Publications by authors named "Catherine A Shaw"

25 Publications

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Prospective validation of the 4C prognostic models for adults hospitalised with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol.

Thorax 2021 Nov 22. Epub 2021 Nov 22.

Respiratory Department, Imperial College, London, UK.

Purpose: To prospectively validate two risk scores to predict mortality (4C Mortality) and in-hospital deterioration (4C Deterioration) among adults hospitalised with COVID-19.

Methods: Prospective observational cohort study of adults (age ≥18 years) with confirmed or highly suspected COVID-19 recruited into the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study in 306 hospitals across England, Scotland and Wales. Patients were recruited between 27 August 2020 and 17 February 2021, with at least 4 weeks follow-up before final data extraction. The main outcome measures were discrimination and calibration of models for in-hospital deterioration (defined as any requirement of ventilatory support or critical care, or death) and mortality, incorporating predefined subgroups.

Results: 76 588 participants were included, of whom 27 352 (37.4%) deteriorated and 12 581 (17.4%) died. Both the 4C Mortality (0.78 (0.77 to 0.78)) and 4C Deterioration scores (pooled C-statistic 0.76 (95% CI 0.75 to 0.77)) demonstrated consistent discrimination across all nine National Health Service regions, with similar performance metrics to the original validation cohorts. Calibration remained stable (4C Mortality: pooled slope 1.09, pooled calibration-in-the-large 0.12; 4C Deterioration: 1.00, -0.04), with no need for temporal recalibration during the second UK pandemic wave of hospital admissions.

Conclusion: Both 4C risk stratification models demonstrate consistent performance to predict clinical deterioration and mortality in a large prospective second wave validation cohort of UK patients. Despite recent advances in the treatment and management of adults hospitalised with COVID-19, both scores can continue to inform clinical decision making.

Trial Registration Number: ISRCTN66726260.
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http://dx.doi.org/10.1136/thoraxjnl-2021-217629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8610617PMC
November 2021

Remote diagnosis of surgical-site infection using a mobile digital intervention: a randomised controlled trial in emergency surgery patients.

NPJ Digit Med 2021 Nov 18;4(1):160. Epub 2021 Nov 18.

Department of Clinical Surgery, University of Edinburgh, 51 Little France Crescent, Edinburgh, UK.

Surgical site infections (SSI) cause substantial morbidity and pose a burden to acute healthcare services after surgery. We aimed to investigate whether a smartphone-delivered wound assessment tool can expedite diagnosis and treatment of SSI after emergency abdominal surgery. This single-blinded randomised control trial (NCT02704897) enroled adult emergency abdominal surgery patients in two tertiary care hospitals. Patients were randomised (1:1) to routine postoperative care or additional access to a smartphone-delivered wound assessment tool for 30-days postoperatively. Patient-reported SSI symptoms and wound photographs were requested on postoperative days 3, 7, and 15. The primary outcome was time-to-diagnosis of SSI (Centers for Disease Control definition). 492 patients were randomised (smartphone intervention: 223; routine care: 269). There was no significant difference in the 30-day SSI rate between trial arms: 21 (9.4%) in smartphone vs 20 (7.4%, p = 0.513) in routine care. Among the smartphone group, 32.3% (n = 72) did not utilise the tool. There was no significant difference in time-to-diagnosis of SSI for patients receiving the intervention (-2.5 days, 95% CI: -6.6-1.6, p = 0.225). However, patients in the smartphone group had 3.7-times higher odds of diagnosis within 7 postoperative days (95% CI: 1.02-13.51, p = 0.043). The smartphone group had significantly reduced community care attendance (OR: 0.57, 95% CI: 0.34-0.94, p = 0.030), similar hospital attendance (OR: 0.76, 95% CI: 0.28-1.96, p = 0.577), and significantly better experiences in accessing care (OR: 2.02, 95% CI: 1.17-3.53, p = 0.013). Smartphone-delivered wound follow-up is feasible following emergency abdominal surgery. This can facilitate triage to the appropriate level of assessment required, allowing earlier postoperative diagnosis of SSI.
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http://dx.doi.org/10.1038/s41746-021-00526-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8602321PMC
November 2021

Genome-wide Analysis Identifies Novel Gallstone-susceptibility Loci Including Genes Regulating Gastrointestinal Motility.

Hepatology 2021 Oct 15. Epub 2021 Oct 15.

Centre for Medical Informatics, Usher Institute, University of Edinburgh.

Background & Aims: Genome-wide association studies (GWAS) have identified several risk loci for gallstone disease. As with most polygenic traits, it is likely many genetic determinants are undiscovered. The aim of this study was to identify novel genetic variants, representing new targets for gallstone research and treatment.

Approach & Results: We performed a GWAS of 28,627 gallstone cases and 348,373 controls in the UK Biobank, replicated findings in a Scottish cohort (1,089 cases, 5,228 controls) and conducted a GWA meta-analysis (43,639 cases,506,798 controls) with the FinnGen cohort. We assessed pathway enrichment using gene-based then gene-set analysis and tissue expression of identified genes in Genotype-Tissue Expression project data. We constructed a polygenic risk score (PRS) and evaluated phenotypic traits associated with the score. Seventy-five risk loci were identified (P < 5 * 10 ), of which forty-six were novel. Pathway enrichment revealed associations with lipid homeostasis, glucuronidation, phospholipid metabolism and gastrointestinal motility. ANO1 and TMEM147, both in novel, replicated loci, are expressed in the gallbladder and gastrointestinal tract. Both regulate gastrointestinal motility. The gallstone risk allele rs7599-A leads to suppression of hepatic TMEM147 expression suggesting the protein protects against gallstone formation. The highest decile of the PRS demonstrated a 6-fold increased odds of gallstones compared to the lowest decile. The PRS was strongly associated with increased body mass index, serum liver enzymes and C-reactive protein concentrations and decreased lipoprotein cholesterol concentrations.

Conclusions: This GWAS demonstrates the polygenic nature of gallstone risk and identifies 46 novel susceptibility loci. For the first time, we implicate genes influencing gastrointestinal motility in the pathogenesis of gallstones.
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http://dx.doi.org/10.1002/hep.32199DOI Listing
October 2021

Genome-Wide Association Study of NAFLD Using Electronic Health Records.

Hepatol Commun 2021 Sep 17. Epub 2021 Sep 17.

Centre for Global Health Research, Usher Institute, University of Edinburgh, Edingburgh, Scotland.

Genome-wide association studies (GWAS) have identified several risk loci for nonalcoholic fatty liver disease (NAFLD). Previous studies have largely relied on small sample sizes and have assessed quantitative traits. We performed a case-control GWAS in the UK Biobank using recorded diagnosis of NAFLD based on diagnostic codes recommended in recent consensus guidelines. We performed a GWAS of 4,761 cases of NAFLD and 373,227 healthy controls without evidence of NAFLD. Sensitivity analyses were performed excluding other co-existing hepatic pathology, adjusting for body mass index (BMI) and adjusting for alcohol intake. A total of 9,723,654 variants were assessed by logistic regression adjusted for age, sex, genetic principal components, and genotyping batch. We performed a GWAS meta-analysis using available summary association statistics. Six risk loci were identified (P < 5*10 ) (apolipoprotein E [APOE], patatin-like phospholipase domain containing 3 [PNPLA3, transmembrane 6 superfamily member 2 [TM6SF2], glucokinase regulator [GCKR], mitochondrial amidoxime reducing component 1 [MARC1], and tribbles pseudokinase 1 [TRIB1]). All loci retained significance in sensitivity analyses without co-existent hepatic pathology and after adjustment for BMI. PNPLA3 and TM6SF2 remained significant after adjustment for alcohol (alcohol intake was known in only 158,388 individuals), with others demonstrating consistent direction and magnitude of effect. All six loci were significant on meta-analysis. Rs429358 (P = 2.17*10 ) is a missense variant within the APOE gene determining ϵ4 versus ϵ2/ϵ3 alleles. The ϵ4 allele of APOE offered protection against NAFLD (odds ratio for heterozygotes 0.84 [95% confidence interval 0.78-0.90] and homozygotes 0.64 [0.50-0.79]). Conclusion: This GWAS replicates six known NAFLD-susceptibility loci and confirms that the ϵ4 allele of APOE is associated with protection against NAFLD. The results are consistent with published GWAS using histological and radiological measures of NAFLD, confirming that NAFLD identified through diagnostic codes from consensus guidelines is a valid alternative to more invasive and costly approaches.
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http://dx.doi.org/10.1002/hep4.1805DOI Listing
September 2021

Characterisation of in-hospital complications associated with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol UK: a prospective, multicentre cohort study.

Lancet 2021 07;398(10296):223-237

Centre for Medical Informatics, Usher Institute, University of Edinburgh, Edinburgh, UK.

Background: COVID-19 is a multisystem disease and patients who survive might have in-hospital complications. These complications are likely to have important short-term and long-term consequences for patients, health-care utilisation, health-care system preparedness, and society amidst the ongoing COVID-19 pandemic. Our aim was to characterise the extent and effect of COVID-19 complications, particularly in those who survive, using the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK.

Methods: We did a prospective, multicentre cohort study in 302 UK health-care facilities. Adult patients aged 19 years or older, with confirmed or highly suspected SARS-CoV-2 infection leading to COVID-19 were included in the study. The primary outcome of this study was the incidence of in-hospital complications, defined as organ-specific diagnoses occurring alone or in addition to any hallmarks of COVID-19 illness. We used multilevel logistic regression and survival models to explore associations between these outcomes and in-hospital complications, age, and pre-existing comorbidities.

Findings: Between Jan 17 and Aug 4, 2020, 80 388 patients were included in the study. Of the patients admitted to hospital for management of COVID-19, 49·7% (36 367 of 73 197) had at least one complication. The mean age of our cohort was 71·1 years (SD 18·7), with 56·0% (41 025 of 73 197) being male and 81·0% (59 289 of 73 197) having at least one comorbidity. Males and those aged older than 60 years were most likely to have a complication (aged ≥60 years: 54·5% [16 579 of 30 416] in males and 48·2% [11 707 of 24 288] in females; aged <60 years: 48·8% [5179 of 10 609] in males and 36·6% [2814 of 7689] in females). Renal (24·3%, 17 752 of 73 197), complex respiratory (18·4%, 13 486 of 73 197), and systemic (16·3%, 11 895 of 73 197) complications were the most frequent. Cardiovascular (12·3%, 8973 of 73 197), neurological (4·3%, 3115 of 73 197), and gastrointestinal or liver (0·8%, 7901 of 73 197) complications were also reported.

Interpretation: Complications and worse functional outcomes in patients admitted to hospital with COVID-19 are high, even in young, previously healthy individuals. Acute complications are associated with reduced ability to self-care at discharge, with neurological complications being associated with the worst functional outcomes. COVID-19 complications are likely to cause a substantial strain on health and social care in the coming years. These data will help in the design and provision of services aimed at the post-hospitalisation care of patients with COVID-19.

Funding: National Institute for Health Research and the UK Medical Research Council.
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http://dx.doi.org/10.1016/S0140-6736(21)00799-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285118PMC
July 2021

Development and validation of the ISARIC 4C Deterioration model for adults hospitalised with COVID-19: a prospective cohort study.

Lancet Respir Med 2021 04 11;9(4):349-359. Epub 2021 Jan 11.

School of Informatics, University of Edinburgh, Edinburgh, UK.

Background: Prognostic models to predict the risk of clinical deterioration in acute COVID-19 cases are urgently required to inform clinical management decisions.

Methods: We developed and validated a multivariable logistic regression model for in-hospital clinical deterioration (defined as any requirement of ventilatory support or critical care, or death) among consecutively hospitalised adults with highly suspected or confirmed COVID-19 who were prospectively recruited to the International Severe Acute Respiratory and Emerging Infections Consortium Coronavirus Clinical Characterisation Consortium (ISARIC4C) study across 260 hospitals in England, Scotland, and Wales. Candidate predictors that were specified a priori were considered for inclusion in the model on the basis of previous prognostic scores and emerging literature describing routinely measured biomarkers associated with COVID-19 prognosis. We used internal-external cross-validation to evaluate discrimination, calibration, and clinical utility across eight National Health Service (NHS) regions in the development cohort. We further validated the final model in held-out data from an additional NHS region (London).

Findings: 74 944 participants (recruited between Feb 6 and Aug 26, 2020) were included, of whom 31 924 (43·2%) of 73 948 with available outcomes met the composite clinical deterioration outcome. In internal-external cross-validation in the development cohort of 66 705 participants, the selected model (comprising 11 predictors routinely measured at the point of hospital admission) showed consistent discrimination, calibration, and clinical utility across all eight NHS regions. In held-out data from London (n=8239), the model showed a similarly consistent performance (C-statistic 0·77 [95% CI 0·76 to 0·78]; calibration-in-the-large 0·00 [-0·05 to 0·05]); calibration slope 0·96 [0·91 to 1·01]), and greater net benefit than any other reproducible prognostic model.

Interpretation: The 4C Deterioration model has strong potential for clinical utility and generalisability to predict clinical deterioration and inform decision making among adults hospitalised with COVID-19.

Funding: National Institute for Health Research (NIHR), UK Medical Research Council, Wellcome Trust, Department for International Development, Bill & Melinda Gates Foundation, EU Platform for European Preparedness Against (Re-)emerging Epidemics, NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, NIHR HPRU in Respiratory Infections at Imperial College London.
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http://dx.doi.org/10.1016/S2213-2600(20)30559-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832571PMC
April 2021

Reliability and accuracy of an expert physical therapist as a reference standard for a manual therapy joint mobilization trial.

J Man Manip Ther 2021 06 24;29(3):189-195. Epub 2020 Nov 24.

School of Physical Therapy, University of the Incarnate Word, San Antonio, TX, USA.

: Previous studies on learning joint mobilization techniques have used expert practitioners as the reference standard as there is no current evidence on what ideal forces would be for effective mobilizations. However, none of these trials have documented the reliability or accuracy of the reference standard. Therefore, the purpose of this study was to report both the reliability and accuracy of an expert physical therapist (PT) acting as a reference standard for a manual therapy joint mobilization trial.: A secondary analysis was performed using data from a published randomized, controlled, crossover study. The mobilization technique studied was the central posterior to anterior (PA) joint mobilization of the L3 vertebra. Reliability and accuracy data for the reference standard were collected over four time periods spanning 16 weeks.: Intrarater reliability of the expert PT for R1 and R2 joint forces was excellent (R1 Force ICC 0.95, 95%CI 0.76-0.99 and R2 Force ICC 0.90, 95%CI 0.49-0.99). Additionally, the expert PT was 92.3% accurate (mean % error±SD, 7.7 ± 5.5) when finding Grade III mean peak mobilization force and 85.1% accurate (mean % error±SD, 14.9 ± 8.3) when finding Grade IV mean peak mobilization force. Finally, correlations between actual applied forces and computed ideal forces were excellent (Pearson r 0.79-0.92, n = 24, < 0.01 for all correlations).: The expert PT in this manual therapy joint mobilization trial showed excellent reliability and accuracy as the reference standard. The study supports the use of implementing quantitative feedback devices into the teaching of joint mobilization when a reliable and accurate reference standard has been identified.: 2b.
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http://dx.doi.org/10.1080/10669817.2020.1844853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183505PMC
June 2021

Risk stratification of patients admitted to hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: development and validation of the 4C Mortality Score.

BMJ 2020 09 9;370:m3339. Epub 2020 Sep 9.

NIHR Health Protection Research Unit, Institute of Infection, Veterinary and Ecological Sciences, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK.

Objective: To develop and validate a pragmatic risk score to predict mortality in patients admitted to hospital with coronavirus disease 2019 (covid-19).

Design: Prospective observational cohort study.

Setting: International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) World Health Organization (WHO) Clinical Characterisation Protocol UK (CCP-UK) study (performed by the ISARIC Coronavirus Clinical Characterisation Consortium-ISARIC-4C) in 260 hospitals across England, Scotland, and Wales. Model training was performed on a cohort of patients recruited between 6 February and 20 May 2020, with validation conducted on a second cohort of patients recruited after model development between 21 May and 29 June 2020 PARTICIPANTS: Adults (age ≥18 years) admitted to hospital with covid-19 at least four weeks before final data extraction.

Main Outcome Measure: In-hospital mortality.

Results: 35 463 patients were included in the derivation dataset (mortality rate 32.2%) and 22 361 in the validation dataset (mortality rate 30.1%). The final 4C Mortality Score included eight variables readily available at initial hospital assessment: age, sex, number of comorbidities, respiratory rate, peripheral oxygen saturation, level of consciousness, urea level, and C reactive protein (score range 0-21 points). The 4C Score showed high discrimination for mortality (derivation cohort: area under the receiver operating characteristic curve 0.79, 95% confidence interval 0.78 to 0.79; validation cohort: 0.77, 0.76 to 0.77) with excellent calibration (validation: calibration-in-the-large=0, slope=1.0). Patients with a score of at least 15 (n=4158, 19%) had a 62% mortality (positive predictive value 62%) compared with 1% mortality for those with a score of 3 or less (n=1650, 7%; negative predictive value 99%). Discriminatory performance was higher than 15 pre-existing risk stratification scores (area under the receiver operating characteristic curve range 0.61-0.76), with scores developed in other covid-19 cohorts often performing poorly (range 0.63-0.73).

Conclusions: An easy-to-use risk stratification score has been developed and validated based on commonly available parameters at hospital presentation. The 4C Mortality Score outperformed existing scores, showed utility to directly inform clinical decision making, and can be used to stratify patients admitted to hospital with covid-19 into different management groups. The score should be further validated to determine its applicability in other populations.

Study Registration: ISRCTN66726260.
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http://dx.doi.org/10.1136/bmj.m3339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116472PMC
September 2020

Can a smartphone-delivered tool facilitate the assessment of surgical site infection and result in earlier treatment? Tracking wound infection with smartphone technology (TWIST): protocol for a randomised controlled trial in emergency surgery patients.

BMJ Open 2019 10 3;9(10):e029620. Epub 2019 Oct 3.

Department of Clinical Surgery, University of Edinburgh, 51 Little France Crescent, Edinburgh, UK.

Introduction: National data suggest that surgical site infection (SSI) complicates 2%-10% of general surgery cases, although the patient-reported incidence is much higher. SSIs cause significant patient morbidity and represent a significant burden on acute healthcare services, in a cohort predominantly suitable for outpatient management. Over three-quarters of UK adults now own smartphones, which could be harnessed to improve access to care. We aim to investigate if a smartphone-delivered wound assessment tool results in earlier treatment.

Methods And Analysis: This is a randomised controlled trial aiming to recruit 500 patients across National Health Service (NHS) hospitals. All emergency abdominal surgery patients over the age of 16 who own smartphones will be considered eligible, with the exclusion of those with significant visual impairment. Participants will be randomised in a 1:1 ratio between standard postoperative care and the intervention - use of the smartphone tool in addition to standard postoperative care. The main outcome measure will be time-to-diagnosis of SSI with secondary outcome measures considering use of emergency department and general practitioner services and patient experience. Follow-up will be conducted by clinicians blinded to group allocation. Analysis of time-to-diagnosis will be by comparison of means using an independent two sample t-test.

Ethics And Dissemination: This is the first randomised controlled trial on the use of a smartphone-delivered wound assessment tool to facilitate the assessment of SSI and the impact on time-to-diagnosis. The intervention is being used in addition to standard postoperative care. The study design and protocol were reviewed and approved by Southeast Scotland Research and Ethics Committee (REC Ref: 16/SS/0072 24/05/2016). Study findings will be presented at academic conferences, published in peer-reviewed journals and are expected in 2020. A written lay summary will be available to study participants on request.

Trial Registration Number: NCT02704897; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2019-029620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797297PMC
October 2019

Decision modeling in donation after circulatory death liver transplantation.

Liver Transpl 2017 05;23(5):594-603

Clinical Surgery, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, Scotland.

Donation after circulatory death (DCD) liver allografts are increasingly used for transplantation. However, the posttransplantation clinical and quality of life outcomes of DCD recipients are traditionally considered to be inferior compared with donation after brain death (DBD) allograft recipients. Decision making for such marginal organs can be difficult. This study investigated the optimal decision to accept or decline a DCD liver allograft for a patient based on their current health. A Markov decision process model was constructed to predict the 5-year clinical course of patients on the liver transplant waiting list. Clinical outcomes were determined from the UK transplant registry or appropriate literature. Quality-adjusted life years (QALYs) were determined using the condition-specific short form of liver disease quality of life (SF-LDQoL) questionnaire. There were 293/374 (78.3%) eligible patients who completed the SF-LDQoL questionnaire. A total of 73 respondents (24.9%) were before transplant and 220 were after transplant (DBD recipient, 56.3%; DCD recipient, 8.5%; ischemic cholangiopathy patient, 2.4%; retransplant recipient, 7.9%). Predictive modeling indicated that QALYs gained at 5 years were significantly higher in DCD recipients (3.77; 95% confidence interval [CI], 3.44-4.10) compared with those who remained on the waiting list for a DBD transplant with Model for End-Stage Liver Disease (MELD) scores of 15-20 (3.36; 95% CI, 3.28-3.43), or >20 (3.07; 95% CI, 3.00-3.14). There was no significant advantage for individuals with MELD scores <15 (3.55; 95% CI, 3.47-3.63). In conclusion, this model predicts that patients on the UK liver transplant waiting list with MELD scores >15 should receive an offered DCD allograft based on the QALYs gained at 5 years. This analysis only accounts for donor-recipient risk pairings seen in current practice. The optimal decision for patients with MELD scores <15 remains unclear. However, a survival benefit was observed when a DCD organ was accepted. Liver Transplantation 23 594-603 2017 AASLD.
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http://dx.doi.org/10.1002/lt.24715DOI Listing
May 2017

Individual surgeon mortality rates: can outliers be detected? A national utility analysis.

BMJ Open 2016 10 31;6(10):e012471. Epub 2016 Oct 31.

Clinical Surgery, Surgical and Perioperative Health Research (SPHeRe), University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, UK.

Objectives: There is controversy on the proposed benefits of publishing mortality rates for individual surgeons. In some procedures, analysis at the level of an individual surgeon may lack statistical power. The aim was to determine the likelihood that variation in surgeon performance will be detected using published outcome data.

Design: A national analysis surgeon-level mortality rates to calculate the level of power for the reported mortality rate across multiple surgical procedures.

Setting: The UK from 2010 to 2014.

Participants: Surgeons who performed colon cancer resection, oesophagectomy or gastrectomy, elective aortic aneurysm repair, hip replacement, bariatric surgery or thyroidectomy.

Outcomes: The likelihood of detecting an individual with a 30-day, 90-day or in-patient mortality rate of up to 5 times the national mean or median (as available). This was represented using a novel heat-map approach.

Results: Overall mortality rates for the procedures ranged from 0.07% to 4.5% and mean/median surgeon volume was between 23 and 75 cases. The national median case volume for colorectal (n=55) and upper gastrointestinal (n=23) cancer resections provides around 20% power to detect a mortality rate of 3 times the national median, while, for hip replacement, this is a rate 5 times the national average. At the mortality rates reported for thyroid (0.08%) and bariatric (0.07%) procedures, it is unlikely a surgeon would perform a sufficient number of procedures in his/her entire career to stand a good chance of detecting a mortality rate 5 times the national average.

Conclusions: At present, surgeons with increased mortality rates are unlikely to be detected. Performance within an expected mortality rate range cannot be considered reliable evidence of acceptable performance. Alternative approaches should focus on commonly occurring meaningful outcome measures, with infrequent events analysed predominately at the hospital level.
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http://dx.doi.org/10.1136/bmjopen-2016-012471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5093625PMC
October 2016

Protein corona formation in bronchoalveolar fluid enhances diesel exhaust nanoparticle uptake and pro-inflammatory responses in macrophages.

Nanotoxicology 2016 09 30;10(7):981-91. Epub 2016 Mar 30.

b Laboratory for Molecular and Cellular Pharmacology , School of Biomedical Sciences, University of Queensland , Brisbane , Australia ;

In biological fluids nanoparticles bind a range of molecules, particularly proteins, on their surface. The resulting protein corona influences biological activity and fate of nanoparticle in vivo. Corona composition is often determined by the biological milieu encountered at the entry portal into the body, and, can therefore, depend on the route of exposure to the nanoparticle. For environmental nanoparticles where exposure is by inhalation, this will be lung lining fluid. This study examined plasma and bronchoalveolar fluid (BALF) protein binding to engineered and environmental nanoparticles. We hypothesized that protein corona on nanoparticles would influence nanoparticle uptake and subsequent pro-inflammatory biological response in macrophages. All nanoparticles bound plasma and BALF proteins, but the profile of bound proteins varied between nanoparticles. Focusing on diesel exhaust nanoparticles (DENP), we identified proteins bound from plasma to include fibrinogen, and those bound from BALF to include albumin and surfactant proteins A and D. The presence on DENP of a plasma-derived corona or one of purified fibrinogen failed to evoke an inflammatory response in macrophages. However, coronae formed in BALF increased DENP uptake into macrophages two fold, and increased nanoparticulate carbon black (NanoCB) uptake fivefold. Furthermore, a BALF-derived corona increased IL-8 release from macrophages in response to DENP from 1720 ± 850 pg/mL to 5560 ± 1380 pg/mL (p = 0.014). These results demonstrate that the unique protein corona formed on nanoparticles plays an important role in determining biological reactivity and fate of nanoparticle in vivo. Importantly, these findings have implications for the mechanism of detrimental properties of environmental nanoparticles since the principle route of exposure to such particles is via the lung.
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http://dx.doi.org/10.3109/17435390.2016.1155672DOI Listing
September 2016

Platelet activation independent of pulmonary inflammation contributes to diesel exhaust particulate-induced promotion of arterial thrombosis.

Part Fibre Toxicol 2016 Feb 9;13. Epub 2016 Feb 9.

Univeristy/ BHF Centre for Cardiovascular Sciences, Edinburgh, EH16 4TJ, UK.

Background: Accelerated thrombus formation induced by exposure to combustion-derived air pollution has been linked to alterations in endogenous fibrinolysis and platelet activation in response to pulmonary and systemic inflammation. We hypothesised that mechanisms independent of inflammation contribute to accelerated thrombus formation following exposure to diesel exhaust particles (DEP).

Methods: Thrombosis in rats was assessed 2, 6 and 24 h after administration of DEP, carbon black (CB; control carbon nanoparticle), DQ12 quartz microparticles (to induce pulmonary inflammation) or saline (vehicle) by either intra-tracheal instillation (0.5 mg, except Quartz; 0.125 mg) or intravenous injection (0.5 mg/kg). Thrombogenicity was assessed by carotid artery occlusion, fibrinolytic variables and platelet-monocyte aggregates. Measures of inflammation were determined in plasma and bronchoalveolar lavage fluid. Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI)-1 were measured following direct in vitro exposure of human umbilical vein endothelial cells (HUVECs) to DEP (10-150 μg/mL).

Results: Instillation of DEP reduced the time to thrombotic occlusion in vivo, coinciding with the peak of DEP-induced pulmonary inflammation (6 h). CB and DQ12 produced greater inflammation than DEP but did not alter time to thrombotic occlusion. Intravenous DEP produced an earlier (2 h) acceleration of thrombosis (as did CB) without pulmonary or systemic inflammation. DEP inhibited t-PA and PAI-1 release from HUVECs, and reduced the t-PA/PAI-1 ratio in vivo; similar effects in vivo were seen with CB and DQ12. DEP, but not CB or DQ12, increased platelet-monocyte aggregates.

Conclusion: DEP accelerates arterial thrombus formation through increased platelet activation. This effect is dissociated from pulmonary and systemic inflammation and from impaired fibrinolytic function.
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http://dx.doi.org/10.1186/s12989-016-0116-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4746929PMC
February 2016

Pulmonary diesel particulate increases susceptibility to myocardial ischemia/reperfusion injury via activation of sensory TRPV1 and β1 adrenoreceptors.

Part Fibre Toxicol 2014 Feb 25;11:12. Epub 2014 Feb 25.

BHF/ University Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh, Edinburgh, Scotland, UK.

Background: Clinical studies have now confirmed the link between short-term exposure to elevated levels of air pollution and increased cardiovascular mortality, but the mechanisms are complex and not completely elucidated. The present study was designed to investigate the hypothesis that activation of pulmonary sensory receptors and the sympathetic nervous system underlies the influence of pulmonary exposure to diesel exhaust particulate on blood pressure, and on the myocardial response to ischemia and reperfusion.

Methods & Results: 6 h after intratracheal instillation of diesel exhaust particulate (0.5 mg), myocardial ischemia and reperfusion was performed in anesthetised rats. Blood pressure, duration of ventricular arrhythmia, arrhythmia-associated death, tissue edema and reperfusion injury were all increased by diesel exhaust particulate exposure. Reperfusion injury was also increased in buffer perfused hearts isolated from rats instilled in vivo, excluding an effect dependent on continuous neurohumoral activation or systemic inflammatory mediators. Myocardial oxidant radical production, tissue apoptosis and necrosis were increased prior to ischemia, in the absence of recruited inflammatory cells. Intratracheal application of an antagonist of the vanilloid receptor TRPV1 (AMG 9810, 30 mg/kg) prevented enhancement of systolic blood pressure and arrhythmia in vivo, as well as basal and reperfusion-induced myocardial injury ex vivo. Systemic β1 adrenoreceptor antagonism with metoprolol (10 mg/kg) also blocked enhancement of myocardial oxidative stress and reperfusion injury.

Conclusions: Pulmonary diesel exhaust particulate increases blood pressure and has a profound adverse effect on the myocardium, resulting in tissue damage, but also increases vulnerability to ischemia-associated arrhythmia and reperfusion injury. These effects are mediated through activation of pulmonary TRPV1, the sympathetic nervous system and locally generated oxidative stress.
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http://dx.doi.org/10.1186/1743-8977-11-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4016506PMC
February 2014

Diesel exhaust particulate increases the size and complexity of lesions in atherosclerotic mice.

Part Fibre Toxicol 2013 Dec 11;10:61. Epub 2013 Dec 11.

Centre for Cardiovascular Sciences, University of Edinburgh, 47 Little France Crescent, EH16 4TJ Edinburgh, Scotland, UK.

Objective: Diesel exhaust particulate (DEP), a major component of urban air pollution, has been linked to atherogenesis and precipitation of myocardial infarction. We hypothesized that DEP exposure would increase and destabilise atherosclerotic lesions in apolipoprotein E deficient (ApoE-/-) mice.

Methods: ApoE-/- mice were fed a 'Western diet' (8 weeks) to induce 'complex' atherosclerotic plaques, with parallel experiments in normal chow fed wild-type mice. During the last 4 weeks of feeding, mice received twice weekly instillation (oropharyngeal aspiration) of 35 μL DEP (1 mg/mL, SRM-2975) or vehicle (saline). Atherosclerotic burden was assessed by en-face staining of the thoracic aorta and histological examination of the brachiocephalic artery.

Results: Brachiocephalic atherosclerotic plaques were larger in ApoE-/- mice treated with DEP (59 ± 10%) than in controls (32 ± 7%; P = 0.017). In addition, DEP-treated mice had more plaques per section of artery (2.4 ± 0.2 vs 1.8 ± 0.2; P = 0.048) and buried fibrous layers (1.2 ± 0.2 vs 0.4 ± 0.1; P = 0.028). These changes were associated with lung inflammation and increased antioxidant gene expression in the liver, but not with changes in endothelial function, plasma lipids or systemic inflammation.

Conclusions: Increased atherosclerosis is caused by the particulate component of diesel exhaust producing advanced plaques with a potentially more vulnerable phenotype. These results are consistent with the suggestion that removal of the particulate component would reduce the adverse cardiovascular effects of diesel exhaust.
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http://dx.doi.org/10.1186/1743-8977-10-61DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907045PMC
December 2013

Nanoparticles and the cardiovascular system: a critical review.

Nanomedicine (Lond) 2013 Mar;8(3):403-23

Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK.

Nanoparticles (NPs) are tiny particles with a diameter of less than 100 nm. Traffic exhaust is a major source of combustion-derived NPs (CDNPs), which represent a significant component in urban air pollution. Epidemiological, panel and controlled human chamber studies clearly demonstrate that exposure to CDNPs is associated with multiple adverse cardiovascular effects in both healthy individuals and those with pre-existing cardiovascular disease. NPs are also manufactured from a large range of materials for industrial use in a vast array of products including for use as novel imaging agents for medical use. There is currently little information available on the impacts of manufactured NPs in humans, but experimental studies demonstrate similarities to the detrimental cardiovascular actions of CDNPs. This review describes the evidence for these cardiovascular effects and attempts to resolve the paradox between the adverse effects of the unintentional exposure of CDNPs and the intentional delivery of manufactured NPs for medical purposes.
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http://dx.doi.org/10.2217/nnm.13.16DOI Listing
March 2013

From particles to patients: oxidative stress and the cardiovascular effects of air pollution.

Future Cardiol 2012 Jul;8(4):577-602

BHF/University Centre for Cardiovascular Science, University of Edinburgh, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh, Scotland, UK.

Air pollution, especially airborne particulate matter (PM), is associated with an increase in both morbidity and mortality from cardiovascular disease, although the underlying mechanisms remain incompletely established. The one consistent observation that links the pulmonary and cardiovascular effects of inhaled PM is oxidative stress. This article examines the evidence for the role of oxidative stress in the cardiovascular effects of air pollution, beginning with observations from epidemiological and controlled exposure studies and then exploring potential mechanistic pathways involving free radical generation from PM itself, to effects of PM on cell cultures, isolated organs, healthy animals and animal models of disease. Particular emphasis is placed on the vascular and atherosclerotic effects of urban air pollution and diesel exhaust emissions as rich sources of environmental ultrafine particles.
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http://dx.doi.org/10.2217/fca.12.43DOI Listing
July 2012

In vivo mononuclear cell tracking using superparamagnetic particles of iron oxide: feasibility and safety in humans.

Circ Cardiovasc Imaging 2012 Jul 10;5(4):509-17. Epub 2012 Jul 10.

Centre of Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom .

Background: Cell therapy is an emerging and exciting novel treatment option for cardiovascular disease that relies on the delivery of functional cells to their target site. Monitoring and tracking cells to ensure tissue delivery and engraftment is a critical step in establishing clinical and therapeutic efficacy. The study aims were (1) to develop a Good Manufacturing Practice-compliant method of labeling competent peripheral blood mononuclear cells with superparamagnetic particles of iron oxide (SPIO), and (2) to evaluate its potential for magnetic resonance cell tracking in humans.

Methods And Results: Peripheral blood mononuclear cells 1-5 × 10(9) were labeled with SPIO. SPIO-labeled cells had similar in vitro viability, migratory capacity, and pattern of cytokine release to unlabeled cells. After intramuscular administration, up to 10(8) SPIO-labeled cells were readily identifiable in vivo for at least 7 days using magnetic resonance imaging scanning. Using a phased-dosing study, we demonstrated that systemic delivery of up to 10(9) SPIO-labeled cells in humans is safe, and cells accumulating in the reticuloendothelial system were detectable on clinical magnetic resonance imaging. In a healthy volunteer model, a focus of cutaneous inflammation was induced in the thigh by intradermal injection of tuberculin. Intravenously delivered SPIO-labeled cells tracked to the inflamed skin and were detectable on magnetic resonance imaging. Prussian blue staining of skin biopsies confirmed iron-laden cells in the inflamed skin.

Conclusions: Human peripheral blood mononuclear cells can be labeled with SPIO without affecting their viability or function. SPIO labeling for magnetic resonance cell tracking is a safe and feasible technique that has major potential for a range of cardiovascular applications including monitoring of cell therapies and tracking of inflammatory cells. Clinical Trial Registration- URL: http://www.clinicaltrials.gov; Unique identifier: NCT00972946, NCT01169935.
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http://dx.doi.org/10.1161/CIRCIMAGING.112.972596DOI Listing
July 2012

Diesel exhaust particulate induces pulmonary and systemic inflammation in rats without impairing endothelial function ex vivo or in vivo.

Part Fibre Toxicol 2012 Apr 5;9. Epub 2012 Apr 5.

Centre of Cardiovascular Science, University of Edinburgh, Edinburgh, Scotland, UK.

Background: Inhalation of diesel exhaust impairs vascular function in man, by a mechanism that has yet to be fully established. We hypothesised that pulmonary exposure to diesel exhaust particles (DEP) would cause endothelial dysfunction in rats as a consequence of pulmonary and systemic inflammation.

Methods: Wistar rats were exposed to DEP (0.5 mg) or saline vehicle by intratracheal instillation and hind-limb blood flow, blood pressure and heart rate were monitored in situ 6 or 24 h after exposure. Vascular function was tested by administration of the endothelium-dependent vasodilator acetylcholine (ACh) and the endothelium-independent vasodilator sodium nitroprusside (SNP) in vivo and ex vivo in isolated rings of thoracic aorta, femoral and mesenteric artery from DEP exposed rats. Bronchoalveolar lavage fluid (BALF) and blood plasma were collected to assess pulmonary (cell differentials, protein levels & interleukin-6 (IL-6)) and systemic (IL-6), tumour necrosis factor alpha (TNFα) and C-reactive protein (CRP)) inflammation, respectively.

Results: DEP instillation increased cell counts, total protein and IL-6 in BALF 6 h after exposure, while levels of IL-6 and TNFα were only raised in blood 24 h after DEP exposure. DEP had no effect on the increased hind-limb blood flow induced by ACh in vivo at 6 or 24 h. However, responses to SNP were impaired at both time points. In contrast, ex vivo responses to ACh and SNP were unaltered in arteries isolated from rats exposed to DEP.

Conclusions: Exposure of rats to DEP induces both pulmonary and systemic inflammation, but does not modify endothelium-dependent vasodilatation. Other mechanisms in vivo limit dilator responses to SNP and these require further investigation.
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http://dx.doi.org/10.1186/1743-8977-9-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3361483PMC
April 2012

Differential susceptibility to nitric oxide-evoked apoptosis in human inflammatory cells.

Free Radic Biol Med 2011 Jan 15;50(1):93-101. Epub 2010 Sep 15.

Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.

Apoptosis of neutrophils and their subsequent phagocytosis is critical to the successful resolution of inflammation. During inflammation, activated inflammatory cells generate reactive oxygen and nitrogen species, including nitric oxide (NO) and superoxide anion (O(2)(•-)), which rapidly combine to generate peroxynitrite (ONOO(-)). NO and ONOO(-) are proapoptotic in human neutrophils. This study examines the effects of NO and ONOO(-) on caspase activation and mitochondrial permeability in human neutrophils and determines the ability of these species to evoke apoptosis in human monocyte-derived macrophages (MDMs). NO or ONOO(-) release from donor compounds was characterized by electrochemistry and electron paramagnetic resonance. Neutrophils and MDMs isolated from the peripheral blood of healthy volunteers were exposed to NO or ONOO(-) before analysis of apoptosis by caspase activation, mitochondrial permeability, and annexin V binding. Both NO and ONOO(-) induced apoptosis via rapid activation of caspases 2 and 3 in neutrophils. In contrast, only ONOO(-) promoted apoptosis in MDMs, whereas a variety of NO donors were ineffective at inducing apoptosis in this cell type. We propose that human macrophages are refractory to NO-stimulated apoptosis in order that they persist long enough within the inflammatory focus to phagocytose apoptotic neutrophils, thereby ensuring successful resolution of inflammation.
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http://dx.doi.org/10.1016/j.freeradbiomed.2010.08.030DOI Listing
January 2011

Diesel exhaust particulate--exposed macrophages cause marked endothelial cell activation.

Am J Respir Cell Mol Biol 2011 Jun 6;44(6):840-51. Epub 2010 Aug 6.

Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, Scotland, UK.

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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http://dx.doi.org/10.1165/rcmb.2010-0011OCDOI Listing
June 2011

Direct impairment of vascular function by diesel exhaust particulate through reduced bioavailability of endothelium-derived nitric oxide induced by superoxide free radicals.

Environ Health Perspect 2009 Apr 17;117(4):611-6. Epub 2008 Dec 17.

Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.

Background: Diesel exhaust particulate (DEP) is a key arbiter of the adverse cardiovascular effects of air pollution.

Objectives: We assessed the in vitro effects of DEP on vascular function, nitric oxide (NO) availability, and the generation of oxygen-centered free radicals.

Methods: We assessed the direct vascular effects of DEP (10-100 microg/mL) in isolated rat aortic rings using myography. We investigated NO scavenging and oxygen-centered free radical generation using an NO electrode and electron paramagnetic resonance (EPR) with the Tempone-H (1-hydroxyl-2,2,6,6-tetramethyl-4-oxo-piperidine) spin trap, respectively.

Results: Acetylcholine-induced relaxation was attenuated by DEP (maximum relaxation reduced from 91 +/- 4% to 49 +/- 6% with 100 microg/mL DEP; p < 0.001) but was restored by superoxide dismutase (SOD; maximum relaxation, 73 +/- 6%; p < 0.001). DEP caused a modest inhibition of relaxation to NO donor drugs, an effect that could be reversed by SOD (p < 0.01). At 10 microg/mL, DEP did not affect verapamil-induced relaxation (p = 0.73), but at 100 microg/mL DEP inhibited relaxation (p < 0.001) by a mechanism independent of SOD. NO concentrations generated by 2-(N,N-diethylamino)-diazenolate-2-oxide (DEA/NO; 10 microM) were reduced by DEP (100 microg/mL; from 5.2 +/- 0.4 to 3.3 +/- 0.4 microM; p = 0.002). Free radical generation was increased by DEP (10 microg/mL; 9-fold increase in EPR spectra; p = 0.004) in a manner that could be attenuated by SOD (p = 0.015).

Conclusions: DEP caused oxidative stress through the generation of oxygen-centered free radicals that reduced the bioavailability of endothelium-derived NO without prior interaction with the lung or vascular tissue. These findings provide a mechanism for the adverse cardiovascular effects of particulate air pollution.
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http://dx.doi.org/10.1289/ehp.0800235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2679606PMC
April 2009

Cyclic GMP protects human macrophages against peroxynitrite-induced apoptosis.

J Inflamm (Lond) 2009 May 7;6:14. Epub 2009 May 7.

Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.

Background: Nitric oxide (NO) can be both pro- and anti-apoptotic in various cell types, including macrophages. This apparent paradox may result from the actions of NO-related species generated in the microenvironment of the cell, for example the formation of peroxynitrite (ONOO-). In this study we have examined the ability of NO and ONOO- to evoke apoptosis in human monocyte-derived macrophages (MDMvarphi), and investigated whether preconditioning by cyclic guanosine monophosphate (cGMP) is able to limit apoptosis in this cell type.

Methods: Characterisation of the NO-related species generated by (Z)-1- [2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA/NO) and 1,2,3,4-oxatriazolium, 5-amino-3-(3,4-dichlorophenyl)-, chloride (GEA-3162) was performed by electrochemistry using an isolated NO electrode and electron paramagnetic resonance (EPR) spectrometry. Mononuclear cells were isolated from peripheral blood of healthy volunteers and cultured to allow differentiation into MDMvarphi. Resultant MDMvarphi were treated for 24 h with DETA/NO (100 - 1000 muM) or GEA-3162 (10 - 300 muM) in the presence or absence of BAY 41-2272 (1 muM), isobutylmethylxanthine (IBMX; 1 muM), 1H- [1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one (ODQ; 20 muM) or 8-bromo-cGMP (1 mM). Apoptosis in MDMvarphi was assessed by flow cytometric analysis of annexin V binding in combination with propidium iodide staining.

Results: Electrochemistry and EPR revealed that DETA/NO liberated free NO radical, whilst GEA-3162 concomitantly released NO and O2-, and is therefore a ONOO- generator. NO (DETA/NO) had no effect on cell viability, but ONOO- (GEA-3162) caused a concentration-dependent induction of apoptosis in MDMvarphi. Preconditioning of MDMvarphi with NO in combination with the phosphodiesterase inhibitor, 3-Isobutyl-1-methylxanthine (IBMX), or the NO-independent stimulator of soluble guanylate cyclase, BAY 41-2272, significantly attenuated ONOO--induced apoptosis in a cGMP-dependent manner.

Conclusion: These results demonstrate disparities between the ability of NO and ONOO- to induce apoptosis in human MDMvarphi. Furthermore, this study provides evidence for a novel cGMP-dependent pre-conditioning mechanism to limit ONOO--induced apoptosis in human MDMvarphi.
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http://dx.doi.org/10.1186/1476-9255-6-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2689212PMC
May 2009

Nitric oxide and the resolution of inflammation: implications for atherosclerosis.

Mem Inst Oswaldo Cruz 2005 Mar 14;100 Suppl 1:67-71. Epub 2005 Jun 14.

Centre for Cardiovascular Science, University of Edinburgh, Teviot Place, Scotland, UK.

The ubiquitous free radical, nitric oxide (NO), plays an important role in many biological processes including the regulation of the inflammatory response. Alterations in NO synthesis by endogenous systems likely influence inflammatory processes occurring in a wide range of diseases including many in the cardiovascular system (e.g. atherosclerosis). Progression of inflammatory conditions depends not only upon the recruitment and activation of inflammatory cells but also upon their subsequent removal from the inflammatory milieu. Apoptosis, or programmed cell death, is a fundamental process regulating inflammatory cell survival and is critically involved in ensuring the successful resolution of an inflammatory response. Apoptosis results in shutdown of secretory pathways and renders effete, but potentially highly histotoxic, cells instantly recognisable for non-inflammatory clearance by phagocytes (e.g., macrophages). However, dysregulation of apoptosis and phagocytic clearance mechanisms can have drastic consequences for development and resolution of inflammatory processes. In this review we highlight the complexities of NO-mediated regulation of inflammatory cell apoptosis and clearance by phagocytes and discuss the molecular mechanisms controlling these NO mediated effects. We believe that manipulation of pathways involving NO may have previously unrecognised therapeutic potential for limiting or resolving inflammatory and cardiovascular disease.
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http://dx.doi.org/10.1590/s0074-02762005000900012DOI Listing
March 2005

GEA 3162 decomposes to co-generate nitric oxide and superoxide and induces apoptosis in human neutrophils via a peroxynitrite-dependent mechanism.

Br J Pharmacol 2004 Sep 2;143(1):179-85. Epub 2004 Aug 2.

Centre for Inflammation Research, Rayne Laboratory, Medical School, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG.

1. GEA 3162 (1,2,3,4,-oxatriazolium, 5-amino-3-(3,4-dichlorophenyl)-chloride), has powerful effects on neutrophil function and apoptosis, but the underlying mechanisms are unclear, particularly with respect to the possible roles of nitric oxide (NO) and/or peroxynitrite (ONOO(-)). 2. Our hypothesis was that GEA 3162 is a generator of ONOO(-) and that its biological effects on neutrophil apoptosis differ from those of a conventional NO donor. The effects of GEA 3162 were compared to those of the established ONOO(-) donor, 3-morpholinosydnonimine (SIN-1), and the NO donor, diethylamine diazeniumdiolate (DEA/NO) in neutrophils from healthy volunteers. Electrochemical detection and electron paramagnetic resonance were used to define the NO-related species generated from these agents. 3. GEA 3162 and SIN-1 influence neutrophil apoptosis differently from DEA/NO. All three compounds induced morphological neutrophil apoptosis. However, both GEA 3162 and SIN-1 paradoxically inhibited internucleosomal DNA fragmentation, whereas DEA/NO induced fragmentation compared to control. 4. In contrast to DEA/NO, generation of free NO was not detectable in solutions of GEA 3162 or SIN-1 (100 microm). However, Cu/Zn superoxide dismutase (SOD; 50-750 U ml(-1)) unmasked NO generated from these compounds in a concentration-dependent manner. GEA 3162 and SIN-1 oxidised the O(2)(-)- and ONOO(-)-sensitive dye, dihydrorhodamine 123 (DHR 123; 1 microm), suggesting that ONOO(-) released from these compounds is responsible for oxidation of DHR 123. 5. We conclude that GEA 3162 is an ONOO(-) donor with pro-apoptotic properties that more closely resemble SIN-1 than the NO donor, DEA/NO. Moreover, unlike NO, ONOO(-) induces apoptosis in neutrophils via a mechanism that does not require DNA fragmentation.
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http://dx.doi.org/10.1038/sj.bjp.0705909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1575270PMC
September 2004
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