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  • Journal article
    Dushianthan A, Clark H, Madsen J, Mogg R, Matthews L, Berry L, Bernardino de la Serna J, Batchelor J, Brealey D, Hussell T, Porter J, Djukanovic R, Feelisch M, Postle A, Grocott MPWet al., 2020,

    Nebulised surfactant for the treatment of severe COVID-19 in adults (COV-Surf): A structured summary of a study protocol for a randomized controlled trial

    , Trials, Vol: 21, Pages: 1-3, ISSN: 1745-6215

    Intervention and comparator: Intervention: The study is based on an investigational drug/device combinationproduct. The surfactant product is Bovactant (Alveofact®), a natural animal derived (bovine) lung surfactantformulated as a lyophilized powder in 108 mg vials and reconstituted to 45 mg/mL in buffer supplied in a prefilledsyringe. It is isolated by lung lavage and, by weight, is a mixture of: phospholipid (75% phosphatidylcholine, 13%phosphatidylglycerol, 3% phosphatidylethanolamine, 1% phosphatidylinositol and 1% sphingomyelin), 5%cholesterol, 1% lipid-soluble surfactant-associated proteins (SP-B and SP-C), very low levels of free fatty acid, lysophosphatidylcholine, water and 0.3% calcium. The Drug Delivery Device is the AeroFact-COVID™ nebulizer, aninvestigational device based on the Aerogen® Solo vibrating mesh nebulizer.The timing and escalation dosing plans for the surfactant are as follows.Cohort 1: Three patients will receive 10 vials (1080 mg) each of surfactant at dosing times of 0 hours, 8 hours and24 hours. 2 controls with no placebo intervention.Cohort 2: Three patients will receive 10 vials (1080 mg) of surfactant at dosing times of 0 hours and 8 hours, and30 vials (3240 mg) at a dosing time of 24 hours. 2 controls with no placebo intervention.Cohort 3: Three patients will receive 10 vials (1080 mg) of surfactant at a dosing time of 0 hours, and 30 vials (3240mg) at dosing times of 8 hours and 24 hours. 2 controls with no placebo intervention.Cohort 4: Three patients will receive 30 (3240 mg) vials each of surfactant at dosing times of 0 hours, 8 hours and24 hours. 2 controls. 2 controls with no placebo intervention.The trial steering committee, advised by the data monitoring committee, will review trial progression and doseescalation/maintenance/reduction after each cohort is completed (48-hour primary outcome timepoint reached)based on available feasibility, adverse event, safety and efficacy data. The trial will not be discontinue

  • Journal article
    Liekkinen J, de Santos Moreno B, Paananen R, Vattulainen I, Monticelli L, Bernardino de la Serna J, Javanainen Met al., 2020,

    Understanding the functional properties of lipid heterogeneity in pulmonary surfactant monolayers at the atomistic level

    , Frontiers in Cell and Developmental Biology, Vol: 8, Pages: 1-16, ISSN: 2296-634X

    Abstract Pulmonary surfactant is a complex mixture of lipids and proteins lining the interior of the alveoli, and constitutes the first barrier to both oxygen and pathogens as they progress toward blood circulation. Despite decades of study, the behavior of the pulmonary surfactant is poorly understood on the molecular scale, which hinders the development of effective surfactant replacement therapies, useful in the treatment of several lung-related diseases. In this work, we combined all-atom molecular dynamics simulations, Langmuir trough measurements, and AFM imaging to study synthetic four-component lipid monolayers designed to model protein-free pulmonary surfactant. We characterized the structural and dynamic properties of the monolayers with a special focus on lateral heterogeneity. Remarkably, simulations reproduce almost quantitatively the experimental data on pressure–area isotherms and the presence of lateral heterogeneities highlighted by AFM. Quite surprisingly, the pressure–area isotherms do not show a plateau region, despite the presence of liquid-condensed nanometer–sized domains at surface pressures larger than 20 mN/m. In the simulations, the domains were small and transient, but they did not coalesce to yield a separate phase. The liquid–condensed domains were only slightly enriched in DPPC and cholesterol, and their chemical composition remained very similar to the overall composition of the monolayer membrane. Instead, they differed from liquid-expanded regions in terms of membrane thickness (in agreement with AFM data), diffusion rates, acyl chain packing, and orientation. We hypothesize that such lateral heterogeneities are crucial for lung surfactant function, as they allow both efficient packing, to achieve low surface tension, and sufficient fluidity, critical for rapid adsorption to the air–liquid interface during the breathing cycle.

  • Journal article
    Gutowska-Owsiak D, Podobas EI, Eggeling C, Ogg G, Bernardino de la Serna Jet al., 2020,

    Addressing differentiation in live human keratinocytes by assessment of membrane packing order

    , Frontiers in Cell and Developmental Biology, Vol: 8, ISSN: 2296-634X

    Differentiation of keratinocytes is critical for epidermal stratification and formation of a protective stratum corneum. It involves a series of complex processes leading through gradual changes in characteristics and functions of keratinocytes up to their programmed cell death via cornification. The stratum corneum is an impermeable barrier, comprised of dead cell remnants (corneocytes) embedded within lipid matrix. Corneocyte membranes are comprised of specialized lipids linked to late differentiation proteins, contributing to the formation of a highly stiff and mechanically strengthen layer. To date, the assessment of the progression of keratinocyte differentiation is only possible by determination of specific differentiation markers, e.g. by using proteomics-based approaches. Unfortunately, this requires fixation or cell lysis, and currently there is no robust methodology available to study differentiation in living cells, neither at a single cell, nor in high throughput. Here, we explore a new live-cell based approaches for screening differentiation advancement in keratinocytes, in a “calcium switch” model. We employ a polarity-sensitive dye, Laurdan, and Laurdan general polarization function (GP) as a reporter of the degree of membrane lateral packing order or condensation, as an adequate marker of differentiation. We show that the assay is straightforward and can be conducted either on a single cell level using confocal spectral imaging or on the ensemble level using a fluorescence plate reader. Such systematic quantification may become useful for understanding mechanisms of keratinocyte differentiation, such as the role of membrane inhomogeneities in stiffness, and for future therapeutic development.

  • Journal article
    Smitten KL, Thick EJ, Southam HM, Bernardino de la Serna J, Foster SJ, Thomas JAet al., 2020,

    Mononuclear ruthenium(ii) theranostic complexes that function as broad-spectrum antimicrobials in therapeutically resistant pathogens through interaction with DNA

    , Chemical Science, Vol: 11, Pages: 8828-8838, ISSN: 2041-6520

    Six luminescent, mononuclear ruthenium(II) complexes based on the tetrapyridophenazine (tpphz) and dipyridophenazine (dppz) ligands are reported. The therapeutic activities of the complexes against Gram-negative bacteria (E. coli, A. baumannii, P. aeruginosa) and Gram-positive bacteria (E. faecalis and S. aureus) including pathogenic multi- and pan-drug resistant strains were assessed. Estimated minimum inhibitory and bactericidal concentrations show the activity of the lead compound is comparable to ampicillin and oxacillin in therapeutically sensitive strains and this activity was retained in resistant strains. Unlike related dinuclear analogues the lead compound does not damage bacterial membranes but is still rapidly taken up by both Gram-positive and Gram-negative bacteria in a glucose independent manner. Direct imaging of the complexes through super-resolution nanoscopy and transmission electron microscopy reveals that once internalized the complexes' intracellular target for both Gram-negative and Gram-positive strains is bacterial DNA. Model toxicity screens showed the compound is non-toxic to Galleria mellonella even at exposure concentrations that are orders of magnitude higher than the bacterial MIC.

  • Journal article
    Pickford P, Lucey M, Fang Z, Bitsi S, Bernardino de la Serna J, Broichhagen J, Hodson DJ, Minnion J, Rutter GA, Bloom SR, Tomas A, Jones Bet al., 2020,

    Signalling, trafficking and glucoregulatory properties of glucagon-like peptide-1 receptor agonists exendin-4 and lixisenatide.

    , British Journal of Pharmacology, Vol: 177, Pages: 3905-3923, ISSN: 0007-1188

    BACKGROUND AND PURPOSE: Amino acid substitutions at the N-termini of glucagon-like peptide-1 receptor agonist (GLP-1RA) peptides result in distinct patterns of intracellular signalling, sub-cellular trafficking and efficacy in vivo. Here we aimed to determine whether sequence differences at the ligand C-termini of clinically approved GLP-1RAs exendin-4 and lixisenatide lead to similar phenomena. EXPERIMENTAL APPROACH: Exendin-4, lixisenatide, and N-terminally substituted analogues with biased signalling characteristics were compared across a range of in vitro trafficking and signalling assays in different cell types. Fluorescent ligands and new time-resolved FRET approaches were developed to study agonist behaviours at the cellular and sub-cellular level. Anti-hyperglycaemic and anorectic effects of each parent ligand, and their biased derivatives, were assessed in mice. KEY RESULTS: Lixisenatide and exendin-4 showed equal binding affinity, but lixisenatide was 5-fold less potent for cAMP signalling. Both peptides induced extensive GLP-1R clustering in the plasma membrane and were rapidly endocytosed, but the GLP-1R recycled more slowly to the cell surface after lixisenatide treatment. These combined deficits resulted in reduced maximal sustained insulin secretion and reduced anti-hyperglycaemic and anorectic effects in mice with lixisenatide. N-terminal substitution of His1 by Phe1 to both ligands had favourable effects on their pharmacology, resulting in improved insulin release and lowering of blood glucose. CONCLUSION AND IMPLICATIONS: Changes to the C-terminus of exendin-4 affect signalling potency and GLP-1R trafficking via mechanisms unrelated to GLP-1R occupancy. These differences were associated with changes in their ability to control blood glucose and therefore may be therapeutically relevant.

  • Journal article
    Bello-Gamboa A, Velasco M, Moreno S, Herranz G, Ilie R, Huetos S, Dávila S, Sánchez A, Bernardino De La Serna J, Calvo V, Izquierdo Met al., 2020,

    Actin reorganization at the centrosomal area and the immune synapse regulates polarized secretory traffic of multivesicular bodies in T lymphocytes

    , Journal of Extracellular Vesicles, Vol: 9, Pages: 1-21, ISSN: 2001-3078

    T-cell receptor stimulation induces the convergence of multivesicular bodies towards the microtubule-organizing centre (MTOC) and the polarization of the MTOC to the immune synapse (IS). These events lead to exosome secretion at the IS. We describe here that upon IS formation centrosomal area F-actin decreased concomitantly with MTOC polarization to the IS. PKCδ-interfered T cell clones showed a sustained level of centrosomal area F-actin associated with defective MTOC polarization. We analysed the contribution of two actin cytoskeleton-regulatory proteins, FMNL1 and paxillin, to the regulation of cortical and centrosomal F-actin networks. FMNL1β phosphorylation and F-actin reorganization at the IS were inhibited in PKCδ-interfered clones. F-actin depletion at the central region of the IS, a requirement for MTOC polarization, was associated with FMNL1β phosphorylation at its C-terminal, autoregulatory region. Interfering all FMNL1 isoforms prevented MTOC polarization; nonetheless, FMNL1β re-expression restored MTOC polarization in a centrosomal area F-actin reorganization-independent manner. Moreover, PKCδ-interfered clones exhibited decreased paxillin phosphorylation at the MTOC, which suggests an alternative actin cytoskeleton regulatory pathway. Our results infer that PKCδ regulates MTOC polarization and secretory traffic leading to exosome secretion in a coordinated manner by means of two distinct pathways, one involving FMNL1β regulation and controlling F-actin reorganization at the IS, and the other, comprising paxillin phosphorylation potentially controlling centrosomal area F-actin reorganization.

  • Journal article
    Javed F, Tamisier R, Pepin J-L, Cowie MR, Wegscheider K, Angermann C, D'Ortho M-P, Erdmann E, Simonds AK, Somers VK, Teschler H, Levy P, Armitstead J, Woehrle Het al., 2020,

    Association of serious adverse events with Cheyne-Stokes respiration characteristics in patients with systolic heart failure and central sleep apnoea: A SERVE-Heart Failure substudy analysis

    , RESPIROLOGY, Vol: 25, Pages: 305-311, ISSN: 1323-7799
  • Journal article
    Bernardino de la Serna J, Mellado M, Dustin ML, Garcia-Parajo MF, Morikis Det al., 2020,

    Editorial: ImmunoPhysics and ImmunoEngineering

    , Frontiers of Physics, Vol: 8, Pages: 1-4, ISSN: 2095-0462
  • Journal article
    Saeed HK, Sreedharan S, Jarman PJ, Archer SA, Fairbanks SD, Foxon SP, Auty AJ, Chekulaev D, Keane T, Meijer AJHM, Weinstein JA, Smythe CGW, Bernardino de la Serna J, Thomas JAet al., 2020,

    Making the Right Link to Theranostics: The Photophysical and Biological Properties of Dinuclear Ru-II-Re-I dppz Complexes Depend on Their Tether

    , JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, Vol: 142, Pages: 1101-1111, ISSN: 0002-7863
  • Journal article
    Nakamura T, Alqurashi Y, Morrell M, Mandic Det al., 2020,

    Hearables: automatic overnight sleep monitoring with standardised in-ear EEG sensor

    , IEEE Transactions on Biomedical Engineering, Vol: 67, Pages: 203-212, ISSN: 0018-9294

    Objective: Advances in sensor miniaturisation and computational power have served as enabling technologies for monitoring human physiological conditions in real-world scenarios. Sleep disruption may impact neural function, and can be a symptom of both physical and mental disorders. This study proposes wearable in-ear electroencephalography (ear- EEG) for overnight sleep monitoring as a 24/7 continuous and unobtrusive technology for sleep quality assessment in the community. Methods: Twenty-two healthy participants took part in overnight sleep monitoring with simultaneous ear-EEG and conventional full polysomnography (PSG) recordings. The ear- EEG data were analysed in the both structural complexity and spectral domains; the extracted features were used for automatic sleep stage prediction through supervised machine learning, whereby the PSG data were manually scored by a sleep clinician. Results: The agreement between automatic sleep stage prediction based on ear-EEG from a single in-ear sensor and the hypnogram based on the full PSG was 74.1% in the accuracy over five sleep stage classification; this is supported by a Substantial Agreement in the kappa metric (0.61). Conclusion: The in-ear sensor is both feasible for monitoring overnight sleep outside the sleep laboratory and mitigates technical difficulties associated with scalp-EEG. It therefore represents a 24/7 continuously wearable alternative to conventional cumbersome and expensive sleep monitoring. Significance: The ‘standardised’ one-size-fits-all viscoelastic in-ear sensor is a next generation solution to monitor sleep - this technology promises to be a viable method for readily wearable sleep monitoring in the community, a key to affordable healthcare and future eHealth.

  • Journal article
    Meldrum K, Robertson S, Romer I, Marczylo T, Gant TW, Smith R, Tetley TD, Leonard MOet al., 2020,

    Diesel exhaust particle and dust mite induced airway inflammation is modified by cerium dioxide nanoparticles

  • Journal article
    Preston GW, Dagnino S, Ponzi E, Sozeri O, van Veldhoven K, Barratt B, Liu S, Grigoryan H, Lu SS, Rappaport SM, Chung KF, Cullinan P, Sinharay R, Kelly FJ, Chadeau-Hyam M, Vineis P, Phillips DHet al., 2020,

    Relationships between airborne pollutants, serum albumin adducts and short-term health outcomes in an experimental crossover study

    , Chemosphere, Vol: 239, ISSN: 1879-1298

    Exposure to air pollution can have both short-term and long-term effects on health. However, the relationships between specific pollutants and their effects can be obscured by characteristics of both the pollution and the exposed population. One way of elucidating the relationships is to link exposures and internal changes at the level of the individual. To this end, we combined personal exposure monitoring (59 individuals, Oxford Street II crossover study) with mass-spectrometry-based analyses of putative serum albumin adducts (fixed-step selected reaction monitoring). We attempted to infer adducts' identities using data from another, higher-resolution mass spectrometry method, and were able to detect a semi-synthetic standard with both methods. A generalised least squares regression method was used to test for associations between amounts of adducts and pollution measures (ambient concentrations of nitrogen dioxide and particulate matter), and between amounts of adducts and short-term health outcomes (measures of lung health and arterial stiffness). Amounts of some putative adducts (e.g., one with a positive mass shift of approximately 143Da) were associated with exposure to pollution (11 associations), and amounts of other adducts were associated with health outcomes (eight associations). Adducts did not appear to provide a link between exposures and short-term health outcomes.

  • Journal article
    Singanayagam A, Loo S-L, Calderazzo MA, Finney LJ, Trujillo Torralbo M-B, Bakhsoliani E, Girkin J, Veerati PC, Pathinayake PS, Nichol KS, Reid AT, Footitt J, Johnston SL, Bartlett NW, Mallia Pet al., 2019,

    Antiviral immunity is impaired in COPD patients with frequent exacerbations

    , American Journal of Physiology: Lung Cellular and Molecular Physiology, Vol: 317, Pages: L893-L903, ISSN: 1040-0605

    Patients with frequent exacerbations represent a chronic obstructive pulmonary disease (COPD) sub-group requiring better treatment options. The aim of this study was to determine the innate immune mechanisms that underlie susceptibility to frequent exacerbations in COPD. We measured sputum expression of immune mediators and bacterial loads in samples from patients with COPD at stable state and during virus-associated exacerbations. In vitro immune responses to rhinovirus infection in differentiated primary bronchial epithelial cells (BECs) sampled from patients with COPD were additionally evaluated. Patients were stratified as frequent exacerbators (>2 exacerbations in the preceding year) or infrequent exacerbators (<2 exacerbations in the preceding year) with comparisons made between these groups. Frequent exacerbators had reduced sputum cell mRNA expression of the anti-viral immune mediators type I and III interferons and reduced interferon-stimulated gene (ISG) expression when clinically stable and during virus-associated exacerbation. A role for epithelial cell-intrinsic innate immune dysregulation was identified: induction of interferons and ISGs during in vitro RV-infection was also impaired in differentiated BECs from frequent exacerbators. Frequent exacerbators additionally had increased sputum bacterial loads at 2 weeks following virus-associated exacerbation onset. These data implicate deficient airway innate immunity involving epithelial cells in the increased propensity to exacerbations observed in some patients with COPD. Therapeutic approaches to boost innate anti-microbial immunity in the lung could be a viable strategy for prevention/treatment of frequent exacerbations.

  • Journal article
    Hiemstra PS, Tetley TD, Janes SM, 2019,

    Airway and alveolar epithelial cells in culture

  • Journal article
    Radermecker C, Sabatel C, Vanwinge C, Ruscitti C, Marechal P, Perin F, Schyns J, Rocks N, Toussaint M, Cataldo D, Johnston SL, Bureau F, Marichal Tet al., 2019,

    Locally instructed CXCR4(hi) neutrophils trigger environment-driven allergic asthma through the release of neutrophil extracellular traps

    , Nature Immunology, Vol: 20, Pages: 1444-1455, ISSN: 1529-2908

    Low exposure to microbial products, respiratory viral infections and air pollution are major risk factors for allergic asthma, yet the mechanistic links between such conditions and host susceptibility to type 2 allergic disorders remain unclear. Through the use of single-cell RNA sequencing, we characterized lung neutrophils in mice exposed to a pro-allergic low dose of lipopolysaccharide (LPS) or a protective high dose of LPS before exposure to house dust mites. Unlike exposure to a high dose of LPS, exposure to a low dose of LPS instructed recruited neutrophils to upregulate their expression of the chemokine receptor CXCR4 and to release neutrophil extracellular traps. Low-dose LPS–induced neutrophils and neutrophil extracellular traps potentiated the uptake of house dust mites by CD11b+Ly-6C+ dendritic cells and type 2 allergic airway inflammation in response to house dust mites. Neutrophil extracellular traps derived from CXCR4hi neutrophils were also needed to mediate allergic asthma triggered by infection with influenza virus or exposure to ozone. Our study indicates that apparently unrelated environmental risk factors can shape recruited lung neutrophils to promote the initiation of allergic asthma.

  • Journal article
    Seys SF, Quirce S, Agache I, Akdis CA, Alvaro-Lozano M, Antolin-Amerigo D, Bjermer L, Bobolea I, Bonini M, Bossios A, Brinkman P, Bush A, Calderon M, Canonica W, Chanez P, Couto M, Davila I, Del Giacco S, Del Pozo V, Erjefalt JS, Gevaert P, Hagedoorn P, Heaney LG, Heffler E, Hellings PW, Jutel M, Kalayci O, Kurowski MM, Loukides S, Nair P, Palomares O, Polverino E, Sanchez-Garcia S, Sastre J, Schwarze J, Spanevello A, Ulrik CS, Usmani O, Van den Berge M, Vasakova M, Vijverberg S, Diamant Zet al., 2019,

    Severe asthma: Entering an era of new concepts and emerging therapies: Highlights of the 4th international severe asthma forum, Madrid, 2018

    , ALLERGY, Vol: 74, Pages: 2244-2248, ISSN: 0105-4538
  • Journal article
    Östling J, van Geest M, Schofield JPR, Jevnikar Z, Wilson S, Ward J, Lutter R, Shaw DE, Bakke PS, Caruso M, Dahlen S-E, Fowler SJ, Horváth I, Krug N, Montuschi P, Sanak M, Sandström T, Sun K, Pandis I, Auffray C, Sousa AR, Guo Y, Adcock IM, Howarth P, Chung KF, Bigler J, Sterk PJ, Skipp PJ, Djukanović R, Vaarala O, U-BIOPRED Study Groupet al., 2019,

    IL-17-high asthma with features of a psoriasis immunophenotype

    , Journal of Allergy and Clinical Immunology, Vol: 144, Pages: 1198-1213, ISSN: 0091-6749

    BACKGROUND: The role of interleukin-17 immunity is well established in inflammatory diseases like psoriasis and inflammatory bowel disease but not in asthma where further study is required. OBJECTIVE: To undertake a deep-phenotyping study of asthmatics with up-regulated interleukin-17 immunity. METHODS: Whole genome transcriptomic analysis was performed using epithelial brushings, bronchial biopsies (91 asthmatics patients and 46 healthy controls) and whole blood samples (n=498) from the U-BIOPRED cohort. Gene signatures induced in vitro by interleukin-17 and interleukin-13 in bronchial epithelial cells were used to identify patients with interleukin-17-high and interleukin-13-high phenotypes of asthma. RESULTS: 22 out of 91 patients were identified with interleukin-17 and 9 patients with interleukin-13 gene signatures. The interleukin-17-high asthmatics were characterised by risk of frequent exacerbations, airway (sputum and mucosal) neutrophilia, decreased lung microbiota diversity and urinary biomarker evidence of activation of the thromboxane B2 pathway. In pathway analysis, the differentially expressed genes in interleukin-17-high patients were shared with those reported as altered in psoriasis lesions, and included genes regulating epithelial barrier function and defence mechanisms, such as interleukin-1β, interleukin-6, interleukin-8, and beta-defensin. CONCLUSION: The interleukin-17-high asthma phenotype, characterized by bronchial epithelial dysfunction, upregulated anti-microbial and inflammatory response, resembles the immunophenotype of psoriasis, including activation of the thromboxane B2 pathway which should be considered as a biomarker for this phenotype in further studies, including clinical trials targeting interleukin-17.

  • Journal article
    Smitten KL, Fairbanks SD, Robertson CC, Bernardino de la Serna J, Foster SJ, Thomas JAet al., 2019,

    Ruthenium based antimicrobial theranostics – using nanoscopy to identify therapeutic targets and resistance mechanisms in Staphylococcus aureus

    , Chemical Science, Vol: 11, Pages: 70-79, ISSN: 2041-6520

    In previous studies we reported that specific dinuclear RuII complexes are particularly active against pathogenic Gram-negative bacteria and, unusually for this class of compounds, appeared to display lowered activity against Gram-positive bacteria. With the aim of identifying resistance mechanisms specific to Gram-positive bacteria, the uptake and antimicrobial activity of the lead complex against Staphylococcus aureus SH1000 and other isolates, including MRSA was investigated. This revealed differential, strain specific, sensitivity to the complex. Exploiting the inherent luminescent properties of the RuII complex, super-resolution STED nanoscopy was used to image its initial interaction with S. aureus and confirm its cellular internalization. Membrane damage assays and transmission electron microscopy confirm that the complex disrupts the bacterial membrane structure before internalization, which ultimately results in a small amount of DNA damage. A known resistance mechanism against cationic antimicrobials in Gram-positive bacteria involves increased expression of the mprF gene as this results in an accumulation of positively charged lysyl-phosphatidylglycerol on the outer leaflet of the cytoplasmic membrane that electrostatically repel cationic species. Consistent with this model, it was found that an mprF deficient strain was particularly susceptible to treatment with the lead complex. More detailed co-staining studies also revealed that the complex was more active in S. aureus strains missing, or with altered, wall teichoic acids.

  • Journal article
    Malekmohammad M, Folkerts G, Kashani BS, Naghan PA, Dastenae ZH, Khoundabi B, Garssen J, Mortaz E, Adcock IMet al., 2019,

    Exhaled nitric oxide is not a biomarker for idiopathic pulmonary arterial hypertension or for treatment efficacy

    , BMC Pulmonary Medicine, Vol: 19, ISSN: 1471-2466

    BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) is a fatal illness. Despite many improvements in the treatment of these patients, there is no unique prognostic variable available to track these patients. The aim of this study was to evaluate the association between fractional exhaled nitric oxide (FeNO) levels, as a noninvasive biomarker, with disease severity and treatment outcome. METHODS: Thirty-six patients (29 women and 7 men, mean age 38.4 ± 11.3 years) with IPAH referred to the outpatient's clinic of Masih Daneshvari Hospital, Tehran, Iran, were enrolled into this pilot observational study. Echocardiography, six-minute walking test (6MWT), FeNO, brain natriuretic peptide (BNP) levels and the functional class of patients was assessed before patients started treatment. Assessments were repeated after three months. 30 healthy non-IPAH subjects were recruited as control subjects. RESULTS: There was no significant difference in FeNO levels at baseline between patients with IPAH and subjects in the control group. There was also no significant increase in FeNO levels during the three months of treatment and levels did not correlate with other disease measures. In contrast, other markers of disease severity were correlated with treatment effect over the three months. CONCLUSION: FeNO levels are a poor non-invasive measure of IPAH severity and of treatment response in patients in this pilot study.

  • Journal article
    Belchamber K, Singh R, Batista C, Moira W, Dockrell D, Kilty I, Matthew R, Wedzicha J, Barnes P, Donnelly Let al., 2019,

    Defective bacterial phagocytosis is associated with dysfunctional mitochondria in COPD macrophages

    , European Respiratory Journal, Vol: 54, Pages: 1-14, ISSN: 0903-1936

    Background: Increased reactive oxygen species (ROS) have been implicated in the pathophysiology of chronic obstructive pulmonary disease (COPD). Objective: This study examined the effect of exogenous and endogenous oxidative stress on macrophage phagocytosis in patients with COPD. Methods: Monocyte-derived macrophages (MDM) were generated from non-smoker, smoker and COPD subjects, differentiated in either GM-CSF (G-Mϕ) or M-CSF (M-Mϕ). Alveolar macrophages were isolated from lung tissue or bronchoalveolar lavage. Macrophages were incubated +/- 200M H2O2 for 24 hours, then exposed to fluorescently-labelled H. influenzae or S. pneumoniae for 4 hours, after which phagocytosis, mitochondrial ROS (mROS), and mitochondrial membrane potential (m) were measured. Results: Phagocytosis of bacteria was significantly decreased in both G-Mϕ and M-Mϕ from COPD patients, compared to non-smoker controls. In non-smokers and smokers, bacterial phagocytosis did not alter mROS or m, however in COPD, phagocytosis increased early mROS and decreased m in both G-Mϕ and M-Mϕ. Exogenous oxidative stress reduced phagocytosis in non-smoker and COPD alveolar macrophages, and non-smoker MDM, associated with reduced mROS production. Conclusion: COPD macrophages show defective phagocytosis, which is associated with altered mitochondrial function and an inability to regulate mROS production. Targeting mitochondrial dysfunction may restore the phagocytic defect in COPD.

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