ORCID Profile
0000-0001-9985-7829
Current Organisation
University of Western Australia
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Publisher: Elsevier BV
Date: 08-2019
Publisher: Elsevier BV
Date: 12-2021
Publisher: Mary Ann Liebert Inc
Date: 07-2001
DOI: 10.1089/10799900152434312
Abstract: In vivo, low-dose orally administered type I interferon (LDOA IFN) therapy has been shown to provide beneficial effects in a number of diseases. These diseases vary in nature (viral, autoimmune, and neoplastic), yet LDOA IFN therapy is able to provide effective treatment. Despite the growing knowledge of the efficacy of such treatment and ongoing human clinical trials, the mechanism by which LDOA IFN acts remains largely unknown. In this study, we examined the phenomenon known as "priming" as a potential mechanism by which LDOA IFN effects may be mediated. Priming is a phenomenon in which pretreatment of cells or entire organisms with type I IFN causes significantly enhanced IFN production after induction of the endogenous IFN system by virus or polyI:C. This phenomenon of priming has been exploited in commercial industry for the mass production of type I IFN for medical and research use. It was found that LDOA IFN treatment did not cause priming in vivo.
Publisher: Springer Science and Business Media LLC
Date: 17-04-2023
DOI: 10.1186/S40635-023-00508-4
Abstract: To investigate the effect of IV fluid resuscitation on endothelial glycocalyx (EG) shedding and activation of the vascular endothelium and inflammation. A planned biomarker sub-study of the REFRESH trial in which emergency department (ED) patients) with suspected sepsis and hypotension were randomised to a restricted fluid/early vasopressor regimen or IV fluid resuscitation with later vasopressors if required (usual care). Blood s les were collected at randomisation (T0) and at 3 h (T3), 6 h (T6)- and 24 h (T24) for measurement of a range of biomarkers if EG shedding, endothelial cell activation and inflammation. Blood s les were obtained in 95 of 99 enrolled patients (46 usual care, 49 restricted fluid). Differences in the change in biomarker over time between the groups were observed for Hyaluronan (2.2-fold from T3 to T24, p = 0.03), SYN-4 (1.5-fold from T3 to T24, P = 0.01) and IL-6 (2.5-fold from T0 to T3, p = 0.03). No difference over time was observed between groups for the other biomarkers. A consistent signal across a range of biomarkers of EG shedding or of endothelial activation or inflammation was not demonstrated. This could be explained by pre-existing EG shedding or overlap between the fluid volumes administered in the two groups in this clinical trial. Trial registration Australia New Zealand Clinical Trials Registry ACTRN126160000006448 Registered 12 January 2016.
Publisher: Wiley
Date: 02-11-2017
Abstract: Clinical diagnosis of anaphylaxis is principally based on symptoms and signs. However, particularly for patients with atypical symptoms, laboratory confirmation of anaphylaxis would be useful. This study investigated the utility of mast cell tryptase, an available clinical biomarker, for differentiating anaphylaxis from other causes of critical illness, which can also involve mast cell activation. Tryptase was measured (ImmunoCAP) in serum from patients with anaphylaxis and non-anaphylactic critical illness (controls) at ED arrival, and after 1-2, 3-4 and 12-24 h. Differences in both peak and delta (difference between highest and lowest) tryptase concentrations between groups were investigated using linear regression models, and diagnostic ability was analysed using Receiver Operating Characteristic curve analysis. Peak tryptase was fourfold (95% CI: 2.9, 5.5) higher in anaphylaxis patients (n = 67) than controls (n = 120) (P < 0.001). Delta-tryptase was 5.1-fold (95% CI: 2.9, 8.9) higher in anaphylaxis than controls (P 11.4 ng/mL and/or delta-tryptase ≥2.0 ng/mL. For hypotensive patients, peak tryptase >11.4 ng/mL had improved test characteristics (sensitivity: 85% [95% CI: 65, 96] and specificity: 92% [95% CI: 85, 97]) the use of delta-tryptase reduced test specificity. While peak and delta tryptase concentrations were higher in anaphylaxis than other forms of critical illness, the test lacks sufficient sensitivity and specificity. Therefore, mast cell tryptase values alone cannot be used to establish the diagnosis of anaphylaxis in the ED. In particular, tryptase has limited utility for differentiating anaphylactic from non-anaphylactic shock.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2004
DOI: 10.1097/01.TP.0000131150.76841.75
Abstract: Myoblast transfer therapy (MTT) is a cell-based gene therapy representing a potential treatment for Duchenne muscular dystrophy. The rapid disappearance of donor myoblasts from transplanted muscles after MTT is one of the most controversial and significant obstacles facing research in this area. Dystrophin-deficient muscles show constitutively high levels of inflammation, thus necessitating an examination of whether inflammatory cells, specifically natural killer (NK) cells, neutrophils, and macrophages, within dystrophic muscle are responsible for poor graft survival. Female mdx mice were treated with RB6-8C5 monoclonal antibody, PK136 monoclonal antibody, or clodronate liposomes to systemically deplete neutrophils, NK cells, and macrophages, respectively. After each depletion regimen, the mice and age-matched controls received 5.0 x 10 male myoblasts injected longitudinally into each tibialis anterior muscle. Donor myoblast survival was assessed by Y-chromosome specific quantitative real-time polymerase chain reaction analysis. RESULTS.: The systemic depletion of host neutrophils and NK cells resulted in a transient improvement in donor myoblast survival at 72 hr and 7 days post-MTT, respectively. Systemic depletion of macrophages had no significant beneficial effect on myoblast survival. Overall, the number of detectable male donor myoblasts was similar at time 0 and 1 hr post-MTT however, there was significant loss by 24 hr (approximately 50%-70%) followed by a continual decline in donor cell numbers. Neutrophils and macrophages do not seem to play a major role in the rapid death of donor myoblasts after transplantation into dystrophic muscle. NK cells similarly seem to have no significant effect, contrary to earlier findings reported by our group.
Publisher: KARGER
Date: 2008
DOI: 10.1159/000170841
Abstract: Numerous retrospective and prospective studies have been conducted to determine the prevalence and significance on long-term graft survival of de novo post-transplant donor-specific antibodies (DSA), directed against both HLA and non-HLA molecules. Moreover, it has been postulated that the development of anti-HLA antibodies may precede the clinical manifestation of chronic rejection, therefore being considered a predictive marker. In this context, the detection of C4d deposition in the failing kidney in patients presenting de novo DSA supports the hypothesis that antibody production and complement deposition could be involved in the pathogenesis of graft failure. Due to the development of more sensitive meth-ods to detect alloantibodies, the number of transplanted patients which show the appearance of DSA at different times following transplantation has increased. Nevertheless, this increased sensitivity has allowed the identification of circulating donor-specific anti-HLA antibodies in many patients with otherwise good graft function. Such findings are worthy of discussion, as it has yet to be determined whether these circulating antibodies can only be considered an early marker of humoral rejection or whether they could play a protective role. The possible relevance of the post-transplant appearance of non-DSA should also be mentioned. This review will focus primarily on de novo anti-donor HLA antibody responses in kidney transplant patients and will only briefly deal with anti-non HLA and non-DSA that will be discussed elsewhere in this issue.
Publisher: Wiley
Date: 14-02-2019
DOI: 10.1111/VEC.12814
Abstract: To investigate the association between synthetic colloids and biomarkers of acute kidney injury (AKI) in dogs with hemorrhagic shock. Experimental interventional study. University. Twenty-four healthy ex-racing Greyhounds. Anesthetized Greyhounds subjected to hemorrhage for 60 min were resuscitated with 20 mL/kg of fresh whole blood (FWB), 6% hydroxyethyl starch (HES) 130/0.4, 4% succinylated gelatin (GELO), or 80 mL/kg of isotonic crystalloid (CRYST) over 20 min (n = 6 per treatment). Concentrations of biomarkers of AKI were measured at baseline, end of hemorrhage, and at 40 (T60), 100 (T120), and 160 (T180) min after fluid bolus. Biomarkers included neutrophil gelatinase-associated lipocalin in urine and serum (uNGAL sNGAL), and urine cystatin C (uCYSC), kidney injury molecule-1 (uKIM), clusterin (uCLUST), osteopontin, gamma-glutamyl transferase, monocyte chemoattractant protein-1 (uMCP), interleukin-6, interleukin-8, protein (uPROT), hyaluronan, and F In dogs treated with GELO, uNGAL fold-change was markedly greater compared with all other groups at T60, T120, and T180 (all P<0.001), and uCYSC was greater at T60 compared with CRYST (P<0.001), and at T120 and T180 compared with all other groups (all P<0.001). Smaller, albeit significant, between-group differences in uKIM, uCLUST, uMCP, and urine protein concentration were observed across the FWB, GELO, and HES groups, compared with CRYST. The GELO group more frequently had marked tubular microvesiculation than the other groups (P = 0.015) although tubular injury scores were comparable. In dogs with hemorrhagic shock, GELO was associated with greater magnitude increases in urine biomarkers of AKI and more frequent marked tubular microvesiculation, compared with FWB, CRYST, and HES.
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.JCRC.2018.06.015
Abstract: Endocan, a component of the endothelial glycocalyx (EG), has been linked with respiratory failure in sepsis. This study explored the temporal patterns of three EG biomarkers, including endocan, and their relationships with inflammation and respiratory failure. Plasma endocan, syndecan-1, and hyaluronan concentrations were measured in Emergency Department (ED) patients with sepsis due to pneumonia (n = 44) on ED arrival (T0), 1 h (T1), 3 h (T3) and 12-24 h (T24) later, with change over time tested using mixed regression models. Biomarker associations with inflammatory cytokine concentrations and with respiratory failure on days 1, 2 or 3, need for mechanical ventilation and 30-day mortality were also tested. Endocan concentration significantly decreased over time (T0-T24, P = 0.003) whereas both syndecan-1 (T0-T3, P = 0.010 T0-T24, P < 0.001) and hyaluronan (T0-T1, P = 0.010 T0-T3, P < 0.001 T0-T24, P = 0.003) significantly increased over time. Increased syndecan-1 was significantly correlated with neutrophil activation biomarkers and significantly increased the odds of respiratory failure (OR 1.18, 95% CI 1.05-1.33, P = 0.004), need for mechanical ventilation (OR 1.24, 95% CI 1.04-1.48, P = 0.014) and 30-day mortality (OR 1.29, 95% CI 1.07-1.55, P = 0.008). Syndecan-1, but not endocan, was associated with neutrophil activation and was the best EG biomarker predictor of adverse clinical outcomes.
Publisher: Wiley
Date: 16-07-2021
DOI: 10.1111/CEA.13982
Abstract: Anaphylaxis is a severe, potentially life‐threatening allergic reaction driven primarily by the activation of mast cells. We still fail to understand factors underlying reaction severity. Furthermore, there is currently no reliable diagnostic test to confirm anaphylaxis in the emergency department (ED). This study sought to explore gene expression changes associated with anaphylaxis severity in peripheral blood leucocytes and evaluate biomarker potential. Microarray analysis (total RNA) was performed using peripheral blood s les from ED patients with moderate ( n = 6) or severe ( n = 12) anaphylaxis and sepsis ( n = 20) at presentation (T0) and one hour later (T1). Results were compared between groups and healthy controls ( n = 10 and n = 11 matched to anaphylaxis and sepsis patients, respectively). Changes in gene expression were determined using R programming language, and pathway analysis applied to explore biological processes and pathways associated with genes. Differentially expressed genes were validated in an independent cohort of anaphylaxis ( n = 30) and sepsis ( n = 20) patients, and healthy controls ( n = 10), using quantitative reverse transcription‐polymerase chain reaction (qRT‐PCR). Significant up‐regulation of small nucleolar RNAs (snoRNAs) was demonstrated in anaphylaxis compared to sepsis patients in the microarray cohort, at T0 and T1. qRT‐PCR analysis of the validation cohort showed five genes: SNORD61 , SNORD8 , SNORD69 , SNORD119 and HIST1H1D to be significantly up‐regulated (adjusted p 0.05) in severe anaphylaxis compared to sepsis. Seven genes ( SNORD61 , SNORD8 , SCARNA21 , SNORD69 , SNORD110 , SNORD119 and SNORD59A ) were significantly up‐regulated (adjusted p 0.05) in severe anaphylaxis compared to healthy controls. This study demonstrates for the first time the unique involvement of snoRNAs in the pathogenesis of anaphylaxis and suggests they are not a general feature of systemic inflammation. Further investigation of snoRNA expression in anaphylaxis could provide insights into disease pathogenesis. SnoRNAs are up‐regulated during acute anaphylaxis in humans and could potentially be used as biomarkers of severe anaphylaxis.
Publisher: Wiley
Date: 2022
DOI: 10.1002/CTI2.1435
Abstract: Mechanisms underlying the anaphylactic reaction in humans are not fully understood. Here, we aimed at improving our understanding of anaphylaxis by investigating gene expression changes. Microarray data set GSE69063 was analysed, describing emergency department (ED) patients with severe anaphylaxis ( n = 12), moderate anaphylaxis ( n = 6), sepsis ( n = 20) and trauma ( n = 11). S les were taken at ED presentation (T0) and 1 h later (T1). Healthy controls were age and sex matched to ED patient groups. Gene expression changes were determined using limma , and pathway analysis applied. Differentially expressed genes were validated in an independent cohort of anaphylaxis patients ( n = 31) and matched healthy controls ( n = 10), using quantitative reverse transcription‐polymerase chain reaction. Platelet aggregation was dysregulated in severe anaphylaxis at T0, but not in moderate anaphylaxis, sepsis or trauma. Dysregulation was not observed in patients who received adrenaline before T0. Seven genes ( GATA1 (adjusted P‐ value = 5.57 × 10 −4 ), TLN1 (adjusted P‐ value = 9.40 × 10 −4 ), GP1BA (adjusted P ‐value = 2.15 × 10 −2 ), SELP (adjusted P ‐value = 2.29 × 10 −2 ), MPL (adjusted P ‐value = 1.20 × 10 −2 ), F13A1 (adjusted P ‐value = 1.39 × 10 −2 ) and SPARC (adjusted P ‐value = 4.06 × 10 −2 )) were significantly downregulated in severe anaphylaxis patients who did not receive adrenaline before ED arrival, compared with healthy controls. One gene ( TLN1 (adjusted P ‐value = 1.29 × 10 −2 )) was significantly downregulated in moderate anaphylaxis patients who did not receive adrenaline before ED arrival, compared with healthy controls. Downregulation of genes involved in platelet aggregation and activation is a unique feature of the early anaphylactic reaction not previously reported and may be associated with reaction severity.
Publisher: Mary Ann Liebert Inc
Date: 09-2001
DOI: 10.1089/107999001753124453
Abstract: The beneficial effects of low-dose orally administered type I interferon (LDOA IFN) have been demonstrated in various animal models of disease and in some human clinical trials. The mechanisms by which LDOA IFN therapy has its effects, however, remain to be established. In the present study, groups of mice were administered 10 IU murine IFN-alpha/beta (MuIFN-alpha/beta) orally for 7 days. Spleens were then collected and analyzed. No differences were detected between the spleen weights of treated mice compared with controls, although reductions in total splenic white blood cell (WBC) number ranging from 15.5% to 35% were observed. Further analysis showed this reduction to be largely restricted to the B cell population, with only minor reductions in CD4(+) or CD8(+) populations being detected. Dose-response studies showed the WBC loss from the spleen to be optimal at 1 IU MuIFN-alpha/beta, whereas both higher and lower doses showed less significant effects. Time course studies show these effects had developed after 2 days of treatment. It is hypothesized that this observed WBC movement from the spleen is part of the mechanism of action of LDOA IFN.
Publisher: Mary Ann Liebert Inc
Date: 08-1999
Abstract: Oral administration of type I interferons (IFNs murine IFN-alpha and IFN-beta) reduces early replication of murine cytomegalovirus (MCMV) in both the spleen and liver of MCMV-infected BALB/c mice. Examination of a range of doses of IFN (1 to 1000 IU) showed that 10 IU administered daily for 1 week prior to virus infection was optimal for inhibition of MCMV replication. Furthermore, low-dose orally administered IFN (10 IU/day) was effective in mice challenged with lethal and sublethal virus inocula. The antiviral efficacy of low-dose orally administered IFN was not restricted by either the route of virus inoculation or the mouse genotype. Analysis by immunohistochemistry of IFN-alpha receptor-bearing cells of the gastrointestinal tract revealed predominant staining of perivascular smooth muscle and the lamina propria of the anterior tongue, small intestine and rectum. These tissues, dense in IFN-alpha receptor-bearing cells, are likely to be the sites of interaction of the orally administered IFNs with the mucosal immune system. In conclusion, we propose that low-dose oral use of type I IFN therapy may have broad applications in the treatment of CMV infections.
Publisher: Springer Science and Business Media LLC
Date: 24-05-2022
DOI: 10.1038/S41598-022-12752-X
Abstract: Endothelial glycocalyx (EG) shedding is associated with septic shock and described following intravenous (IV) fluid administration. To investigate the possible impact of IV fluids on the pathobiology of septic shock we investigated associations between biomarkers of EG shedding and endothelial cell activation, and relationships with IV fluid volume. Serum s les were obtained on admission (T0) and at 24 h (T24) in patients undergoing haemodynamic resuscitation for suspected septic shock in the emergency department. Biomarkers of EG shedding—Syndecan-1 (Syn-1), Syndecan-4 (Syn-4), Hyaluronan, endothelial activation—Endothelin-1 (ET-1), Angiopoeitin-2 (Ang-2), Vascular Endothelial Growth Factor Receptor-1(VEGF-1) and leucocyte activation/inflammation—Resistin, Neutrophil Gelatinase Associated Lipocalin (NGAL) and a marker of cardiac stretch—Pro-Atrial Natriuretic Peptide (Pro-ANP) were compared to the total IV fluid volume administered using Tobit regression. Data on 86 patients (52 male) with a mean age of 60 (SD 18) years were included. The mean fluid volume administered to T24 was 4038 ml (SD 2507 ml). No significant association between fluid volume and Pro-ANP or any of the biomarkers were observed. Syn-1 and Syn-4 were significantly correlated with each other (Spearman Rho 0.43, p 0.001) but not with Hyaluronan. Syn-1 and Syn-4 both correlated with VEGFR-1 (Rho 0.56 and 0.57 respectively, p 0.001) whereas Hyaluronan correlated with ET-1 (Rho 0.43, p 0.001) and Ang-2 (Rho 0.43, p 0.001). There was no correlation between Pro-ANP and any of the EG biomarkers. Distinct patterns of association between biomarkers of EG shedding and endothelial cell activation were observed among patients undergoing resuscitation for sepsis. No relationship between IV fluid volume and Pro-ANP or any of the other biomarkers was observed.
Publisher: Elsevier BV
Date: 12-2017
DOI: 10.1016/J.JCRC.2017.07.001
Abstract: Endothelial glycocalyx (EG) shedding may promote organ failure in sepsis. This study describes temporal changes in EG biomarkers from Emergency Department (ED) arrival, and associations with clinical characteristics. This prospective observational study included 23 patients with simple infection, 86 with sepsis and 29 healthy controls. Serum EG biomarkers included syndecan-1, syndecan-4 and hyaluronan. S les were taken on enrolment in the ED (T0), 1 hour (T1), 3 hours (T3) and 12 to 24 hours (T24) later. Syndecan-1 concentration increased incrementally over time (T0-T24, both patient groups, P < .001) whereas hyaluronan concentration peaked at T3 (T0-T3, sepsis group, P < .001). Hyaluronan was positively associated with cumulative fluid volumes (P < .001) at T0, T1, and T3, independent of illness severity. Both syndecan-1 (OR 1.04, 95% CI 1.01-1.07, P = .017) and hyaluronan (OR 1.83, 95% CI 1.46-2.30, P < .001) were associated with organ failure, independent of age and comorbidity. Syndecan-4 concentration was not different between groups or over time. In contrast to previous ICU studies, EG biomarkers increased during the first 24 hours of sepsis treatment and were associated with fluid volumes and organ failure. Further investigation is required to determine if interventions delivered in the ED contribute to EG shedding.
Publisher: Oxford University Press (OUP)
Date: 2005
DOI: 10.1093/BMB/LDH061
Abstract: Research efforts have shed light on the immunological obstacles to long-term survival of pig organs transplanted into primates and allowed the identification of targets for specific immune intervention. Accordingly, the development of genetically engineered animals has overcome the hyperacute rejection barrier, with acute humoral xenograft rejection (AHXR) currently remaining the most important immunological obstacle. At this stage, a better control of the elicited anti-pig humoral immune response and avoidance of coagulation disorders are the two primary research fronts being pursued in order to overcome AHXR. Nonetheless, it is encouraging that porcine xenografts can sustain the life of non-human primates for several months. Proactive research aimed at the development of a safer organ source is also underway. It is anticipated that ongoing research in several fields, including accommodation, tolerance, immune suppression and genetic engineering, will result in further improvements in non-human primate survival. However, until convincing efficacy data and a more favourable risk/benefit ratio can be established in relevant animal models, progression to the clinic should not be viewed as an option.
Publisher: Wiley
Date: 03-05-2022
DOI: 10.1111/JCH.14479
Abstract: Elevated office blood pressure (BP) has previously been associated with increased levels of circulating extracellular vesicles (EVs). The present study aimed to assess the relationship between levels of platelet derived EVs, ambulatory BP parameters, and pulse wave velocity as a marker of macrovascular organ damage. A total of 96 participants were included in the study. Platelet‐derived extracellular vesicles (pEVs) were evaluated by flow cytometry (CD41+/Annexin v+). BP evaluation included unobserved automated office BP and ambulatory BP monitoring. Carotid‐femoral pulse wave velocity (PWV) was measured as a marker of macrovascular damage. pEVs correlated with nocturnal systolic BP (r = 0.31 p = .003) and nocturnal dipping (r = ‐0.29 p = .01) in univariable analysis. Multivariable regression models confirmed robustness of the association of EVs and nocturnal blood pressure ( p = .02). In contrast, systolic office, 24h‐ and daytime‐BP did not show significant associations with pEVs. No correlations were found with diastolic BP. Circulating pEVs correlated with pulse wave velocity (r = 0.25 p = .02). When comparing different hypertensive phenotypes, higher levels of EVs and PWV were evident in patients with sustained hypertension compared to patients with white coat HTN and healthy persons. Circulating platelet derived EVs were associated with nocturnal BP, dipping, and PWV. Given that average nocturnal BP is the strongest predictor of CV events, platelet derived EVs may serve as an integrative marker of vascular health, a proposition that requires testing in prospective clinical trials.
Publisher: Wiley
Date: 09-2016
Publisher: Elsevier BV
Date: 05-2019
Publisher: SAGE Publications
Date: 10-2004
DOI: 10.3727/000000004783983369
Abstract: The transplantation of muscle precursor cells (myoblasts) is a potential therapy for Duchenne muscular dystrophy. A commonly used method to detect cell survival is quantitation of the Y chromosome following transplantation of male donor cells into female hosts. This article presents a direct comparison between real-time quantitative PCR (Q-PCR) and the DNA hybridization (slot-blot) technique for quantitation of Y chromosome DNA. Q-PCR has a significantly greater linear quantitation range and is up to 40-fold more sensitive at low concentrations of male DNA, detecting as little as 1 ng of male DNA in each female tibialis anterior (TA) muscle. At high male DNA concentrations, accurate quantitation by Q-PCR is 2.5 times higher than the maximum possible with slot-blot. In conclusion, Q-PCR has a higher dynamic range and is more efficient than slot-blot analysis for the detection of donor cell engraftment in a transsexual transplantation model.
Publisher: Wiley
Date: 13-01-2017
DOI: 10.1111/CEA.12868
Abstract: The mechanisms involved in the lification of the mast cell response during anaphylaxis are unclear. Mouse models of anaphylaxis demonstrate the critical involvement of neutrophils. These innate immune cells are highly abundant in peripheral blood and can be rapidly activated to trigger both local and systemic inflammation. To investigate neutrophil activation in peripheral blood during acute human anaphylaxis. Patients presenting to the emergency department with anaphylaxis underwent blood s ling upon enrolment and at up to three subsequent time-points. Traditional anaphylaxis biomarkers, histamine and mast cell tryptase, were measured by ELISA and ImmunoCAP, respectively. Plasma myeloperoxidase concentrations were measured by ELISA, serum soluble CD62L concentrations by cytometric bead array, and both compared to healthy controls. In 72 patients, 37 (51%) had severe anaphylaxis, 33 (60%) were histamine positive, and 47 (70%) were mast cell tryptase positive. At enrolment, myeloperoxidase concentrations were 2.9- (95% CI: 1.3, 6.5) and 5.0- (95% CI: 2.4, 10.5) fold higher in moderate and severe patients, respectively, compared with healthy controls, and remained stable over the first 5 h following symptom onset. At enrolment, soluble CD62L was 29% (95% CI: 19, 38) and 31% (95% CI: 22, 40) lower in moderate and severe patients, respectively, than healthy controls, and was stable over the first 5 h. There were no associations between myeloperoxidase or soluble CD62L concentrations and either histamine or mast cell tryptase concentrations. These results provide compelling evidence for the involvement of neutrophils during acute human anaphylaxis, suggesting they are activated early in the reaction, regardless of mast cell activation. This important finding increases our understanding of the basic mechanisms of anaphylaxis, a necessary precursor to improving treatment and prevention.
Publisher: Springer Science and Business Media LLC
Date: 19-04-2017
DOI: 10.1007/S00011-017-1043-5
Abstract: Resistin and neutrophil gelatinase-associated lipocalin (NGAL) are upregulated in circulating leucocytes in sepsis, but the significance of this is uncertain. We evaluated associations between Resistin and NGAL with endothelial cell activation and clinical outcomes in a prospective observational study in the Emergency Department (ED). Serum levels of Resistin, NGAL, inflammatory cytokines (IL-6, IL-10) and soluble endothelial adhesion molecules (VCAM-1, ICAM-1) were measured at defined time points up to 24 h. Patterns and relationships between markers were investigated using linear mixed regression models. Predictive values for clinical outcomes for markers at enrollment were assessed by logistic regression and receiver operator characteristic (ROC) curves. 186 participants (89 septic-shock, 69 sepsis, 28 uncomplicated infection) were compared with 29 healthy controls. Median Resistin and NGAL were higher in uncomplicated infection compared to controls, and in septic shock compared to non-shock sepsis. Resistin and NGAL correlated with IL-6 and IL-10, with VCAM-1 and ICAM-1, and with organ failure. Resistin and NGAL were associated with septic shock but had limited predictive utility for mortality. Resistin and NGAL correlate with expression of endothelial cell adhesion molecules in sepsis. Further evaluation of the role of Resistin and NGAL in sepsis pathogenesis is warranted.
Publisher: Wiley
Date: 09-2016
DOI: 10.1111/IMJ.36_13197
Publisher: Elsevier BV
Date: 2017
DOI: 10.1016/J.JOCN.2016.09.011
Abstract: We previously reported on a 26-year-old patient who presented early during a large and eventually fatal cerebral infarct. Microarray analysis of blood s les from this patient demonstrated initially up-regulated and subsequently down-regulated Granzyme B (GzmB) expression, along with progressive up-regulation of genes for S100 calcium binding protein A12 (S100A12) and matrix metalloproteinase 9 (MMP-9). To confirm these findings, we investigated these parameters in patients with suspected stroke presenting within 6h of symptom onset to a single centre. Blood s les were taken at enrolment, then 1h, 3h and 24h post-enrolment for the examination of cellular, protein and genetic changes. Patients with subsequently confirmed ischaemic (n=18) or haemorrhagic stroke (n=11) showed increased intracellular concentrations of GzmB in all cell populations investigated (CD8
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D2FO02403A
Abstract: Increasing dietary nitrate consumption over 7 days is not effective in reducing soluble inflammatory mediators in in iduals with treated hypertension.
Publisher: Springer Science and Business Media LLC
Date: 04-05-2018
DOI: 10.1007/S10753-018-0797-4
Abstract: Shedding of the endothelial glycocalyx precedes leukocyte activation and adherence in acute inflammation. Rapid administration of crystalloid or colloid fluids for treating hemorrhagic shock may cause endothelial glycocalyx shedding, thereby increasing inflammation. This study aimed to compare the effect of different fluid treatments in a canine shock model on glycocalyx biomarker, hyaluronan, and inflammatory biomarkers. Greyhound dogs under general anesthesia subject to hemorrhage for 60 min were given 20 mL kg
Publisher: MDPI AG
Date: 10-09-2022
Abstract: Elevated circulating platelet-derived extracellular vesicles (EVs) have been reported in conditions associated with thrombotic risk. The present study aimed to assess the relationship between circulating platelet-derived EV levels, cardiovascular risk stratification and vascular organ damage, as assessed by pulse wave velocity (PWV). A total of 92 patients were included in the present analysis. Platelet EV were evaluated by flow cytometry (CD41+/Annexin v+). The cardiovascular risk was determined using the 2021 ESC guideline stratification and SCORE2 and SCORE-OP. PWV was performed as a surrogate to assess macrovascular damage. Risk stratification revealed significant group differences in EV levels (ANOVA, p = 0.04). Post hoc analysis demonstrated significantly higher levels of EVs in the very high-risk group compared with the young participants (12.53 ± 8.69 vs. 7.51 ± 4.67 EV/µL, p = 0.03). Linear regression models showed SCORE2 and SCORE-OP (p = 0.04) was a predictor of EV levels. EVs showed a significant association with macrovascular organ damage measured by PWV (p = 0.01). PWV progressively increased with more severe cardiovascular risk (p 0.001) and was also associated with SCORE2 and SCORE-OP (p 0.001). Within the pooled group of subjects with low to moderate risk and young participants ( years), those with EV levels in the highest tertile had a trend towards higher nocturnal blood pressure levels, fasting glucose concentration, lipid levels, homocysteine and PWV. Levels of platelet-derived EVs were highest in those patients with very high CV risk. Within a pooled group of patients with low to moderate risk, an unfavourable cardiometabolic profile was present with higher EV levels.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-11-2005
DOI: 10.1097/01.TP.0000178377.55615.8B
Abstract: Fibrin deposition is central to the acute humoral rejection process occurring in the presence of consumptive coagulopathy when pig organs are transplanted into primates. To assess whether strategies aimed at preventing fibrin formation may extend xenograft survival, we administered high daily doses of recombinant human antithrombin (rhAT) (500 U/kg twice daily) to obtain both anticoagulant and anti-inflammatory effects in immunosuppressed primate recipients of porcine kidneys. Some degree of consumptive coagulopathy developed in both rhAT-treated (n=3) and untreated (n=3) primates. No major differences in the coagulation parameters analyzed were observed between the 2 groups. Similarly, no difference in survival was seen between rhAT-treated (20.6+/-4 days range: 15-23 days) and untreated animals (17.3+/-11.6 days range: 7-30 days), although the rhAT-treated primates had a higher bleeding tendency. Despite the high daily dose of rhAT, considerable fibrin deposition was observed in the graft as early as 2 weeks after transplantation. These results suggest that a high daily dose of rhAT fails to influence survival or prevent fibrin formation and deposition in the graft in our pig-to-primate model. However, the potential role of rhAT administered in combination with heparins or other clotting inhibitor concentrates in this model remains to be determined.
Publisher: S. Karger AG
Date: 06-09-2018
DOI: 10.1159/000492301
Abstract: b i Background: /i /b We have previously identified the upregulation of the innate immune response, neutrophil activation, and apoptosis during anaphylaxis using a microarray approach. This study aimed to validate the differential gene expression and investigate protein concentrations of “hub genes” and upstream regulators during anaphylaxis. b i Methods: /i /b S les were collected from patients with anaphylaxis on their arrival at the emergency department, and after 1 and 3 h. mRNA levels of 11 genes ( i interleukin-6 [IL-6], IL-10, oncostatin M [OSM], S100A8, S100A9, matrix metalloproteinase 9 [MMP9], FASL, toll-like receptor 4 [TLR4], MYD88, triggering receptor expressed on myeloid cells 1 [TREM1] /i , and i cluster of differentiation 64 [CD64] /i ) were measured in peripheral blood leucocytes using qPCR. Serum protein concentrations were measured by ELISA or cytometric bead array for 6 of these candidates. b i Results: /i /b Of 69 anaphylaxis patients enrolled, 36 (52%) had severe reactions, and 38 (55%) were female. Increases in both mRNA and protein of IL-10, S100A9, MMP9, and TREM1 were observed. i OSM /i , i S100A8 /i , i TLR4 /i , and i CD64 /i were upregulated and IL-6 protein concentrations were increased during anaphylaxis. Both i FASL /i and soluble Fas ligand decreased during anaphylaxis. b i Conclusion: /i /b These results provide evidence for the involvement of innate immune pathways and myeloid cells during human anaphylaxis, validating previous microarray findings. Elevated i S100A8 /i , i S100A9 /i , i TLR4 /i , and i TREM1 /i expression, and increased S100A9 and soluble TREM1 protein concentrations strongly suggest that neutrophils are activated during acute anaphylaxis.
Publisher: Research Square Platform LLC
Date: 08-06-2022
DOI: 10.21203/RS.3.RS-1714832/V1
Abstract: INTRODUCTIONIntravenous (IV) fluid resuscitation is recommended first line therapy in septic shock, but the effectiveness and safety of this approach has been questioned. To investigate potential mechanisms of harm from IV fluid resuscitation, we measured biomarkers of endothelial glycocalyx (EG) shedding, activation of the vascular endothelium and inflammation over the first 24 hours in a clinical trial comparing a fluid-restricted resuscitation regimen to usual care with no IV fluid restriction. METHODSA planned biomarker sub-study of the REFRESH trial in which emergency department (ED) patients) with suspected sepsis and a systolic blood pressure of mmHg after at least 1000ml of crystalloid fluid were randomised to restricted fluids (with a vasopressor infusion if needed to restore perfusion targets) or additional IV fluid resuscitation with later vasopressor if required (usual care). Blood s les were collected at randomisation (T0) and at 3 hours (T3), 6 hours (T6)- and 24 hours (T24) for measurement of Pro-Atrial Natriuretic Peptide (Pro-ANP) EG biomarkers - Syndecans 1 & 4 (SYN-1, SYN-4), Hyaluronan, Heparan Sulphate Endothelial cell markers - Vascular Cell Adhesion Molecule (VCAM), Intercellular Adhesion Molecule (ICAM), E-selectin, Vascular Endothelial Growth Factor 1 (VEGFR-1) and inflammatory biomarkers - Interleukins 6 & 10 (IL-6, IL-10), Neutrophil Gelatinase Associated Lipocalin (NGAL) and Resistin. RESULTSBlood s les were obtained in 95 of 99 enrolled patients (46 usual care, 49 restricted fluid). Differences in the change in biomarker over time between the groups were observed for Hyaluronan (2.2-fold from T3-T24, p=0.03), SYN-4 (1.5-fold T3 to T24, P=0.01) and IL-6 (2.5-fold from T0 to T3, p=0.03). No difference over time was observed between groups for the other biomarkers. CONCLUSIONSDifferences in the change over time for Hyaluronan, SYN-4 and IL-6 were observed during the first 24 hours among patients with suspected sepsis randomised to difference resuscitation regimens. This supports the hypothesis that IV fluids can lead to shedding of the endothelial glycocalyx and promote inflammation. Conversely no effect was seen for other EG components (SYN-1 and Heparan Sulphate), or for a range of endothelial activation and inflammatory markers. TRIAL REGISTRATIONAustralia New Zealand Clinical Trials Registry ACTRN126160000006448 Registered 12 January 2016
Publisher: Wiley
Date: 03-2009
DOI: 10.1111/J.1399-3089.2009.00521.X
Abstract: Carbon monoxide (CO) interferes with inflammatory and apoptotic processes associated with ischemia-reperfusion injury and graft rejection. Here, the in vitro effects of carbon monoxide releasing molecule-3 (CORM-3), a novel water-soluble carbonyl CO carrier, have been investigated on porcine aortic endothelial cells (PAEC) and primate peripheral blood mononuclear cells (PBMC). Furthermore, the pharmacodynamics and pharmacotolerance of CORM-3 after administration of single and multiple doses in the primate have been assessed in view of its potential application in pig-to-primate xenotransplantation models. For in vitro studies, PAEC and primate PBMC were exposed for 24, 48 and 72 h to CORM-3 (20 to 1000 microm) and viability was measured using an MTS assay. PAEC and primate PBMC proliferation after exposure to CORM-3 was assessed by CFSE labelling. Proliferation of primate PBMC against irradiated pig lymphocytes was also assessed. Tumor necrosis factor alpha (TNF-alpha) production and Caspase-3 and -7 activity in Concanavalin A (conA)-stimulated primate PBMC were measured following treatment with CORM-3. In vivo, CORM-3 was administered i.v. to cynomolgus monkeys at 4 mg/kg, as single or multiple doses for up to 30 days. The effect of CORM-3 was evaluated by the assessment of production of TNF-alpha and interleukin 1beta following PBMC stimulation with LPS by species-specific ELISA. Complete hematologic and biochemical analyses were routinely performed in treated primates. At concentrations or =50 microm inhibited conA-activated primate lymphocyte proliferation (IC(50) of 345.8 +/- 51.9 microm) and the primate xenogeneic response against pig PBMC. Such responses were demonstrated to be CO-dependent. In addition, CORM-3 significantly inhibited caspase-3 and -7 activity at concentrations between 200 and 500 microm and caused a significant reduction in TNF-alpha production (IC(50) 332.8 +/- 33.9 microm). In vivo, following the administration of multiple doses, TNF-alpha production was significantly reduced in comparison to pre-treatment responses, with decreased levels maintained throughout the study. Moreover, a slight and transient increase in transaminases and bilirubin was observed in animals exposed to multiple doses of CORM-3. These studies suggest that CORM-3 has anti-inflammatory and immunomodulatory properties in primates that may result in clinical benefit to allo- and xenografted organs.
Publisher: Informa UK Limited
Date: 2009
DOI: 10.4161/ORG.7578
Publisher: Elsevier BV
Date: 06-2010
DOI: 10.1016/J.IMMUNI.2010.05.010
Abstract: Tumor growth is associated with a profound alteration in myelopoiesis, leading to recruitment of immunosuppressive cells known as myeloid-derived suppressor cells (MDSCs). We showed that among factors produced by various experimental tumors, the cytokines GM-CSF, G-CSF, and IL-6 allowed a rapid generation of MDSCs from precursors present in mouse and human bone marrow (BM). BM-MDSCs induced by GM-CSF+IL-6 possessed the highest tolerogenic activity, as revealed by the ability to impair the priming of CD8(+) T cells and allow long term acceptance of pancreatic islet allografts. Cytokines inducing MDSCs acted on a common molecular pathway and the immunoregulatory activity of both tumor-induced and BM-derived MDSCs was entirely dependent on the C/EBPbeta transcription factor. Adoptive transfer of tumor antigen-specific CD8(+) T lymphocytes resulted in therapy of established tumors only in mice lacking C/EBPbeta in the myeloid compartment, suggesting that C/EBPbeta is a critical regulator of the immunosuppressive environment created by growing cancers.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2008
Publisher: Bentham Science Publishers Ltd.
Date: 06-2005
Abstract: Antibody-mediated mechanisms are central to the rejection that occurs when pig organs are transplanted into primates. In this article, the histopathological features of the humoral rejection process in these species combinations, namely hyperacute rejection and acute humoral xenograft rejection, will be illustrated. The profile of the natural and elicited antibodies involved will also be discussed. It has now been demonstrated that the natural immune response to a porcine xenograft is primarily directed to Galalpha1-3Gal (alphaGal) specificities, whilst the elicited immune response is directed to both alphaGal and non-alphaGal antigens. The principal characteristics of anti-alphaGal, anti-non-alphaGal and polyreactive antibodies will be described, together with the identification of the molecules recognised by natural and elicited xenoreactive antibodies. The role of the humoral immune response in the rejection of porcine islets in the primate is still uncertain and the current views on the subject will be discussed. Finally, a concise but comprehensive review of the different strategies that have been attempted to prevent the onset of antibody-mediated rejection is presented. These strategies encompass approaches aimed at interfering with the binding of xenoreactive antibodies with their targets, the use of conventional or novel immunosuppressants and splenectomy. It is undeniable that significant progress has been recently achieved in understanding the humoral rejection process of pig organs transplanted into primates. It is expected that a more comprehensive elucidation of the mechanisms underlying accommodation and tolerance may, in the not too distant future, further extend survival of pig organs transplanted into primates.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-08-2022
No related grants have been discovered for Erika Bosio.