death in RRT recipients mainly relate to the everyday management of common medical problems and not the technical aspects of RRT. Efforts to avoid harm in this population should address these ubiquitous causes of harm.
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- 2013
27. Minimal oxidation and inflammogenicity of pristine graphene with residence in the lung
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Vasileios Koutsos, Ken Donaldson, Khellil Sefiane, Alexandros Askounis, Anja Schinwald, Fiona Murphy, and Colin Campbell
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Pathology ,medicine.medical_specialty ,Materials science ,Biomedical Engineering ,Inflammation ,Spectrum Analysis, Raman ,Toxicology ,Horseradish peroxidase ,law.invention ,Mice ,law ,medicine ,Animals ,Platelet ,Lung ,Horseradish Peroxidase ,Inhalation exposure ,Inhalation Exposure ,biology ,Graphene ,Pulmonary inflammation ,Pneumonia ,In vitro ,Surgery ,Mice, Inbred C57BL ,medicine.anatomical_structure ,biology.protein ,Female ,Graphite ,medicine.symptom ,Oxidation-Reduction - Abstract
Two-dimensional graphitic carbon, graphene, is a new form of nanomaterial with great potential in a wide variety of applications. It is therefore crucial to investigate the behaviour of graphene in biological systems to assess potential adverse effects that might follow from inhalation exposure. In this study we focussed on medium-term effects of graphene in lung tissue by investigating the pulmonary inflammation 6 weeks after pharyngeal aspiration of unoxidised multilayered graphene platelets (GPs) in mice and assessed their biopersistence in the lung tissue using Raman spectroscopy. Additionally, GP degradation in vitro was examined after horseradish peroxidase (HRP) treatment up to 1 week. Building on our previous report showing acute inflammation in mice lungs at 1 day, pristine GP showed minimal inflammation in mouse lungs after 6 weeks even though no degradation of GP in lung tissue was observed and large deposits of GP were evident in the lungs. Raman analysis of GP in tissue sections showed minimal oxidation, and in vitro examinations of enzymatic oxidation of GP via HRP and H2O2 showed only slight increases in ID/IG ratio and the appearance of the Raman D' band at 1620 cm(-1) (surrogates of graphene oxidation). Our results showing non-inflammogenicity at medium time points have important implications in the hazard identification of GPs following inhalation exposure and for their use in biomedical applications. Additionally, the biopersistence of pristine GP in vivo with no associated inflammation could open the way to applications in tissue engineering and drug delivery.
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- 2013
28. Nanotoxicity: challenging the myth of nano-specific toxicity
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Craig A Poland and Ken Donaldson
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Computer science ,Pulmonary inflammation ,Biomedical Engineering ,Bioengineering ,Nanotechnology ,02 engineering and technology ,010501 environmental sciences ,021001 nanoscience & nanotechnology ,Risk Assessment ,01 natural sciences ,Hazard ,Specific toxicity ,13. Climate action ,Nanotoxicology ,Humans ,Nanoparticles ,Biochemical engineering ,0210 nano-technology ,Lung ,Limited resources ,0105 earth and related environmental sciences ,Biotechnology - Abstract
The analysis of nanoparticle (NP) hazard is currently a major research pre-occupation for particle toxicologists since there is a pressing requirement for a comprehensive understanding of nanoparticle hazard because of the wide spectrum of NP varying in composition, shape and size that require testing for risk assessment. The Biologically Effective Doses (BEDs) of nanoparticles, the dose entity that drives toxicity include charge, solubility, contaminants, shape and the ability to translocate from the site of deposition in the lungs. We point out here that all of these modes of toxicity are relevant and described for conventional pathogenic particles. There is no evidence that particles below 100nm, the threshold definition of a NP, show any step-change in their hazard meaning that there is no evidence of novel 'nano-specific hazard'. Therefore conventional particle toxicology data are useful and relevant to the determination of the nanoparticle hazard. Emphasis away from 'nano-specific effects' and the availability of hazard data from conventional particles will focus limited resource towards a full understanding of the NP hazard. This will lead to improved ability to identify and test for their effects and measure their toxicokinetics and so contribute to their risk assessment.
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- 2013
29. The respiratory health hazard of tephra from the 2010 Centennial eruption of Merapi with implications for occupational mining of deposits
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David E. Damby, C. Nattrass, Ken Donaldson, Claire J. Horwell, Pierre Delmelle, Bice Fubini, Peter J. Baxter, Sinbad Sweeney, Maura Tomatis, Teresa D. Tetley, F. A. Murphy, and Christina Dunster
- Subjects
geography ,geography.geographical_feature_category ,Lahar ,Industrial scale ,Geochemistry ,Hazard ,Geophysics ,Mining engineering ,Volcano ,Geochemistry and Petrology ,Direct exposure ,Tephra ,Geology ,Respiratory health ,Volcanic ash - Abstract
Ashfall into heavily populated areas during the October–November 2010 eruption of Merapi volcano, Indonesia created anxiety regarding the growing impacts to health as the eruption escalated and the hazard zone widened. We made a preliminary assessment of the respiratory hazards to human health of the tephra deposits (ashfall, lahar, and PDC surge) from the eruption using a laboratory protocol specifically developed to study the toxic potential of volcanic ash particles. Twenty samples collected from a range of locations were analysed for health-pertinent mineralogical parameters (grain size, crystalline silica content, morphology, surface area, bulk chemistry, and leachable elements) and bio-reactivity (hydroxyl radical generation, haemolytic potential, oxidative capacity, pro-inflammatory response). The grain size pertinent to respiratory health was variable, ranging from 1.4–15.6 vol.% sub-4 μm and 3.0–28.9 vol.% sub-10 μm diameter material. No fibre-like particles were observed. Cristobalite was present in all samples, ranging from 1.9–9.5 wt.%, but surface reactivity and in vitro toxicity assays showed low reactivity for all samples tested. The risk of direct exposure to ash from fallout was in any case low due to seasonal rains limiting its re-suspension and the immediate and effective clean-up of communities by local people who supplied the ash to the Indonesian construction industry for use as aggregate. However, mining of the lahar and thick PDC deposits in the valleys draining the volcano is performed on a vast, industrial scale, which could result in high occupational exposure to thousands of sand miners at Merapi during the dry seasons. Further study of the health hazard of the mined Merapi deposits is warranted
- Published
- 2013
30. Engineered nanomaterial risk. Lessons learnt from completed nanotoxicology studies: potential solutions to current and future challenges
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Ken Donaldson, Helinor Jane Johnston, Wolfgang G. Kreyling, Giulio Pojana, Antonio Marcomini, Steffen Loft, Lang Tran, Vicki Stone, Stefano Zuin, Håkan Wallin, Catherine McGuiness, Dominique Balharry, Peter Møller, Manuela Semmler-Behnke, and Nicklas Raun Jacobsen
- Subjects
Risk ,Physicochemical Phenomenon ,Chemical Phenomena ,Computer science ,Nanotechnology ,Toxicology ,Risk Assessment ,Hazard ,Nanostructures ,Human health ,Risk analysis (engineering) ,Nanomaterials ,Nanotoxicology ,Multidisciplinary approach ,Models, Animal ,Toxicity Tests ,Animals ,Humans ,European commission ,Risk assessment - Abstract
PARTICLE_RISK was one of the first multidisciplinary projects funded by the European Commission's Framework Programme that was responsible for evaluating the implications of nanomaterial (NM) exposure on human health. This project was the basis for this review which identifies the challenges that exist within the assessment of NM risk. We have retrospectively reflected on the findings of completed nanotoxicology studies to consider what progress and advances have been made within the risk assessment of NMs, as well as discussing the direction that nanotoxicology research is taking and identifying the limitations and failings of existing research. We have reflected on what commonly encountered challenges exist and explored how these issues may be resolved. In particular, the following is discussed (i) NM selection (ii) NM physico-chemical characterisation; (iii) NM dispersion; (iv) selection of relevant doses and concentrations; (v) identification of relevant models, target sites and endpoints; (vi) development of alternatives to animal testing; and (vii) NM risk assessment. These knowledge gaps are relatively well recognised by the scientific community and recommendations as to how they may be overcome in the future are provided. It is hoped that this will help develop better defined hypothesis driven research in the future that will enable comprehensive risk assessments to be conducted for NMs. Importantly, the nanotoxicology community has responded and adapted to advances in knowledge over recent years to improve the approaches used to assess NM hazard, exposure and risk. It is vital to learn from existing information provided by ongoing or completed studies to avoid unnecessary duplication of effort, and to offer guidance on aspects of the experimental design that should be carefully considered prior to the start of a new study.
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- 2012
31. SERS as a tool for in vitro toxicology
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Lauren E. Jamieson, Colin Campbell, James R. Hopgood, Stephen McLaughlin, Jing Jiang, Jennifer A. McLeish, Ken Donaldson, and Kate M. Fisher
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0301 basic medicine ,Silver ,Cell Survival ,Nanoparticle ,Metal Nanoparticles ,Nanotechnology ,02 engineering and technology ,medicine.disease_cause ,Spectrum Analysis, Raman ,Redox ,Comparative evaluation ,03 medical and health sciences ,Cell Line, Tumor ,Toxicity Tests ,medicine ,Humans ,Physical and Theoretical Chemistry ,Chemistry ,In vitro toxicology ,Oxidation reduction ,Surface-enhanced Raman spectroscopy ,Hydrogen-Ion Concentration ,021001 nanoscience & nanotechnology ,Oxidative Stress ,030104 developmental biology ,Spectrum analysis ,Zinc Oxide ,0210 nano-technology ,Oxidation-Reduction ,Oxidative stress ,Algorithms - Abstract
Measuring markers of stress such as pH and redox potential are important when studying toxicology in in vitro models because they are markers of oxidative stress, apoptosis and viability. While surface enhanced Raman spectroscopy is ideally suited to the measurement of redox potential and pH in live cells, the time-intensive nature and perceived difficulty in signal analysis and interpretation can be a barrier to its broad uptake by the biological community. In this paper we detail the development of signal processing and analysis algorithms that allow SERS spectra to be automatically processed so that the output of the processing is a pH or redox potential value. By automating signal processing we were able to carry out a comparative evaluation of the toxicology of silver and zinc oxide nanoparticles and correlate our findings with qPCR analysis. The combination of these two analytical techniques sheds light on the differences in toxicology between these two materials from the perspective of oxidative stress.
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- 2016
32. Adjuvanticity and toxicity of cobalt oxide nanoparticles as an alternative vaccine adjuvant
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Ken Donaldson, Wan-Seob Cho, Kenneth Dart, Sarah E. M. Howie, Dominika J. Nowakowska, and Xiaozhong Zheng
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medicine.medical_treatment ,Intraperitoneal injection ,Biomedical Engineering ,Metal Nanoparticles ,Medicine (miscellaneous) ,Enzyme-Linked Immunosorbent Assay ,Bioengineering ,Development ,Cell Line ,Mice ,chemistry.chemical_compound ,Immune system ,Adjuvants, Immunologic ,Antigen ,Adjuvanticity ,medicine ,Animals ,General Materials Science ,biology ,Alum ,Oxides ,Cobalt ,Mice, Inbred C57BL ,Vaccination ,Microscopy, Electron ,Ovalbumin ,chemistry ,Immunology ,biology.protein ,Female ,Adjuvant - Abstract
Aim: There are very few adjuvants licensed for use in human vaccination, and alum-based adjuvants are the most widely used. Alum adjuvants predominantly boost Th2 immune responses and there is a need for new adjuvants that also stimulate Th1 immunity. We recently reported that cobalt oxide nanoparticles (Co3O4NPs) stimulate Th1-type immune responses in vivo. Here, we exploited this property to examine whether Co3O4NP could act as an adjuvant using the model antigen ovalbumin. Materials & methods: Female C57BL/6 mice were immunized subcutaneously twice with ovalbumin plus adjuvant (Co3O4NPs or Imject® Alum) followed by intraperitoneal stimulation with soluble ovalbumin. Results: Co3O4NPs induced a more balanced Th1- and Th2-type response, triggering higher specific Th1-dependent IgG2c production in addition to Th2-dependent IgG1 and less ‘allergic’ IgE production, and induced less inflammation at both the subcutaneous and intraperitoneal injection sites. Discussion: Co3O4NPs could be a very useful adjuvant where both Th1 and Th2 responses are needed to clear pathogens. Original submitted 22 August 2011; Revised submitted 28 February 2012; Published online 20 July 2012
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- 2012
33. The Biologically Effective Dose in Inhalation Nanotoxicology
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Anja Schinwald, Fiona Murphy, Craig A Poland, Wan-Seob Cho, Rodger Duffin, Lang Tran, and Ken Donaldson
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Dose-Response Relationship, Drug ,Inhalation ,Chemistry ,Macrophages ,Nanotechnology ,General Medicine ,General Chemistry ,Pharmacology ,medicine.disease_cause ,Effective dose (pharmacology) ,Structure-Activity Relationship ,Nanotoxicology ,Total dose ,Administration, Inhalation ,Toxicity ,medicine ,Humans ,Nanoparticles ,Particle Size ,Genotoxicity - Abstract
In all branches of toxicology, the biologically effective dose (BED) is the fraction of the total dose of a toxin that actually drives any toxic effect. Knowledge of the BED has a number of applications including in building structure-activity relationships, the selection of metrics, the design of safe particles, and the determination of when a nanoparticle (NP) can be considered to be "new" for regulatory purposes. In particle toxicology, we define the BED as "the entity within any dose of particles in tissue that drives a critical pathophysiogically relevant form of toxicity (e.g., oxidative stress, inflammation, genotoxicity, or proliferation) or a process that leads to it." In conventional chemical toxicology, researchers generally use the mass as the metric to describe dose (such as mass per unit tissue or cells in culture) because of its convenience. Concentration, calculated from mass, may also figure in any description of dose. In the case of a nanoparticle dose, researchers use either the mass or the surface area. The mass of nanoparticles is not the only driver of their activity: the surfaces of insoluble particles interact with biological systems, and soluble nanoparticles can release factors that interact with these systems. Nanoparticle shape can modify activity. In this Account, we describe the current knowledge of the BED as it pertains to different NP types. Soluble toxins released by NPs represent one potential indicator of BED for wholly or partially soluble NPs composed of copper or zinc. Rapid dissolution of these NPs into their toxic ions in the acidic environment of the macrophage phagolysosome causes those ions to accumulate, which leads to lysosome destabilization and inflammation. In contrast, soluble NPs that release low toxicity ions, such as magnesium oxide NPs, are not inflammogenic. For insoluble NPs, ζ potential can serve as a BED measurement because the exposure of the particle surface to the acidic milieu of the phagolysosome and interactions with the lysosomal membrane can compromise the integrity of the NPs. Researchers have explored oxidative potential of NPs most extensively as an indicator of the BED: the ability of an NP to cause oxidative stress in cells is a key factor in determining cell toxicity, inflammogenicity, and oxidative DNA adduct formation. Finally we discuss BEDs for high aspect ratio nanoparticles because long fibers or nanoplatelets can cause inflammation and further effects. These consequences arise from the paradoxically small aerodynamic diameter of fibers or thin platelets. As a result, these NPs can deposit beyond the ciliated airways where their extended dimensions prevent them from being fully phagocytosed by macrophages, leading to frustrated phagocytosis. Although knowledge is accumulating on the BED for NPs, many questions and challenges remain in understanding and utilizing this important nanotoxicological parameter.
- Published
- 2012
34. Graphene-Based Nanoplatelets: A New Risk to the Respiratory System as a Consequence of Their Unusual Aerodynamic Properties
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Ken Donaldson, A D Jones, William MacNee, Anja Schinwald, and Fiona Murphy
- Subjects
Materials science ,General Physics and Astronomy ,Nanoparticle ,Nanotechnology ,law.invention ,Mice ,In vivo ,law ,Administration, Inhalation ,Materials Testing ,medicine ,Animals ,General Materials Science ,Respiratory system ,Lung ,Aerosols ,Inhalation exposure ,Inhalation ,Graphene ,General Engineering ,Carbon black ,medicine.anatomical_structure ,Biophysics ,Cytokines ,Nanoparticles ,Graphite - Abstract
Graphene is a new nanomaterial with unusual and useful physical and chemical properties. However, in the form of nanoplatelets this new, emerging material could pose unusual risks to the respiratory system after inhalation exposure. The graphene-based nanoplatelets used in this study are commercially available and consist of several sheets of graphene (few-layer graphene). We first derived the respirability of graphene nanoplatelets (GP) from the basic principles of the aerodynamic behavior of plate-shaped particles which allowed us to calculate their aerodynamic diameter. This showed that the nanoplatelets, which were up to 25 μm in diameter, were respirable and so would deposit beyond the ciliated airways following inhalation. We therefore utilized models of pharyngeal aspiration and direct intrapleural installation of GP, as well as an in vitro model, to assess their inflammatory potential. These large but respirable GP were inflammogenic in both the lung and the pleural space. MIP-1α, MCP-1, MIP-2, IL-8, and IL-1β expression in the BAL, the pleural lavage, and cell culture supernatant from THP-1 macrophages were increased with GP exposure compared to controls but not with nanoparticulate carbon black (CB). In vitro, macrophages exposed to GP showed expression of IL-1β. This study highlights the importance of nanoplatelet form as a driver for in vivo and in vitro inflammogenicity by virtue of their respirable aerodynamic diameter, despite a considerable 2-dimensional size which leads to frustrated phagocytosis when they deposit in the distal lungs and macrophages attempt to phagocytose them. Our data suggest that nanoplatelets pose a novel nanohazard and structure-toxicity relationship in nanoparticle toxicology.
- Published
- 2012
35. Length-dependent pathogenic effects of nickel nanowires in the lungs and the peritoneal cavity
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Fiona Byrne, Rodger Duffin, Ken Donaldson, Yurii Gounko, Gemma-Louise Davies, Adriele Prina-Mello, Yuri Volkov, Craig A. Poland, J. M. D. Coey, Wan-Seob Cho, and Fiona Murphy
- Subjects
Pathology ,medicine.medical_specialty ,Materials science ,Biomedical Engineering ,Nanowire ,chemistry.chemical_element ,02 engineering and technology ,Toxicology ,Mice ,03 medical and health sciences ,Peritoneal cavity ,Nickel ,Fibrosis ,medicine ,Animals ,Macrophage ,Lung ,Peritoneal Cavity ,030304 developmental biology ,0303 health sciences ,Nanowires ,Hazard potential ,021001 nanoscience & nanotechnology ,medicine.disease ,Pathogenicity ,Mice, Inbred C57BL ,medicine.anatomical_structure ,chemistry ,Lung aspiration ,Biophysics ,Female ,0210 nano-technology - Abstract
The use of fibre-shaped nanomaterials in commercial applications has met with concern that they could cause health effects similar to those seen with pathogenic fibres such as certain forms of asbestos. Of the attributes which form the fibre pathogenicity paradigm, fibre length is thought to be a critical factor in determining fibre toxicity. We have previously shown that carbon nanotubes display such length-dependent pathogenicity but it remains unclear if other forms of fibrous nanomaterials conform to the fibre pathogenicity paradigm. As such, our aim is to determine the generality of this hypothesis by asking whether a radically different form of fibrous nanomaterial, nickel nanowires, show length-dependent pathogenicity. Our results indicate that nickel nanowires synthesised to be predominantly long (>20 mm) show the ability to elicit strong inflammation in the mouse peritoneal model in a dose-dependent manner; inflammation or fibrosis was not seen with the short (
- Published
- 2012
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36. Reducing Personal Exposure to Particulate Air Pollution Improves Cardiovascular Health in Patients with Coronary Heart Disease
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Ken Donaldson, Xi Li, Nicholas A. Boon, Matthew M.Y. Lee, Jing Li, Jeremy P. Langrish, Shengfeng Wang, Mark R. Miller, Flemming R. Cassee, Gareth Barnes, David E. Newby, Lixin Jiang, Liming Li, and Nicholas L. Mills
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Male ,Mean arterial pressure ,China ,face mask ,Health, Toxicology and Mutagenesis ,air pollution ,Air pollution ,Urban Issues ,Coronary Disease ,medicine.disease_cause ,Heart Rate ,Heart rate ,medicine ,Heart rate variability ,Humans ,Combustion Emissions ,Prospective Studies ,International Environmental Health ,News | Science Selections ,Aged ,Inhalation exposure ,Inhalation Exposure ,Cross-Over Studies ,medicine.diagnostic_test ,Cardiovascular Health ,business.industry ,Incidence ,Research ,Public Health, Environmental and Occupational Health ,Urban Health ,heart rate variability ,blood pressure ,Arrhythmias, Cardiac ,Blood Pressure Monitoring, Ambulatory ,Middle Aged ,Crossover study ,myocardial ischemia ,Blood pressure ,Anesthesia ,Electrocardiography, Ambulatory ,Female ,Particulate Matter ,business ,Electrocardiography - Abstract
Background: Air pollution exposure increases cardiovascular morbidity and mortality and is a major global public health concern.\ud \ud Objectives: We investigated the benefits of reducing personal exposure to urban air pollution in patients with coronary heart disease.\ud \ud Methods: In an open randomized crossover trial, 98 patients with coronary heart disease walked on a predefined route in central Beijing, China, under different conditions: once while using a highly efficient face mask, and once while not using the mask. Symptoms, exercise, personal air pollution exposure, blood pressure, heart rate, and 12-lead electrocardiography were monitored throughout the 24-hr study period.\ud \ud Results: Ambient air pollutants were dominated by fine and ultrafine particulate matter (PM) that was present at high levels [74 μg/m3 for PM2.5 (PM with aerodynamic diamater
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- 2012
37. The Threshold Length for Fiber-Induced Acute Pleural Inflammation: Shedding Light on the Early Events in Asbestos-Induced Mesothelioma
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Dania Movia, Anja Schinwald, Janet C. Dickerson, David A. Schultz, William MacNee, Ken Donaldson, James R. Glass, Craig A Poland, Adriele Prina-Mello, C. E. Jeffree, Fiona Murphy, and Fiona Byrne
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Mesothelioma ,Pathology ,medicine.medical_specialty ,Parietal Pleura ,Nanofibers ,Inflammation ,02 engineering and technology ,Toxicology ,medicine.disease_cause ,Asbestos ,Lesion ,Mice ,03 medical and health sciences ,Phagocytosis ,In vivo ,medicine ,Animals ,Fiber ,Pleurisy ,030304 developmental biology ,0303 health sciences ,Chemistry ,021001 nanoscience & nanotechnology ,medicine.disease ,3. Good health ,Mice, Inbred C57BL ,Metals ,Nanofiber ,Microscopy, Electron, Scanning ,Female ,medicine.symptom ,0210 nano-technology - Abstract
Suspicion has been raised that high aspect ratio nanoparticles or nanofibers might possess asbestos-like pathogenicity. The pleural space is a specific target for disease in individuals exposed to asbestos and by implication of nanofibers. Pleural effects of fibers depends on fiber length, but the key threshold length beyond which adverse effects occur has never been identified till now because all asbestos and vitreous fiber samples are heterogeneously distributed in their length. Nanotechnology advantageously allows for highly defined length distribution of synthetically engineered fibers that enable for in-depth investigation of this threshold length. We utilized the ability to prepare silver nanofibers of five defined length classes to demonstrate a threshold fiber length for acute pleural inflammation. Nickel nanofibers and carbon nanotubes were then used to strengthen the relationship between fiber length and pleural inflammation. A method of intrapleural injection of nanofibers in female C57Bl/6 strain mice was used to deliver the fiber dose, and we then assessed the acute pleural inflammatory response. Chest wall sections were examined by light and scanning electron microscopy to identify areas of lesion; furthermore, cell– nanowires interaction on the mesothelial surface of the parietal pleura in vivo was investigated. Our results showed a clear threshold effect, demonstrating that fibers beyond 4 µm in length are pathogenic to the pleura. The identification of the threshold length for nanofiber-induced pathogenicity in the pleura has important implications for understanding the structure–toxicity relationship for asbestos-induced mesothelioma and consequent risk assessment with the aim to contribute to the engineering of synthetic nanofibers by the adoption of a benign-by-design approach.
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- 2012
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38. Differential effects of long and short carbon nanotubes on the gas-exchange region of the mouse lung
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Peter Gehr, Rodger Duffin, Craig A Poland, Ken Donaldson, Christian Mühlfeld, Barbara Rothen-Rutishauser, Fiona Murphy, and Christina Brandenberger
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Pathology ,medicine.medical_specialty ,Materials science ,Cell ,Biomedical Engineering ,Stereology ,Toxicology ,Muscle hypertrophy ,Mice ,Microscopy, Electron, Transmission ,Parenchyma ,medicine ,Animals ,Particle Size ,Lung ,medicine.diagnostic_test ,Nanotubes, Carbon ,Electron Spin Resonance Spectroscopy ,Pneumonia ,respiratory system ,Hyperplasia ,medicine.disease ,Immunohistochemistry ,respiratory tract diseases ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Bronchoalveolar lavage ,Microscopy, Electron, Scanning ,Female ,Gases - Abstract
We hypothesise that inflammatory response and morphological characteristics of lung parenchyma differ after exposure to short or long multi-walled carbon nanotubes (MWCNT). Mice were subjected to a single dose of vehicle, short or long MWCNT by pharyngeal aspiration. Bronchoalveolar lavage fluid (BALF) obtained at 24 h was analysed for inflammatory reaction and lung tissue was analysed for morphological alterations using stereology. Short MWCNT had stronger potential to induce polymorphonuclear cells whereas long MWCNT increased interleukin-6 levels in BALF. Alveolar septal fibrosis was only observed with short MWCNT. Type II pneumocyte hypertrophy was only detected with long MWCNT. There was no reduction in total alveolar surface area and no sign of type II cell hyperplasia. We observed mild inflammatory and pathological responses to short and long MWCNT in the lung parenchyma depending on the size of the applied MWCNT.
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- 2011
39. A hypothetical model for predicting the toxicity of high aspect ratio nanoparticles (HARN)
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Ken Donaldson, Robert John Aitken, Ratna Tantra, Vicki Stone, B. Ross, Steven M. Hankin, C. L. Tran, and A. D. Jones
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Materials science ,Bioengineering ,Nanotechnology ,General Chemistry ,Condensed Matter Physics ,Pathogenicity ,Atomic and Molecular Physics, and Optics ,Toxicology studies ,Diameter ratio ,Modeling and Simulation ,Toxicity ,General Materials Science ,Biochemical engineering ,Public acceptance ,Reference standards - Abstract
The ability to predict nanoparticle (dimensional structures which are less than 100 nm in size) toxicity through the use of a suitable model is an important goal if nanoparticles are to be regulated in terms of exposures and toxicological effects. Recently, a model to predict toxicity of nanoparticles with high aspect ratio has been put forward by a consortium of scientists. The High aspect ratio nanoparticles (HARN) model is a platform that relates the physical dimensions of HARN (specifically length and diameter ratio) and biopersistence to their toxicity in biological environments. Potentially, this model is of great public health and economic importance, as it can be used as a tool to not only predict toxicological activity but can be used to classify the toxicity of various fibrous nanoparticles, without the need to carry out time-consuming and expensive toxicology studies. However, this model of toxicity is currently hypothetical in nature and is based solely on drawing similarities in its dimensional geometry with that of asbestos and synthetic vitreous fibres. The aim of this review is two-fold: (a) to present findings from past literature, on the physicochemical property and pathogenicity bioassay testing of HARN (b) to identify some of the challenges and future research steps crucial before the HARN model can be accepted as a predictive model. By presenting what has been done, we are able to identify scientific challenges and research directions that are needed for the HARN model to gain public acceptance. Our recommendations for future research includes the need to: (a) accurately link physicochemical data with corresponding pathogenicity assay data, through the use of suitable reference standards and standardised protocols, (b) develop better tools/techniques for physicochemical characterisation, (c) to develop better ways of monitoring HARN in the workplace, (d) to reliably measure dose exposure levels, in order to support future epidemiological studies.
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- 2011
40. The carcinogenic action of crystalline silica: A review of the evidence supporting secondary inflammation-driven genotoxicity as a principal mechanism
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Paul J. A. Borm, Ken Donaldson, and Lang Tran
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Inflammation ,Dose-Response Relationship, Drug ,Mutagenicity Tests ,Stereochemistry ,Chemistry ,Quartz ,Silicon Dioxide ,Toxicology ,medicine.disease_cause ,Rats ,Occupational Exposure ,Carcinogens ,Principal mechanism ,medicine ,Cancer research ,Animals ,Humans ,Occupational exposure ,Mutagenicity Test ,Carcinogen ,Genotoxicity ,International agency - Abstract
In 1987 the International Agency for Research on Cancer (IARC) classified crystalline silica (CS) as a probable carcinogen and in 1997 reclassified it as a Group 1 carcinogen, i.e., that there was sufficient evidence for carcinogenicity in experimental animals and sufficient evidence for carcinogenicity in humans. The Working Group noted that "carcinogenicity in humans was not detected in all industrial circumstances studied, carcinogenicity may be dependent on inherent characteristics of the crystalline silica or on external factors affecting its biological activity or distribution of its polymorphs." This unusual statement that the physicochemical form of the CS influences its carcinogenicity is well understood at the toxicological level and arises as a consequence of the fact that CS activity depends on the reactivity of the CS surface, which can be blocked by a number of agents. We reviewed the literature on CS genotoxicity that has been published since the 1997 monograph, with special reference to the mechanism of CS genotoxicity. The mechanism of CS genotoxicity can be primary, a result of direct interaction of CS with target cells, or indirect, as a consequence of inflammation elicited by quartz, where the inflammatory cell-derived oxidants cause the genotoxicity. The review revealed a number of papers supporting the hypothesis that the CS genotoxic and inflammatory hazard is a variable one. In an attempt to attain a quantitative basis for the potential mechanism, we carried out analysis of published data and noted a 5-fold greater dose required to reach a threshold for genotoxic effects than for proinflammatory effects in the same cell line in vitro. When we related the calculated threshold dose at the proximal alveolar region for inflammation in a published study with the threshold dose for genotoxicity in vitro, we noted that a 60-120-fold greater dose was required for direct genotoxic effects in vitro. These data strongly suggests that inflammation is the driving force for genotoxicity and that primary genotoxicity of deposited CS would play a role only at very high, possibly implausible, exposures and deposited doses. Although based on rat studies and in vitro studies, and therefore with caveats, the analysis supports the hypothesis that the mechanism of CS genotoxicity is via inflammation-driven secondary genotoxicity. This may have implications for setting of the CS standard in workplaces. During the writing of this review (in May 2009), IARC undertook a review of carcinogenic substances, including CS. The Working Group met to reassess 10 separate agents including CS. This was not a normal monograph working group published as a large single monograph, but was published as a two-page report. This review group reaffirmed the carcinogenicity of "silica dust, crystalline in the form of quartz or cristobalite" as a Group 1 agent, with the lung as the sole tumor site. Of special relevance to the present review is that the cited "established mechanism events" for CS are restricted to the words "impaired particle clearance leading to macrophage activation and persistent inflammation." The lack of mention of direct genotoxicity is in line with the conclusions reached in the present review.
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- 2011
41. Combustion-derived nanoparticulate induces the adverse vascular effects of diesel exhaust inhalation
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Patrick W. F. Hadoke, Nicholas A. Boon, Laura Flint, Ken Donaldson, Jon Beveridge, Anders Blomberg, Rodger Duffin, Mark R. Miller, Paul H. B. Fokkens, Flemming R. Cassee, David E. Newby, Nicholas L. Mills, Thomas Sandström, A. John F. Boere, and Andrew J. Lucking
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Male ,Diesel exhaust ,Prevention and Epidemiology ,Vasodilator Agents ,Blood Pressure ,Vasodilation ,030204 cardiovascular system & hematology ,010501 environmental sciences ,Pharmacology ,01 natural sciences ,Muscle, Smooth, Vascular ,chemistry.chemical_compound ,0302 clinical medicine ,Vasoconstrictor Agents ,Aorta ,Vehicle Emissions ,Inhalation exposure ,Air Pollutants ,Inhalation Exposure ,Cross-Over Studies ,Inhalation ,Blood flow ,Particulates ,3. Good health ,Forearm ,Anesthesia ,Sodium nitroprusside ,Cardiology and Cardiovascular Medicine ,Muscle Contraction ,medicine.drug ,Adult ,Adolescent ,Air pollution ,Bradykinin ,complex mixtures ,Young Adult ,03 medical and health sciences ,Double-Blind Method ,Clinical Research ,medicine ,Animals ,Humans ,Endothelium ,0105 earth and related environmental sciences ,business.industry ,Carbon ,Diesel Exhaust Particulate ,Rats ,chemistry ,13. Climate action ,Nanoparticles ,business ,human activities - Abstract
AimExposure to road traffic and air pollution may be a trigger of acute myocardial infarction, but the individual pollutants responsible for this effect have not been established. We assess the role of combustion-derived-nanoparticles in mediating the adverse cardiovascular effects of air pollution. Methods and resultsTo determine the in vivo effects of inhalation of diesel exhaust components, 16 healthy volunteers were exposed to (i) dilute diesel exhaust, (ii) pure carbon nanoparticulate, (iii) filtered diesel exhaust, or (iv) filtered air, in a randomized double blind cross-over study. Following each exposure, forearm blood flow was measured during intra-brachial bradykinin, acetylcholine, sodium nitroprusside, and verapamil infusions. Compared with filtered air, inhalation of diesel exhaust increased systolic blood pressure (145 ± 4 vs. 133 ± 3 mmHg, P< 0.05) and attenuated vasodilatation to bradykinin (P= 0.005), acetylcholine (P= 0.008), and sodium nitroprusside (P< 0.001). Exposure to pure carbon nanoparticulate or filtered exhaust had no effect on endothelium-dependent or -independent vasodilatation. To determine the direct vascular effects of nanoparticulate, isolated rat aortic rings (n= 6–9 per group) were assessed in vitro by wire myography and exposed to diesel exhaust particulate, pure carbon nanoparticulate and vehicle. Compared with vehicle, diesel exhaust particulate (but not pure carbon nanoparticulate) attenuated both acetylcholine (P< 0.001) and sodium-nitroprusside (P= 0.019)-induced vasorelaxation. These effects were partially attributable to both soluble and insoluble components of the particulate. ConclusionCombustion-derived nanoparticulate appears to predominately mediate the adverse vascular effects of diesel exhaust inhalation. This provides a rationale for testing environmental health interventions targeted at reducing traffic-derived particulate emissions.
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- 2011
42. Diesel Exhaust Particulate–Exposed Macrophages Cause Marked Endothelial Cell Activation
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Ken Donaldson, David E. Newby, Mark R. Miller, Patrick W. F. Hadoke, Rodger Duffin, Sarah Robertson, Caroline M. Tabor, and Catherine A Shaw
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Pulmonary and Respiratory Medicine ,Endothelium ,Monocyte chemotaxis ,Cell Survival ,Clinical Biochemistry ,Models, Biological ,complex mixtures ,Monocytes ,Umbilical vein ,Proinflammatory cytokine ,Phagocytosis ,medicine ,Humans ,Interleukin 8 ,Particle Size ,Molecular Biology ,Vehicle Emissions ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,Chemistry ,Chemotaxis ,Macrophages ,Monocyte ,Interleukin-8 ,Endothelial Cells ,Cell Biology ,respiratory system ,Molecular biology ,respiratory tract diseases ,Endothelial stem cell ,medicine.anatomical_structure ,Immunology ,Tumor necrosis factor alpha ,Endothelium, Vascular - Abstract
Exposure to air pollution containing diesel exhaust particulate (DEP) is linked to adverse cardiovascular events. This study tested the hypothesis that DEP not only causes direct endothelial cell injury, but also induces indirect endothelial cell activation via the release of soluble proinflammatory cytokines from macrophages. Human umbilical vein endothelial cells (HUVECs) and monocyte-derived macrophages (MDMs) were incubated with DEP (1-100 μg/ml; 24 h). Supernatants were analyzed for monocyte chemotactic protein (MCP)-1, IL6, IL8, and TNF-α. Indirect actions of DEP were investigated by incubating HUVECs with conditioned media from DEP-exposed MDMs in the presence and absence of the TNF-α inhibitor, etanercept. A modified Boyden chamber assay was used to determine whether HUVECs treated in this manner induced monocyte chemotaxis. Direct incubation with DEP induced a modest increase in MCP-1 concentration, but had no effect on IL-6 or IL-8 release from HUVECs. In contrast, direct treatment of MDMs with DEP had no effect on MCP-1, but elevated IL-8 and TNF-α concentrations. Incubation with conditioned media from DEP-exposed MDMs caused a dramatic amplification in MCP-1 and IL-6, but not IL-8, release from HUVECs. The potentiation of HUVEC activation was suppressed by TNF-α inhibition. MCP-1- and IL-6-containing HUVEC supernatants caused increased monocyte chemotaxis that was not inhibited by anti-MCP-1 antibodies. We conclude that DEP has only modest direct endothelial effects. In contrast, proinflammatory cytokines released from particle-laden MDMs appear to exacerbate endothelial activation after DEP exposure.
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- 2011
43. Quantification of the pathological response and fate in the lung and pleura of chrysotile in combination with fine particles compared to amosite-asbestos following short-term inhalation exposure
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S. E. Holm, Rick A. Rogers, P. Kunzendorf, S. Gaering, Rosalinda Sepulveda, D.M. Bernstein, Ken Donaldson, Jörg Chevalier, and D. Schuler
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Male ,Pathology ,medicine.medical_specialty ,Time Factors ,Asbestos, Serpentine ,Amosite Asbestos ,Endpoint Determination ,Health, Toxicology and Mutagenesis ,Pilot Projects ,Validation Studies as Topic ,Toxicology ,law.invention ,Microscopy, Electron, Transmission ,Confocal microscopy ,law ,Chrysotile ,medicine ,Animals ,Particle Size ,Rats, Wistar ,Lung ,Aerosols ,Inhalation exposure ,Inhalation Exposure ,Pleural Cavity ,Inhalation ,Chemistry ,Pleural cavity ,Fibrosis ,Rats ,Joint compound ,medicine.anatomical_structure ,Microscopy, Electron, Scanning ,Pleura ,Particulate Matter ,Asbestos, Amosite - Abstract
The marked difference in biopersistence and pathological response between chrysotile and amphibole asbestos has been well documented. This study is unique in that it has examined a commercial chrysotile product that was used as a joint compound. The pathological response was quantified in the lung and translocation of fibers to and pathological response in the pleural cavity determined. This paper presents the final results from the study. Rats were exposed by inhalation 6 h/day for 5 days to a well-defined fiber aerosol. Subgroups were examined through 1 year. The translocation to and pathological response in the pleura was examined by scanning electron microscopy and confocal microscopy (CM) using noninvasive methods. The number and size of fibers was quantified using transmission electron microscopy and CM. This is the first study to use such techniques to characterize fiber translocation to and the response of the pleural cavity. Amosite fibers were found to remain partly or fully imbedded in the interstitial space through 1 year and quickly produced granulomas (0 days) and interstitial fibrosis (28 days). Amosite fibers were observed penetrating the visceral pleural wall and were found on the parietal pleural within 7 days postexposure with a concomitant inflammatory response seen by 14 days. Pleural fibrin deposition, fibrosis, and adhesions were observed, similar to that reported in humans in response to amphibole asbestos. No cellular or inflammatory response was observed in the lung or the pleural cavity in response to the chrysotile and sanded particles (CSP) exposure. These results provide confirmation of the important differences between CSP and amphibole asbestos.
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- 2011
44. Length-Dependent Retention of Carbon Nanotubes in the Pleural Space of Mice Initiates Sustained Inflammation and Progressive Fibrosis on the Parietal Pleura
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Rodger Duffin, Craig A Poland, Fiona Byrne, Antonio Nunes, Ken Donaldson, Maurizio Prato, Fiona Murphy, William MacNee, Alberto Bianco, Khuloud T. Al-Jamal, Hanene Ali-Boucetta, Adriele Prina-Mello, William A Wallace, Shouping Li, Yuri Volkov, Kostas Kostarelos, Stephen J. Mather, Queen's Medical Researche Institute, University of Edinburgh, The Nanomedicine Laboratory, Nanomedicine Laboratory, Queen Mary University of London (QMUL), Department of Pharmacy, Kings' College London, Centre for Research on Adaptive Nanostructures and Nanodevices, Trinity College Dublin, Center for excellence for Nanostructured Materials, University of Trieste, Department of Nuclear Medicine, St Bartholomew's Hospital London, Immunologie et chimie thérapeutiques (ICT), Cancéropôle du Grand Est-Centre National de la Recherche Scientifique (CNRS), Department of Pathology, College of Medicine and Veterinary Medicine, F. A., Murphy, C. A., Poland, R., Duffin, K. T., Al Jamal, H., Ali Boucetta, A., Nune, F., Byrne, A., Prina Mello, Y., Volkov, S., Li, and Prato, Maurizio
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Pathology ,Time Factors ,Parietal Pleura ,02 engineering and technology ,Epithelium ,law.invention ,Mice ,carbon nanotubes toxicity ,law ,Fibrosis ,FIBROSIS ,Mesothelioma ,Pleural Cavity ,0303 health sciences ,Chemistry ,Mediastinum ,Regular Article ,respiratory system ,021001 nanoscience & nanotechnology ,medicine.anatomical_structure ,[SDV.TOX]Life Sciences [q-bio]/Toxicology ,Disease Progression ,Pleura ,medicine.symptom ,0210 nano-technology ,medicine.medical_specialty ,EPITHELIUM ,Inflammation ,Carbon nanotube ,NANOWIRES ,Pathology and Forensic Medicine ,Computed tomographic ,03 medical and health sciences ,INFLAMMATION ,medicine ,Animals ,Particle Size ,nanotubes, carbon ,Cell Proliferation ,030304 developmental biology ,Tomography, Emission-Computed, Single-Photon ,Nanotubes, Carbon ,Nanowires ,DISEASE PROGRESSION ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,Pleural cavity ,Pathogenicity ,medicine.disease ,mediastinum ,respiratory tract diseases ,MICE ,Lymph Nodes ,Tomography, X-Ray Computed - Abstract
International audience; The fibrous shape of carbon nanotubes (CNTs) raises concern that they may pose an asbestos-like inhalation hazard, leading to the development of diseases, especially mesothelioma. Direct instillation of long and short CNTs into the pleural cavity, the site of mesothelioma development, produced asbestos-like length-dependent responses. The response to long CNTs and long asbestos was characterized by acute inflammation, leading to progressive fibrosis on the parietal pleura, where stomata of strictly defined size limit the egress of long, but not short, fibers. This was confirmed by demonstrating clearance of short, but not long, CNT and nickel nanowires and by visualizing the migration of short CNTs from the pleural space by single-photon emission computed tomographic imaging. Our data confirm the hypothesis that, although a proportion of all deposited particles passes through the pleura, the pathogenicity of long CNTs and other fibers arises as a result of length-dependent retention at the stomata on the parietal pleura.
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- 2011
45. Particle Traps Prevent Adverse Vascular and Prothrombotic Effects of Diesel Engine Exhaust Inhalation in Men
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Thomas Sandström, Manjit K. Sidhu, Stefan Barath, Nicholas L. Mills, Ken Donaldson, Christoffer Boman, David E. Newby, Juan J. Badimon, Andrew J. Lucking, Miriam E. Gerlofs-Nijland, Jeremy P. Langrish, Jamshid Pourazar, Flemming R. Cassee, Magnus Lundbäck, Nicholas A. Boon, and Anders Blomberg
- Subjects
medicine.medical_specialty ,Pathology ,Inhalation ,business.industry ,Diesel engine ,medicine.disease ,Human exposure ,Physiology (medical) ,Internal medicine ,Cardiology ,Medicine ,Thrombus ,Cardiology and Cardiovascular Medicine ,business ,Vascular function - Abstract
Background— In controlled human exposure studies, diesel engine exhaust inhalation impairs vascular function and enhances thrombus formation. The aim of the present study was to establish whether an exhaust particle trap could prevent these adverse cardiovascular effects in men. Methods and Results— Nineteen healthy volunteers (mean age, 25±3 years) were exposed to filtered air and diesel exhaust in the presence or absence of a particle trap for 1 hour in a randomized, double-blind, 3-way crossover trial. Bilateral forearm blood flow and plasma fibrinolytic factors were assessed with venous occlusion plethysmography and blood sampling during intra-arterial infusion of acetylcholine, bradykinin, sodium nitroprusside, and verapamil. Ex vivo thrombus formation was determined with the use of the Badimon chamber. Compared with filtered air, diesel exhaust inhalation was associated with reduced vasodilatation and increased ex vivo thrombus formation under both low- and high-shear conditions. The particle trap markedly reduced diesel exhaust particulate number (from 150 000 to 300 000/cm 3 to 30 to 300/cm 3 ; P 3 ; P Conclusions— Exhaust particle traps are a highly efficient method of reducing particle emissions from diesel engines. With a range of surrogate measures, the use of a particle trap prevents several adverse cardiovascular effects of exhaust inhalation in men. Given these beneficial effects on biomarkers of cardiovascular health, the widespread use of particle traps on diesel-powered vehicles may have substantial public health benefits and reduce the burden of cardiovascular disease. Clinical Trial Registration— http://www.clinicaltrials.gov . Unique identifier: NCT00745446.
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- 2011
46. Zeta Potential Mediated Reaction Monitoring on Nano and Microparticles
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Ken Donaldson, Frank Thielbeer, and Mark Bradley
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Pharmacology ,Molecular Structure ,Surface Properties ,Chemistry ,Organic Chemistry ,Biomedical Engineering ,Pharmaceutical Science ,Nanoparticle ,Chemical modification ,Bioengineering ,Nanotechnology ,Zeta Potential Analysis ,chemistry.chemical_compound ,Nano ,Zeta potential ,Nanoparticles ,Polystyrenes ,Particle ,Particle analysis ,Derivatization ,Fluorescent Dyes ,Biotechnology - Abstract
Nano and microparticles are widely used across the life science interface, with applications ranging from chemical probes of biological function to fluorescent particles for flow cytometry and cellular tracking. Increasingly, particles are modified with a variety of chemistries to boost their functionality and broaden their biological applicability. However, although particle modification has become standard laboratory practice, the ability to determine the extent and efficiency of chemical modification is often very limited and empirical in nature. Herein, we report the use of zeta potential analysis as a simple and rapid "direct-on-particle" approach allowing levels of bead modification and derivatization to be evaluated. As a proof-of-concept, aminomethyl-functionalized nano and microparticles were derivatized to display a variety of surface functionalities and their zeta potentials measured, allowing verification of the applicability of the approach for particle analysis. We demonstrate that zeta potential measurement is a convenient approach which allows multistep reaction sequences to be followed, and show that this method can be used to verify and validate successful particle modification.
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- 2011
47. Physicochemical characterization and cytotoxicity of ambient coarse, fine, and ultrafine particulate matters in Shanghai atmosphere
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Jinping Zhang, An Jing, Man Feng, Shinich Yonemochi, Ken Donaldson, Minghong Wu, Jiamo Fu, Senlin Lu, Zhenkun Yao, Zhong Yufang, Qingyue Wang, and Guoying Sheng
- Subjects
Atmosphere ,Atmospheric Science ,Adverse health effect ,Environmental chemistry ,Ultrafine particle ,Environmental engineering ,Air pollution ,medicine ,Environmental science ,Particulates ,medicine.disease_cause ,General Environmental Science ,Characterization (materials science) - Abstract
Epidemiological studies have demonstrated positive relationships between increases in air pollution and adverse health effects. Physicochemical characterization and toxicity of ambient coarse particles (1.8–10 μm diameter), fine particles (1.8–10 μm diameter) and ultrafine particles (
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- 2011
48. Identifying the pulmonary hazard of high aspect ratio nanoparticles to enable their safety-by-design
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Ken Donaldson, Rodger Duffin, Craig A Poland, Anja Schinwald, and Fiona Murphy
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Lung Diseases ,Mesothelioma ,Mineral Fibers ,Materials science ,Biomedical Engineering ,Medicine (miscellaneous) ,Nanoparticle ,Asbestos ,Bioengineering ,Nanotechnology ,Development ,Pathogenicity ,Nanotoxicology ,Nanofiber ,Asbestos fibers ,Animals ,Humans ,Nanoparticles ,General Materials Science - Abstract
High aspect ratio, or fiber-shaped, nanoparticles (HARNs) represent a growth area in nanotechnology as their useful properties become more apparent. Carbon nanotubes, the best known and studied of the HARNs are handled on an increasingly large scale, with subsequent potential for human inhalation exposure. Their resemblance to asbestos fibers precipitated fears that they might show the same type of pathology as that caused by asbestos and there is emerging evidence to support this possibility. The large number of other HARNs, including nanorods, nanowires and other nanofibers, require similar toxicological scrutiny. In this article we describe the unusual hazard associated with fibers, with special reference to asbestos, and address the features of fibers that dictate their pathogenicity as developed in the fiber pathogenicity paradigm. This paradigm is a robust structure:toxicity model that identifies thin, long, biopersistent fibers as the effective dose for fiber-type pathogenic effects. It is likely that HARNs will in general conform to the paradigm and such an understanding of the features that make fibers pathogenic should enable us to design safer HARNs.
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- 2011
49. Diesel exhaust inhalation does not affect heart rhythm or heart rate variability
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Thomas Sandström, Nicholas A. Boon, Colin Goudie, Keith A.A. Fox, Manuel Gonzalez, Håkan Törnqvist, Ken Donaldson, Nicholas L. Mills, Stefan Barath, Anders Blomberg, Alexander E. Finlayson, Stefan Söderberg, Elen Vink, Jeremy P. Langrish, and David E. Newby
- Subjects
Adult ,Male ,medicine.medical_specialty ,Diesel exhaust ,Air pollution ,Coronary Disease ,medicine.disease_cause ,complex mixtures ,Young Adult ,Double-Blind Method ,Heart Rate ,Internal medicine ,Heart rate ,Humans ,Medicine ,Heart rate variability ,Aged ,Vehicle Emissions ,Inhalation Exposure ,Cross-Over Studies ,Inhalation ,medicine.diagnostic_test ,business.industry ,Arrhythmias, Cardiac ,Middle Aged ,Heart Rhythm ,Anesthesia ,Circulatory system ,Electrocardiography, Ambulatory ,Cardiology ,Particulate Matter ,Cardiology and Cardiovascular Medicine ,business ,human activities ,Electrocardiography - Abstract
Exposure to air pollution is associated with increases in cardiovascular morbidity and mortality. This study was undertaken to determine the effect of diesel exhaust inhalation on heart rhythm and heart rate variability in healthy volunteers and patients with coronary heart disease.Double-blind randomised crossover studies in a university teaching hospital.32 healthy non-smoking volunteers and 20 patients with prior myocardial infarction.All 52 subjects were exposed for 1 h to dilute diesel exhaust (particle concentration 300 μg/m³) or filtered air.Heart rhythm and heart rate variability were monitored during and for 24 h after the exposure using continuous ambulatory electrocardiography and assessed using standard time and frequency domain analysis.No significant arrhythmias occurred during or following exposures. Patients with coronary heart disease had reduced autonomic function in comparison to healthy volunteers, with reduced standard deviations of the NN interval (SDNN, p0.001) and triangular index (p0.001). Diesel exhaust did not affect heart rate variability compared with filtered air (p0.05 for all) in healthy volunteers (SDNN 101 ± 6 vs 91 ± 6, triangular index 20 ± 1 vs 21 ± 1) or patients with coronary heart disease (SDNN 47 ± 5 vs 38 ± 4, triangular index 8 ± 1 vs 7 ± 1).Brief exposure to dilute diesel exhaust does not alter heart rhythm or heart rate variability in healthy volunteers or well-treated patients with stable coronary heart disease. Autonomic dysfunction does not appear to be a dominant mechanism that can explain the observed excess in cardiovascular events following exposure to combustion-derived air pollution.
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- 2010
50. The pathological response and fate in the lung and pleura of chrysotile in combination with fine particles compared to amosite asbestos following short-term inhalation exposure: interim results
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D.M. Bernstein, P. Kunzendorf, Jörg Chevalier, S. E. Holm, D. Schuler, S. Gaering, Rosalinda Sepulveda, Rick A. Rogers, and Ken Donaldson
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Time Factors ,Asbestos, Serpentine ,Amosite Asbestos ,Health, Toxicology and Mutagenesis ,Pilot Projects ,Pathological response ,Toxicology ,Chrysotile ,medicine ,Animals ,Lung ,Inhalation exposure ,Inhalation Exposure ,Inhalation ,business.industry ,Rats ,Joint compound ,medicine.anatomical_structure ,Pleura ,Particulate Matter ,Asbestos, Amosite ,business - Abstract
The pathological response and translocation of a commercial chrysotile product similar to that which was used through the mid-1970s in a joint compound intended for sealing the interface between adjacent wall boards was evaluated in comparison to amosite asbestos. This study was unique in that it presents a combined real-world exposure and was the first study to investigate whether there were differences between chrysotile and amosite asbestos fibers in time course, size distribution, and pathological response in the pleural cavity. Rats were exposed by inhalation 6 h/day for 5 days to either sanded joint compound consisting of both chrysotile fibers and sanded joint compound particles (CSP) or amosite asbestos. Subgroups were examined through 1-year postexposure. No pathological response was observed at any time point in the CSP-exposure group. The long chrysotile fibers (L20 microm) cleared rapidly (T(1/2) of 4.5 days) and were not observed in the pleural cavity. In contrast, a rapid inflammatory response occurred in the lung following exposure to amosite resulting in Wagner grade 4 interstitial fibrosis within 28 days. Long amosite fibers had a T(1/2)1000 days and were observed in the pleural cavity within 7 days postexposure. By 90 days the long amosite fibers were associated with a marked inflammatory response on the parietal pleural. This study provides support that CSP following inhalation would not initiate an inflammatory response in the lung, and that the chrysotile fibers present do not migrate to, or cause an inflammatory response in the pleural cavity, the site of mesothelioma formation.
- Published
- 2010
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