Multiple mechanisms have been proposed to explain disease severity in coronavirus disease 2019. T... more Multiple mechanisms have been proposed to explain disease severity in coronavirus disease 2019. Therapeutic approaches need to be underpinned by sound biological rationale. We evaluated whether serum levels of a range of proposed coronavirus disease 2019 therapeutic targets discriminated between patients with mild or severe disease. Design: A search of ClinicalTrials.gov identified coronavirus disease 2019 immunological drug targets. We subsequently conducted a retrospective observational cohort study investigating the association of serum biomarkers within the first 5 days of hospital admission relating to putative therapeutic biomarkers with illness severity and outcome. Setting: University College London, a tertiary academic medical center in the United Kingdom. Patients: Patients admitted to hospital with a diagnosis of coronavirus disease 2019. Interventions: None. Measurements and Main Results: Eighty-six patients were recruited, 44 (51%) with mild disease and 42 (49%) with severe disease. We measured levels of 10 cytokines/signaling proteins related to the most common therapeutic targets (granulocyte-macrophage colony-stimulating factor, interferon-α2a, interferon-β, interferon-γ, interleukin-1β, interleukin-1 receptor antagonist, interleukin-6, interleukin-7, interleukin-8, tumor necrosis factor-α), immunoglobulin G antibodies directed against either coronavirus disease 2019 spike protein or nucleocapsid protein, and neutralization titers of antibodies. Four-hundred seventy-seven randomized trials, including 168 different therapies against 83 different pathways, were identified. Six of the 10 markers (interleukin-6, interleukin-7, interleukin-8, interferon-α2a, interferon-β, interleukin-1 receptor antagonist) discriminated between patients with mild and severe disease, although most were similar or only modestly raised above that seen in healthy volunteers. A similar proportion of patients with mild or severe disease had detectable spike protein or nucleocapsid protein immunoglobulin G antibodies with equivalent levels between groups. Neutralization titers were higher among patients with severe disease. Conclusions: Some therapeutic and prognostic biomarkers may be useful in identifying coronavirus disease 2019 patients who may benefit from specific immunomodulatory therapies, particularly interleukin-6. However, biomarker absolute values often did not discriminate between patients with mild and severe disease or death, implying that these immunomodulatory treatments may be of limited benefit.
Przedmiotem tego artykułu są wybrane frazy przyimkowe, wchodzące w skład grupy nominalnej, służąc... more Przedmiotem tego artykułu są wybrane frazy przyimkowe, wchodzące w skład grupy nominalnej, służące do przypisywania rozmaitych atrybutów zarówno referentom wyrażenia ktoś, jak i coś. Chodzi więc o pewien podzbiór konstrukcji, które w tradycyjnych gramatykach noszą nazwę przydawek przyimkowych. Mówię tu o pewnym podzbiorze tych części zdania, ponieważ w opracowaniach wspomnianego rodzaju przydawki defi niowane są zazwyczaj za Z. Klemensiewiczem [1969] czysto formalnie, jako określenia rzeczownika, niezależnie od tego, czy wraz z nim tworzą podstawowe wyrażenie predykatywne 1 (np. odezwa do wyborców), czy też wprowadzają predykacje w stosunku do danego słowa całkiem niezależne (list z gratulacjami). Przy podejściu semantycznym, a taka właśnie perspektywa będzie mnie tu interesowała, w pierwszej ze wskazanych sytuacji mamy do czynienia z rzeczownikowym dopełnieniem nieciągłej jednostki odezwa do_, nie zaś z przydawką przyimkową charakteryzującą słowo odezwa. W swojej wypowiedzi zajmę się wyłącznie konstrukcjami stricte przydawkowymi. Przedmiot badań trzeba jednak jeszcze ograniczyć, wprowadzając tym samym konieczne rozróżnienia i uporządkowania w obszarze rzeczy podobnych, które przy nazbyt pobieżnym oglądzie mogłyby zostać zmieszane i nieopatrznie ze sobą nawzajem utożsamione. Wyrażenia atrybutywne można bowiem utworzyć z udziałem niemal wszystkich przyimków, na przykład: człowiek bez lewego ucha, mleko dla niemowląt, spódnica do kostek, pieśń ku czci poległych, ścieżka między sosnami, starzec na drewnianej nodze, dom nad rozlewiskiem, dziecko o lnianych włosach, chłopak od rzeźnika, torba przez ramię, miejscówka przy oknie, pacjent po przeszczepie, dom pod topolami, pracownik poza podejrzeniami, palce u rąk, spodnie w kratkę, dziewczyna z warkoczami, chata za miastem i tym podobne.
Cell viability assays on inhibitors in both RASMCs and J774 macrophages .. 150 3.4.10 Expression ... more Cell viability assays on inhibitors in both RASMCs and J774 macrophages .. 150 3.4.10 Expression of JAK2, Tyk-2 and their phosphorylated proteins in RASMCs and J774 macrophages ..
A single nucleotide polymorphism (SNP) C5507G of the complement receptor 1 (CR1) gene has been as... more A single nucleotide polymorphism (SNP) C5507G of the complement receptor 1 (CR1) gene has been associated with genetic susceptibility to sarcoidosis in an Italian population. In order to provide further data on the possible involvement of CR1 gene polymorphisms in sarcoidosis, CR1 SNPs C5507G and A3650G were investigated in Czech (n = 210) and Dutch (n = 116) patients with sarcoidosis with ethnically matched groups of healthy control subjects (Czech, n = 203; Dutch, n = 112). CR1 C5507G and A3650G SNPs were not associated with susceptibility to sarcoidosis or its clinical course. Further, CR1 messenger RNA expression in bronchoalveolar lavage cells investigated by quantitative reverse transcriptase-polymerase chain reaction did not differ between sarcoidosis patients and control subjects and was not associated with the presence of the CR1 5507*G allele.
Vascular remodelling occurs during all stages of atherosclerotic progression. Anti-atheroscleroti... more Vascular remodelling occurs during all stages of atherosclerotic progression. Anti-atherosclerotic drugs may function by restoring regulation of the processes involved in remodelling of the extracellular matrix. A key group of enzymes involved . in these processes are the matrix metalloproteinases MMPs . Oestrogens have been demonstrated to possess anti-athero- sclerotic properties at low concentrations while being associated with lesion formation at high concentrations. We examined . the effect of 17b-oestradiol on MMP-2 expression in human coronary artery CAVSMC and umbilical artery vascular . smooth muscle cells UAVSMC . MMP-2 expression was measured by chemiluminescent immunoblotting and quantified by laser densitometry. pro-MMP-2 was secreted by VSMCs and increasing levels of 17b-oestradiol, from physiological through supraphysiological, were associated with significant dose-dependent increases in MMP-2 levels in culture media. This effect was dependent on de novo protein synth...
The heterogeneous disease course of COVID-19 is unpredictable, ranging from mild self-limiting sy... more The heterogeneous disease course of COVID-19 is unpredictable, ranging from mild self-limiting symptoms to cytokine storms, acute respiratory distress syndrome (ARDS), multi-organ failure and death. Identification of high-risk cases will enable appropriate intervention and escalation. This study investigates the routine laboratory tests and cytokines implicated in COVID-19 for their potential application as biomarkers of disease severity, respiratory failure and need of higher-level care. From analysis of 203 samples, CRP, IL-6, IL-10 and LDH were most strongly correlated with the WHO ordinal scale of illness severity, the fraction of inspired oxygen delivery, radiological evidence of ARDS and level of respiratory support (p≤0.001). IL-6 levels of >3.27pg/ml provide a sensitivity of 0.87 and specificity of 0.64 for a requirement of ventilation, and a CRP of >37mg/L of 0.91 and 0.66. Reliable stratification of high-risk cases has significant implications on patient triage, reso...
A large proportion of the beneficial effects that oestrogens demonstrate on the vasculature are b... more A large proportion of the beneficial effects that oestrogens demonstrate on the vasculature are believed to be mediated via direct effects on the vascular wall. In this study we compared a number of oestrogenic compounds isolated from pregnant mare's urine including 17b-oestradiol and oestrone, in terms of their abilities to inhibit stimulated endothelin-1 release from normal human coronary artery endothelial cells (CAEC). We also examined their ability to stimulate expression of constitutive endothelial nitric oxide synthase (eNOS) and explored their effects on cellular angiotensin converting enzyme (ACE). All the oestrogens tested were able to inhibit serum-stimulated ET-1 release. Oestrone and 17a-dihydroequilenin failed to significantly affect cellular eNOS levels. 17b-oestradiol and oestrone significantly increased cellular ACE levels while 17b,D 8,9-dehydroestradiol decreased cellular ACE. We discuss these observations in terms of their potential clinical relevance and use as a means of screening novel oestrogen-like compounds.
Multiple mechanisms have been proposed to explain disease severity in coronavirus disease 2019. T... more Multiple mechanisms have been proposed to explain disease severity in coronavirus disease 2019. Therapeutic approaches need to be underpinned by sound biological rationale. We evaluated whether serum levels of a range of proposed coronavirus disease 2019 therapeutic targets discriminated between patients with mild or severe disease. Design: A search of ClinicalTrials.gov identified coronavirus disease 2019 immunological drug targets. We subsequently conducted a retrospective observational cohort study investigating the association of serum biomarkers within the first 5 days of hospital admission relating to putative therapeutic biomarkers with illness severity and outcome. Setting: University College London, a tertiary academic medical center in the United Kingdom. Patients: Patients admitted to hospital with a diagnosis of coronavirus disease 2019. Interventions: None. Measurements and Main Results: Eighty-six patients were recruited, 44 (51%) with mild disease and 42 (49%) with severe disease. We measured levels of 10 cytokines/signaling proteins related to the most common therapeutic targets (granulocyte-macrophage colony-stimulating factor, interferon-α2a, interferon-β, interferon-γ, interleukin-1β, interleukin-1 receptor antagonist, interleukin-6, interleukin-7, interleukin-8, tumor necrosis factor-α), immunoglobulin G antibodies directed against either coronavirus disease 2019 spike protein or nucleocapsid protein, and neutralization titers of antibodies. Four-hundred seventy-seven randomized trials, including 168 different therapies against 83 different pathways, were identified. Six of the 10 markers (interleukin-6, interleukin-7, interleukin-8, interferon-α2a, interferon-β, interleukin-1 receptor antagonist) discriminated between patients with mild and severe disease, although most were similar or only modestly raised above that seen in healthy volunteers. A similar proportion of patients with mild or severe disease had detectable spike protein or nucleocapsid protein immunoglobulin G antibodies with equivalent levels between groups. Neutralization titers were higher among patients with severe disease. Conclusions: Some therapeutic and prognostic biomarkers may be useful in identifying coronavirus disease 2019 patients who may benefit from specific immunomodulatory therapies, particularly interleukin-6. However, biomarker absolute values often did not discriminate between patients with mild and severe disease or death, implying that these immunomodulatory treatments may be of limited benefit.
Przedmiotem tego artykułu są wybrane frazy przyimkowe, wchodzące w skład grupy nominalnej, służąc... more Przedmiotem tego artykułu są wybrane frazy przyimkowe, wchodzące w skład grupy nominalnej, służące do przypisywania rozmaitych atrybutów zarówno referentom wyrażenia ktoś, jak i coś. Chodzi więc o pewien podzbiór konstrukcji, które w tradycyjnych gramatykach noszą nazwę przydawek przyimkowych. Mówię tu o pewnym podzbiorze tych części zdania, ponieważ w opracowaniach wspomnianego rodzaju przydawki defi niowane są zazwyczaj za Z. Klemensiewiczem [1969] czysto formalnie, jako określenia rzeczownika, niezależnie od tego, czy wraz z nim tworzą podstawowe wyrażenie predykatywne 1 (np. odezwa do wyborców), czy też wprowadzają predykacje w stosunku do danego słowa całkiem niezależne (list z gratulacjami). Przy podejściu semantycznym, a taka właśnie perspektywa będzie mnie tu interesowała, w pierwszej ze wskazanych sytuacji mamy do czynienia z rzeczownikowym dopełnieniem nieciągłej jednostki odezwa do_, nie zaś z przydawką przyimkową charakteryzującą słowo odezwa. W swojej wypowiedzi zajmę się wyłącznie konstrukcjami stricte przydawkowymi. Przedmiot badań trzeba jednak jeszcze ograniczyć, wprowadzając tym samym konieczne rozróżnienia i uporządkowania w obszarze rzeczy podobnych, które przy nazbyt pobieżnym oglądzie mogłyby zostać zmieszane i nieopatrznie ze sobą nawzajem utożsamione. Wyrażenia atrybutywne można bowiem utworzyć z udziałem niemal wszystkich przyimków, na przykład: człowiek bez lewego ucha, mleko dla niemowląt, spódnica do kostek, pieśń ku czci poległych, ścieżka między sosnami, starzec na drewnianej nodze, dom nad rozlewiskiem, dziecko o lnianych włosach, chłopak od rzeźnika, torba przez ramię, miejscówka przy oknie, pacjent po przeszczepie, dom pod topolami, pracownik poza podejrzeniami, palce u rąk, spodnie w kratkę, dziewczyna z warkoczami, chata za miastem i tym podobne.
Cell viability assays on inhibitors in both RASMCs and J774 macrophages .. 150 3.4.10 Expression ... more Cell viability assays on inhibitors in both RASMCs and J774 macrophages .. 150 3.4.10 Expression of JAK2, Tyk-2 and their phosphorylated proteins in RASMCs and J774 macrophages ..
A single nucleotide polymorphism (SNP) C5507G of the complement receptor 1 (CR1) gene has been as... more A single nucleotide polymorphism (SNP) C5507G of the complement receptor 1 (CR1) gene has been associated with genetic susceptibility to sarcoidosis in an Italian population. In order to provide further data on the possible involvement of CR1 gene polymorphisms in sarcoidosis, CR1 SNPs C5507G and A3650G were investigated in Czech (n = 210) and Dutch (n = 116) patients with sarcoidosis with ethnically matched groups of healthy control subjects (Czech, n = 203; Dutch, n = 112). CR1 C5507G and A3650G SNPs were not associated with susceptibility to sarcoidosis or its clinical course. Further, CR1 messenger RNA expression in bronchoalveolar lavage cells investigated by quantitative reverse transcriptase-polymerase chain reaction did not differ between sarcoidosis patients and control subjects and was not associated with the presence of the CR1 5507*G allele.
Vascular remodelling occurs during all stages of atherosclerotic progression. Anti-atheroscleroti... more Vascular remodelling occurs during all stages of atherosclerotic progression. Anti-atherosclerotic drugs may function by restoring regulation of the processes involved in remodelling of the extracellular matrix. A key group of enzymes involved . in these processes are the matrix metalloproteinases MMPs . Oestrogens have been demonstrated to possess anti-athero- sclerotic properties at low concentrations while being associated with lesion formation at high concentrations. We examined . the effect of 17b-oestradiol on MMP-2 expression in human coronary artery CAVSMC and umbilical artery vascular . smooth muscle cells UAVSMC . MMP-2 expression was measured by chemiluminescent immunoblotting and quantified by laser densitometry. pro-MMP-2 was secreted by VSMCs and increasing levels of 17b-oestradiol, from physiological through supraphysiological, were associated with significant dose-dependent increases in MMP-2 levels in culture media. This effect was dependent on de novo protein synth...
The heterogeneous disease course of COVID-19 is unpredictable, ranging from mild self-limiting sy... more The heterogeneous disease course of COVID-19 is unpredictable, ranging from mild self-limiting symptoms to cytokine storms, acute respiratory distress syndrome (ARDS), multi-organ failure and death. Identification of high-risk cases will enable appropriate intervention and escalation. This study investigates the routine laboratory tests and cytokines implicated in COVID-19 for their potential application as biomarkers of disease severity, respiratory failure and need of higher-level care. From analysis of 203 samples, CRP, IL-6, IL-10 and LDH were most strongly correlated with the WHO ordinal scale of illness severity, the fraction of inspired oxygen delivery, radiological evidence of ARDS and level of respiratory support (p≤0.001). IL-6 levels of >3.27pg/ml provide a sensitivity of 0.87 and specificity of 0.64 for a requirement of ventilation, and a CRP of >37mg/L of 0.91 and 0.66. Reliable stratification of high-risk cases has significant implications on patient triage, reso...
A large proportion of the beneficial effects that oestrogens demonstrate on the vasculature are b... more A large proportion of the beneficial effects that oestrogens demonstrate on the vasculature are believed to be mediated via direct effects on the vascular wall. In this study we compared a number of oestrogenic compounds isolated from pregnant mare's urine including 17b-oestradiol and oestrone, in terms of their abilities to inhibit stimulated endothelin-1 release from normal human coronary artery endothelial cells (CAEC). We also examined their ability to stimulate expression of constitutive endothelial nitric oxide synthase (eNOS) and explored their effects on cellular angiotensin converting enzyme (ACE). All the oestrogens tested were able to inhibit serum-stimulated ET-1 release. Oestrone and 17a-dihydroequilenin failed to significantly affect cellular eNOS levels. 17b-oestradiol and oestrone significantly increased cellular ACE levels while 17b,D 8,9-dehydroestradiol decreased cellular ACE. We discuss these observations in terms of their potential clinical relevance and use as a means of screening novel oestrogen-like compounds.
Uploads
Papers by Edmund Garr