Interleukin 6 trans-signalling : cardiovascular risk marker or therapeutical target?

Background: Interleukin (IL) 6 signals in two pathways. In classical signalling, essential in antimicrobial defence and tissue regeneration, IL6 binds the membrane- bound IL6 receptor (IL6R) which associates with the signal transducing receptor gp130. The pro-inflammatory effects of IL6 on the other hand, are governed by IL6 trans-signalling via the binary complex of IL6 and the soluble IL6R (sIL6R) through gp130 binding. The binary IL6:sIL6R complex is neutralised by the soluble gp130 (sgp130) thereby preventing IL6 trans-signalling. IL6 trans-signalling is associated with chronic inflammatory conditions. Overarching aim: To analyse the association of IL6 trans-signalling, estimated by a ratio between the active binary IL6:sIL6R complex and the inactive ternary IL6:sIL6R:sgp130 complex (the binary/ternary complex ratio [B/T ratio]), with the risk of cardiovascular event (CVE) and investigate the presence of IL6 signal- ling in manifest atherosclerosis. Methods and results Study I: In a prospective cohort of 60-year-olds (60YO) without prevalent cardiovas- cular disease (CVD) (n=3645), the binary IL6:sIL6R and ternary IL6:sIL6R:sgp130 complex levels, expressed in nanomole/litre, were derived from baseline serum concentrations of IL6, sIL6R, and sgp130. IL6 trans-signalling was estimated by a ratio between the pro-inflammatory binary complex and the inactivated ternary complex, the B/T ratio. Cox regression was used to assess the risk of CVE (myo- cardial infarction, angina pectoris and ischaemic stroke), expressed as hazard ratio (HR) with 95% confidence interval (CI), associated with increasing circulating levels of IL6, sIL6R, sgp130 and with the B/T ratio, the latter analysed both as a continuous variable and dichotomised at the median. Estimates were adjusted for the common cardiovascular risk factors. The discriminatory ability of the B/T ratio as predictor was assessed by the area under the curve (AUC) and net reclassifica- tion index (NRI) in relation to the Framingham risk score (FRS) and IL6. The B/T ratio >median associates with increased CVE risk (adjusted HR 1.44, 95% CI 1.21–1.72). The prediction of CVE improved by adding the B/T ratio to the FRS and IL6 and 10% of subjects were re-classified. Study II: In the 60YO cohort, CVE risk associated with B/T ratio >median was investigated in subjects with low-intermediate cardiovascular risk defined by LDL ≤ / >4.0 mmol/L or according to the FRS. The difference in time to event (years; 95% CI) was analysed with quantile regression. In secondary analyses, risk of coronary and cerebrovascular events and time to event was analysed. Biological interaction between LDL and B/T ratio was estimated on the additive scale and the incremental discriminatory value of the B/T ratio with FRS and IL6 was compared in subjects with LDL≤ and >4.0 mmol/L. B/T ratio was associated with an increased risk of CVE primarily the LDL≤4.0 group (adjusted HR 1.59; 95% CI 1.24-2.05) but also in FRS <20% 10-year risk. The highest risk and earliest events were seen for ischemic stroke. No interaction between LDL and the B/T ratio was seen and the B/T ratio improved prediction in the LDL ≤4.0 group. Study III: Carotid artery plaques were obtained during endarterectomy in patients with high-grade carotid artery stenosis in the Biobank of Karolinska Endarterectomies (BiKE) study. Oligoprimers were designed to selectively amplify IL6R, sIL6R, GP130 and sGP130 genes. Using cDNA reverse transcribed from RNA extracted from plaques quantitative real time-PCR was performed and the relative difference in expression between groups was estimated using the ∆CT method (n=78). Correlations between plaque gene expression and plasma levels were tested using Spearman’s correlation coefficient. Gene expression of IL6, IL6R, sIL6R, GP130 and sGP130 were detected in all plaques. A pattern of differential plaque expression depending on disease severity was seen as well as a trend towards positive correlations between IL6 and sIL6R plaque expression and corresponding protein levels in the circulation. Study IV: In the 60YO cohort, risk of incident ischemic stroke associated with the B/T ratio >median was analysed using Cox regression and stratified by prevalent or incident atrial fibrillation (AF). In secondary analyses, the risk of first-time diagnosis of AF associated with the B/T ratio >median was analysed. The B/T ratio was associated with ischemic stroke risk only in subjects without AF (adjusted HR 1.49; 95% CI 1.08-2.06). In addition, no association between the B/T ratio and risk of first-ever AF (HR 0.96; 95% CI 0.75-1.24) was seen albeit an indication of an association with IL6. Conclusions: Pro-inflammatory IL6 trans-signalling, estimated by B/T ratio>median mirroring a relative excess of the binary complex (IL6:sIL6R) in relation to the inactive ternary complex (IL6:sIL6R:sgp130), is associated with an increased risk of future CVE in subjects without prevalent CVD, primarily in individuals at low- intermediate risk of CVE. IL6 signalling is present in carotid artery plaques and the B/T ratio is associated with an increased risk of atherothrombotic ischemic stroke and early stroke events albeit no association was established for ischemic stroke in relation to AF or for AF per se

Breast cancer worry in higher-risk women offered preventive therapy: a UK multicentre prospective study

PURPOSE: Women's worry about developing breast cancer may influence their decision to use preventive therapy. However, the direction of this relationship has been questioned. We prospectively investigated the relationship between breast cancer worry and uptake of preventive therapy. The socio-demographic and clinical factors associated with high breast cancer worry were also investigated. METHODS: Women at increased risk of developing breast cancer were recruited from clinics across England (n = 408). Participants completed a survey on their breast cancer worry, socio-demographic and clinical factors. Uptake of tamoxifen was recorded at 3 months (n = 258 women, 63.2%). Both primary and sensitivity analyses were conducted using different classifications of low, medium and high worry. RESULTS: 39.5% of respondents reported medium breast cancer worry at baseline and 21.2% reported high worry. Ethnic minority women were more likely to report high worry than white women (OR = 3.02, 95%CI 1.02, 8.91, p = 0.046). Women educated below degree level were more likely to report high worry than those with higher education (OR = 2.29, 95%CI 1.28, 4.09, p = 0.005). No statistically significant association was observed between worry and uptake. In the primary analysis, fewer respondents with medium worry at baseline initiated tamoxifen (low worry = 15.5%, medium = 13.5%, high = 15.7%). In the sensitivity analysis, participants with medium worry reported the highest uptake of tamoxifen (19.7%). CONCLUSIONS: No association was observed between worry and uptake, although the relationship was affected by the categorisation of worry. Standardised reporting of the classification of worry is warranted to allow transparent comparisons across cohorts

Future challenges in cephalopod research

We thank Anto´nio M. de Frias Martins, past President of the Unitas Malacologica and Peter Marko, President of the American Malacological Society for organizing the 2013 World Congress of Malacology, and the Cephalopod International Advisory Committee for endorsing a symposium held in honour of Malcolm R. Clarke. In particular, we would like to thank the many professional staff from the University of the Azores for their hospitality, organization, troubleshooting and warm welcome to the Azores. We also thank Malcolm Clarke’s widow, Dorothy, his daughter Zoe¨, Jose´ N. Gomes-Pereira and numerous colleagues and friends of Malcolm’s from around the world for joining us at Ponta Delgada. We are grateful to Lyndsey Claro (Princeton University Press) for granting copyright permissions.Peer reviewedPublisher PD

Myeloid protein tyrosine phosphatase 1B (PTP1B) deficiency protects against atherosclerotic plaque formation in the ApoE-/- mouse model of atherosclerosis with alterations in IL10/AMPKa pathway

Objective: Cardiovascular disease (CVD) is the most prevalent cause of mortality among patients with Type 1 or Type 2 diabetes, due to accelerated atherosclerosis. Recent evidence suggests a strong link between atherosclerosis and insulin resistance due to impaired insulin receptor (IR) signaling. Moreover, inflammatory cells, in particular macrophages, play a key role in pathogenesis of atherosclerosis and insulin resistance in humans. We hypothesized that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of the IR, specifically in macrophages, would have beneficial anti-inflammatory effects and lead to protection against atherosclerosis and CVD. Methods: We generated novel macrophage-specific PTP1B knockout mice on atherogenic background (ApoE−/−/LysM-PTP1B). Mice were fed standard or pro-atherogenic diet, and body weight, adiposity (echoMRI), glucose homeostasis, atherosclerotic plaque development, and molecular, biochemical and targeted lipidomic eicosanoid analyses were performed. Results: Myeloid-PTP1B knockout mice on atherogenic background (ApoE−/−/LysM-PTP1B) exhibited a striking improvement in glucose homeostasis, decreased circulating lipids and decreased atherosclerotic plaque lesions, in the absence of body weight/adiposity differences. This was associated with enhanced phosphorylation of aortic Akt, AMPKα and increased secretion of circulating anti-inflammatory cytokine interleukin-10 (IL-10) and prostaglandin E2 (PGE2), without measurable alterations in IR phosphorylation, suggesting a direct beneficial effect of myeloid-PTP1B targeting. Conclusions: Here we demonstrate that inhibiting the activity of PTP1B specifically in myeloid lineage cells protects against atherosclerotic plaque formation, under atherogenic conditions, in an ApoE−/− mouse model of atherosclerosis. Our findings suggest for the first time that macrophage PTP1B targeting could be a therapeutic target for atherosclerosis treatment and reduction of CVD risk

Soluble angiotensin-converting enzyme 2 is transiently elevated in COVID-19 and correlates with specific inflammatory and endothelial markers

The main entry receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is angiotensin-converting enzyme 2 (ACE2). SARS-CoV-2 interactions with ACE2 may increase ectodomain shedding but consequences for the renin-angiotensin system and pathology in Coronavirus disease 2019 (COVID-19) remain unclear. We measured soluble ACE2 (sACE2) and sACE levels by enzyme-linked immunosorbent assay in 114 hospital-treated COVID-19 patients compared with 10 healthy controls; follow-up samples after four months were analyzed for 58 patients. Associations between sACE2 respectively sACE and risk factors for severe COVID-19, outcome, and inflammatory markers were investigated. Levels of sACE2 were higher in COVID-19 patients than in healthy controls, median 5.0 (interquartile range 2.8-11.8) ng/ml versus 1.4 (1.1-1.6) ng/ml, p < .0001. sACE2 was higher in men than women but was not affected by other risk factors for severe COVID-19. sACE2 decreased to 2.3 (1.6-3.9) ng/ml at follow-up, p < .0001, but remained higher than in healthy controls, p = .012. sACE was marginally lower during COVID-19 compared with at follow-up, 57 (45-70) ng/ml versus 72 (52-87) ng/ml, p = .008. Levels of sACE2 and sACE did not differ depending on survival or disease severity. sACE2 during COVID-19 correlated with von Willebrand factor, factor VIII and D-dimer, while sACE correlated with interleukin 6, tumor necrosis factor alpha, and plasminogen activator inhibitor 1. Conclusions: sACE2 was transiently elevated in COVID-19, likely due to increased shedding from infected cells. sACE2 and sACE during COVID-19 differed in correlations with markers of inflammation and endothelial dysfunction, suggesting release from different cell types and/or vascular beds

Contrasting state-dependent effects of natural forcing on global and local climate variability

Natural forcing from solar and volcanic activity contributes significantly to climate variability. The post-eruption cooling of strong volcanic eruptions was hypothesized to have led to millennial-scale variability during Glacials. Cooling induced by volcanic eruption is potentially weaker in the warmer climate. The underlying question is whether the climatic response to natural forcing is state-dependent. Here, we quantify the response to natural forcing under Last Glacial and Pre-Industrial conditions in an ensemble of climate model simulations. We evaluate internal and forced variability on annual to multicentennial scales. The global temperature response reveals no state dependency. Small local differences result mainly from state-dependent sea ice changes. Variability in forced simulations matches paleoclimate reconstructions significantly better than in unforced scenarios. Considering natural forcing is therefore important for model-data comparison and future projections

Composites Part B: Engineering

Coronary artery disease (CAD) is the narrowing or blockage of the coronary arteries, usually caused by atherosclerosis. An interventional procedure using stents is a promising approach for treating CAD because stents can effectively open narrowed coronary arteries to improve blood flow to the heart. However, stents often suffer from catastrophic failures, such as fractures and migration of ligaments, resulting in fatal clinical events. In this work, we report a new type of tubular lattice metamaterial with enhanced mechanical resilience under radial compression, which can be used as an alternative for the current stent design. We begin by comparing the radial mechanical performance of the proposed auxetic tubular lattice (ATL) with the conventional diamond tubular lattice (DTL). Our results show that the ductility of ATL increases by 72.7% compared with that of the DTL structure. The finite element simulations reveal that the stress is more uniformly spread on the sinusoidal ligaments for ATL, while rather concentrated on the joints of straight ligaments for DTL. This phenomenon is intrinsically due to the bending of sinusoidal ligaments along both radial and axial directions, while straight beams bend mainly along the radial direction. We then investigated the effects of the geometrical parameters of the sinusoidal ligament on radial mechanical performance. Experimental results indicate that the beam depth h/l has the most significant effect on the stiffness and peak load. The stiffness and maximum load surge by 789% and 1131%, respectively, when h/l increases from 0.15 to 0.30. In contrast, the beam amplitude A/l has a minor effect on the stiffness and peak load compared to beam depth and beam thickness. However, increasing the amplitude of the sinusoidal ligament can enlarge the ductility strikingly. The ductility can increase by 67.5% if the amplitude is augmented from A/l=0.1 to A/l=0.35. The findings from this work can provide guidance for designing more mechanically robust stents for medical engineering

Predictors of vitamin D status and its association with parathyroid hormone in young New Zealand children.

BACKGROUND: Despite increased awareness of the adverse health effects of low vitamin D status, few studies have evaluated 25-hydroxyvitamin D [25(OH)D] status in young children. OBJECTIVES: We aimed to assess vitamin D status on the basis of 25(OH)D and its relation with parathyroid hormone (PTH) and to identify possible predictors of 25(OH)D status in young children living in a country with minimal vitamin D fortification. DESIGN: Serum 25(OH)D and PTH concentrations were measured in a cross-sectional sample of children aged 12-22 mo [n = 193 for 25(OH)D, n = 144 for PTH] living in Dunedin, New Zealand (latitude: 45 degrees S). Anthropometric, dietary, and sociodemographic data were collected. RESULTS: The majority of children sampled in the summer (94%; 47 of 50) had 25(OH)D >50 nmol/L; however, nearly 80% of children sampled in the winter (43 of 55) had serum concentrations 60-65 nmol/L, a plateau in PTH was evident. CONCLUSIONS: Seasonal variation in 25(OH)D concentration implies that postsummer vitamin D stores were insufficient to maintain status >50 nmol/L year-round. Examination of the predictors of 25(OH)D in our model shows few modifiable risk factors, and thus effective dietary strategies may be required if future research determines that children with 25(OH)D concentrations <50 nmol/L are at significant health risk. This trial was registered at www.actr.org.au as ACTRN12605000487617

Humoral and cellular responses to SARS-CoV-2 in patients with B-cell haematological malignancies improve with successive vaccination

Patients with haematological malignancies are more likely to have poor responses to vaccination. Here we provide detailed analysis of the humoral and cellular responses to COVID-19 vaccination in 69 patients with B-cell malignancies. Measurement of anti-spike IgG in serum demonstrated a low seroconversion rate with 27.1% and 46.8% of patients seroconverting after the first and second doses of vaccine, respectively. In vitro pseudoneutralisation assays demonstrated a poor neutralising response, with 12.5% and 29.5% of patients producing a measurable neutralising titre after the first and second doses, respectively. A third dose increased seropositivity to 54.3% and neutralisation to 51.5%, while a fourth dose further increased both seropositivity and neutralisation to 87.9%. Neutralisation titres post-fourth dose showed a positive correlation with the size of the B-cell population measured by flow cytometry, suggesting an improved response correlating with recovery of the B-cell compartment after B-cell depletion treatments. In contrast, interferon gamma ELISpot analysis showed a largely intact T-cell response, with the percentage of patients producing a measurable response boosted by the second dose to 75.5%. This response was maintained thereafter, with only a small increase following the third and fourth doses, irrespective of the serological response at these timepoints