Publications by authors named "Marc J George"

8 Publications

  • Page 1 of 1

Aortic thrombosis in COVID-19.

Clin Infect Pract 2021 Jan 7;9:100059. Epub 2020 Dec 7.

Hospital for Tropical Diseases, University College London Hospitals NHS Foundation Trust, London, UK.

Background: Venous thrombo-embolism is now well-recognised as a common complication of severe COVID-19 disease. Arterial thrombosis has been less well recognised, although it is increasingly reported, mostly in the context of myocardial infarction and stroke.

Case Report: A 63-year-old man developed a pale, cold foot with an absent dorsalis pedis pulse 7 days into his admission with COVID-19. A CT angiogram demonstrated a large thrombus in the lower thoracic aorta, which had not been present on CT pulmonary angiogram the preceding week, along with occlusion of both popliteal arteries. He was managed with therapeutic dose of low molecular weight heparin (LMWH) for 6 weeks.

Results: This case adds to the growing list of potential sites and consequences of thrombosis in COVID-19.

Conclusion: This case underscores the urgent need for pathophysiological studies and clinical trials to target treatments and guidelines for thromboprophylaxis in COVID-19.
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http://dx.doi.org/10.1016/j.clinpr.2020.100059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836879PMC
January 2021

Novel Insights Into the Effects of Interleukin 6 Antagonism in Non-ST-Segment-Elevation Myocardial Infarction Employing the SOMAscan Proteomics Platform.

J Am Heart Assoc 2020 06 9;9(12):e015628. Epub 2020 Jun 9.

K.G. Jebsen Thrombosis Research and Expertise Center University of Tromsø Tromsø Norway.

Background Interleukin 6 concentration is associated with myocardial injury, heart failure, and mortality after myocardial infarction. In the Norwegian tocilizumab non-ST-segment-elevation myocardial infarction trial, the first randomized trial of interleukin 6 blockade in myocardial infarction, concentration of both C-reactive protein and troponin T were reduced in the active treatment arm. In this follow-up study, an aptamer-based proteomic approach was employed to discover additional plasma proteins modulated by tocilizumab treatment to gain novel insights into the effects of this therapeutic approach. Methods and Results Plasma from percutaneous coronary intervention-treated patients, 24 in the active intervention and 24 in the placebo-control arm, drawn 48 hours postrandomization were randomly selected for analysis with the SOMAscan assay. Employing slow off-rate aptamers, the relative abundance of 1074 circulating proteins was measured. Proteins identified as being significantly different between groups were subsequently measured by enzyme immunoassay in the whole trial cohort (117 patients) at all time points (days 1-3 [7 time points] and 3 and 6 months). Five proteins identified by the SOMAscan assay, and subsequently confirmed by enzyme immunoassay, were significantly altered by tocilizumab administration. The acute-phase proteins lipopolysaccharide-binding protein, hepcidin, and insulin-like growth factor-binding protein 4 were all reduced during the hospitalization phase, as was the monocyte chemoattractant C-C motif chemokine ligand 23. Proteinase 3, released primarily from neutrophils, was significantly elevated. Conclusions Employing the SOMAscan aptamer-based proteomics platform, 5 proteins were newly identified that are modulated by interleukin 6 antagonism and may mediate the therapeutic effects of tocilizumab in non-ST-segment-elevation myocardial infarction.
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http://dx.doi.org/10.1161/JAHA.119.015628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429051PMC
June 2020

Resistant Hypertension: Trials and Tribulations.

Hypertension 2018 05 2;71(5):772-780. Epub 2018 Apr 2.

From the Department of Clinical Pharmacology, University College London Hospital NHS Foundation Trust, United Kingdom (M.J.G., R.S., J.M., A.H.); Centre for Molecular Medicine, University College London, United Kingdom (D.J.B.M.); Nephrology, Royal Free London NHS Foundation Trust, United Kingdom (T.R.); Silver Creek Pharmaceuticals, San Francisco, CA (R.B.); Dorset County Hospital, Dorchester, United Kingdom (R.M.); Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom (R.M.T.); Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Belgium (J.A.S.); Hadassah-Hebrew University Medical Center, Mount-Scopus, Jerusalem, Israel (M.B.); Department of Nephrology, Galway University Hospitals, Ireland (D.L.); and University Paris Descartes, AP-HP, Hypertension Unit, Hospital European Georges Pompidou, France (M.B.).

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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.10864DOI Listing
May 2018

Pro-resolving mediators promote resolution in a human skin model of UV-killed Escherichia coli-driven acute inflammation.

JCI Insight 2018 03 22;3(6). Epub 2018 Mar 22.

Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, University College London, London, United Kingdom.

While the treatment of inflammatory disorders is generally based on inhibiting factors that drive onset of inflammation, these therapies can compromise healing (NSAIDs) or dampen immunity against infections (biologics). In search of new antiinflammatories, efforts have focused on harnessing endogenous pathways that drive resolution of inflammation for therapeutic gain. Identification of specialized pro-resolving mediators (SPMs) (lipoxins, resolvins, protectins, maresins) as effector molecules of resolution has shown promise in this regard. However, their action on inflammatory resolution in humans is unknown. Here, we demonstrate using a model of UV-killed Escherichia coli-triggered skin inflammation that SPMs are biosynthesized at the local site at the start of resolution, coinciding with the expression of receptors that transduce their actions. These include receptors for lipoxin A4 (ALX/FPR2), resolvin E1 (ChemR23), resolvin D2 (GPR18), and resolvin D1 (GPR32) that were differentially expressed on the endothelium and infiltrating leukocytes. Administering SPMs into the inflamed site 4 hours after bacterial injection caused a reduction in PMN numbers over the ensuing 6 hours, the phase of active resolution in this model. These results indicate that in humans, the appearance of SPMs and their receptors is associated with the beginning of inflammatory resolution and that their therapeutic supplementation enhanced the resolution response.
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http://dx.doi.org/10.1172/jci.insight.94463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5926908PMC
March 2018

Potent Anti-Inflammatory and Pro-Resolving Effects of Anabasum in a Human Model of Self-Resolving Acute Inflammation.

Clin Pharmacol Ther 2018 10 30;104(4):675-686. Epub 2018 Jan 30.

Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, University College London, London, UK.

Anabasum is a synthetic analog of Δ -tetrahydrocannabinol (THC)-11-oic acid that in preclinical models of experimental inflammation exerts potent anti-inflammatory actions with minimal central nervous system (CNS) cannabimimetic activity. Here we used a novel model of acute inflammation driven by i.d. UV-killed E. coli in healthy humans and found that anabasum (5 mg) exerted a potent anti-inflammatory effect equivalent to that of prednisolone in terms of inhibiting neutrophil infiltration, the hallmark of acute inflammation. These effects arose from the inhibition of the neutrophil chemoattractant LTB , while the inhibition of antiphagocytic prostanoids (PGE , TxB , and PGF α) resulted in enhanced clearance of inflammatory stimulus from the injected site. Anabasum at the higher dose of 20 mg possessed the additional properties of triggering the biosynthesis of specialized pro-resolving lipid mediators including LXA , LXB , RvD1, and RvD3. Collectively, we demonstrate for the first time a striking anti-inflammatory and pro-resolution effects of a synthetic analog of THC in healthy humans.
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http://dx.doi.org/10.1002/cpt.980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175297PMC
October 2018

A Comparison of Human Neutrophils Acquired from Four Experimental Models of Inflammation.

PLoS One 2016 25;11(10):e0165502. Epub 2016 Oct 25.

Centre for Clinical Pharmacology, Division of Medicine, University College London, London, United Kingdom.

Defects in neutrophil function have been implicated in a wide spectrum of clinical conditions. Several models are employed to study activated human neutrophils akin to those found at a site of inflammation. These include whole blood (WB) ex vivo stimulation with lipopolysaccharide (LPS) and in vivo techniques: cantharidin blister, skin windows and intra-dermal injection of UV-killed E.coli (UVKEc). Neutrophils obtained from these have never been compared. We compared the activation status of neutrophils from each technique in order to inform the optimal model for use in human studies. Healthy male volunteers were randomised to undergo one of the four techniques (n = 5/group). LPS: WB stimulated with 1ng/ml of LPS for 4 hours. Cantharidin: 12.5μl of 0.1% cantharidin elicited a single blister, aspirated at 24 hours. Skin windows: four 6mm mechanical-suction blisters created, de-roofed and an exudate-collection chamber placed over the windows for 4 hours before aspiration. UVKEc: 1.5 x 107 UVKEc injected intra-dermally. A single 10mm mechanical-suction blister formed and aspirated at 4 hours. Unstimulated WB used as the control. Flow cytometry was used to determine activation status using CD16, CD11b, CD54, CD62L and CD88. Functional status was assessed with a phagocytosis assay. The pattern of neutrophil activation was similar in all models. Neutrophil CD11b was elevated in all models, most markedly in UVKEc (p<0.0001), and CD54 was also elevated but only significant in the LPS model (p = 0.001). CD62L was significantly reduced in all 4 models (p<0.0001) and CD88 was also suppressed in all. There were no changes in CD16 in any model, neither was there any significant difference in the phagocytic capacity of the neutrophils. In summary, there are no significant differences in activation marker expression or phagocytic capacity in the neutrophils obtained from each technique. Therefore we believe whole blood stimulation is the best model in experimentally challenging inpatient populations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0165502PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5079626PMC
June 2017

Early postoperative bleeding in polytrauma patients treated with fondaparinux: literature review and institutional experience.

Curr Vasc Pharmacol 2011 Jan;9(1):42-7

Academic Department of Trauma and Orthopaedics, University of Leeds, School of Medicine, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Clarendon Wing A, Great George Street, Leeds, LS1 3EX, UK.

Surgery for pelvic or acetabular fractures carries a high risk of deep-vein thrombosis (DVT). Reports indicate that fondaparinux is a more effective thromboprophylactic agent than low molecular weight heparin (LMWH) after major orthopaedic surgery. The safety and efficacy of fondaparinux was evaluated in a new protocol used for DVT prophylaxis. One hundred and twenty seven patients with pelvic or acetabular fractures received either fondaparinux or enoxaparin and were analysed in a historical non-concurrent study. Specific review points included clinical deep-vein thrombosis (DVT) or pulmonary embolism (PE) and evidence of adverse effects such as bleeding or allergic reactions. Two patients that received enoxaparin were found to have a DVT and one patient had a PE. There was no documented DVT or PE in patients that received fondaparinux. The mean number of units of blood transfused postoperatively was higher in the enoxaparin group; however, multivariate regression modelling demonstrated no significant difference between the groups. The most current large randomised controlled studies investigating the administration of fondaparinux following joint arthroplasty or hip fracture surgery, have demonstrated a slight increase or a similar number of bleeding events in patients treated with fondaparinux when compared to those treated with enoxaparin. The current report supports that fondaparinux, in patients with pelvic and acetabular fractures, can be equally effective as enoxaparin and not associated with adverse bleeding events.
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http://dx.doi.org/10.2174/157016111793744670DOI Listing
January 2011

The value of the Duke Activity Status Index (DASI) in predicting ischaemia in myocardial perfusion scintigraphy - a prospective study.

Nucl Med Rev Cent East Eur 2010 ;13(2):59-63

Department of Nuclear Medicine, Royal Free Hospital, London, UK.

Background: Functional capacity assessment may be a useful tool to stratify patients according to risk of coronary artery disease (CAD). The Duke Activity Status Index (DASI) is a functional assessment based on activities of daily living and cardiovascular fitness, assessed using a self-administered questionnaire.

Material And Methods: We assessed the relationship between established clinical risk factors for CAD and the DASI with results of myocardial perfusion scintigraphy (MPS). The MPS results used in the analysis were the presence of reversible ischaemia and the resting left ventricular ejection fraction (LVEF). A DASI self-administered questionnaire was completed by 117 consecutive participants, and a patient history was taken to ascertain established risk factors. All participants underwent a stress test, and myocardial perfusion scintigraphy was performed. Statistical analysis consisted of logistic and linear regression using a statistical software package.

Results: The DASI was the only factor that correlated significantly with reversible ischaemia on MPS. None of the previously established risk factors had a significant association with reversible ischaemia within the model. Our study found a potential relationship between the DASI score and the left ventricular ejection fraction (LVEF) although this was not statistically significant.

Conclusions: Our study findings suggest that the DASI may represent a powerful tool for risk stratification prior to investigation of CAD. A further study with a larger sample size will be required to investigate the predictive value of the DASI and the association with LVEF.
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December 2011