Clinical Immunology

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 Ž . in these processes are the matrix metalloproteinases MMPs . Oestrogens have been demonstrated to possess anti-atherosclerotic properties at low concentrations while being associated with lesion formation at high concentrations. We examined Ž . the effect of 17b-oestradiol on MMP-2 expression in human coronary artery CAVSMC and umbilical artery vascular Ž . 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 synthesis and could be antagonised by the oestrogen receptor antagonist, tamoxifen, and the specific receptor antagonist ICI 182,780. 17b-Oestradiol appears to be a specific stimulator of MMP-2 release from human vascular cells. The concentration dependence of this effect suggests a basis for the differential effects of low and high oestrogen levels on vascular integrity. q 1998 Elsevier Science B.V.

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. : S 0 3 0 3 -7 2 0 7 ( 9 9 ) 0 0 0 2 7 -1

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 ≥3.27 pg/ml provide a sensitivity of 0.87 and specificity of 0.64 for
a requirement of ventilation, and a CRP of ≥37 mg/l of 0.91 and 0.66.
Reliable stratification of high-risk cases has significant implications on patient triage, resource management
and potentially the initiation of novel therapies in severe patients.

Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre -including this research content -immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Influence of IL-6 levels on patient survival in COVID-19 Editor COVID-19 is characterized by a proinflammatory phenotype, with an underlying cytokine storm thought to be key in determining disease severity. Levels of the proinflammatory cytokine interleukin-6 (IL-6) discriminate between patients with mild and severe disease, [1] making IL-6 inhibition an attractive therapeutic strategy . Despite a common underlying aetiology of COVID-19, outcomes from clinical trials are not consistent. Whilst some studies demonstrate an association between the use of Tocilizumab and reduction in mortality [3], others have been terminated early due to excess mortality associated with Tocilizumab [4]. It is difficult to reconcile such conflicting data. We therefore explored the association between patient demographics, respiratory failure severity, and IL-6 levels on mortality in a cohort of hospitalized COVID-19 patients who were naïve to immunotherapy. Differences in clinical outcome between clinical trials may relate to variable pre-treatment levels of IL-6. We included patients aged ≥18 years admitted to University College London Hospitals with a positive real-time reverse transcriptionpolymerase chain reaction (rRT-PCR) test for SARS-CoV-2 RNA between 1 March and 30 June 2020, following local research ethics committee approval (REC reference 20/HRA/2505). Multiplex panels (MesoScale Discovery, Rockville, MD, USA) were used to analyse IL-6. For this analysis, blood was centrifuged within 4 h of collection, separated and sera frozen at -80 °C before batch analysis. Continuous and categorical variables are reported as median (interquartile range) and n (%), respectively. Comparison of non-parametric continuous data between groups was performed using the Kruskal Wallis test (for comparison between >2 groups). Cytokine values were analysed on a logarithmic scale. Categorical data were compared using the chisquare test. Area under the receiver operator curve (AUROC) was constructed to ascertain the predictive value of IL-6 for mortality. Graphs were constructed, and statistical analysis performed using Prism 9.0 (GraphPad Software, La Jolla, CA, USA) and SPSS version 24.0 (IBM Corp). Eighty-six COVID-19 patients were included; 44 (51%) patients with mild disease, 22 (26%) with critical illness who survived, and 20 (23%) who died in hospital. Patients who died were older than those who survived critical illness or those with mild disease (both p = 0•002). Compared to patients with mild disease, progression to critical illness and death was associated with severity of respiratory failure (lower SpO 2 :FiO 2 ratio) (p < 0.001) and higher levels of CRP (p < 0•001) on admission (Table ).