CCL18 aggravates atherosclerosis by inducing CCR6-dependent T-cell influx and polarization

IntroductionThe CC chemokine ligand 18 (CCL18) is a chemokine highly expressed in chronic inflammation in humans. Recent observations of elevated CCL18 plasma levels in patients with acute cardiovascular syndromes prompted an investigation into the role of CCL18 in the pathogenesis of human and mouse atherosclerosis.Methods and resultsCCL18 was profoundly upregulated in ruptured human atherosclerotic plaque, particularly within macrophages. Repeated administration of CCL18 in Western-type diet–fed ApoE−/− mice or PCSK9mut-overexpressing wild type (WT) mice led to increased plaque burden, enriched in CD3+ T cells. In subsequent experimental and molecular modeling studies, we identified CCR6 as a functional receptor mediating CCL18 chemotaxis, intracellular Ca2+ flux, and downstream signaling in human Jurkat and mouse T cells. CCL18 failed to induce these effects in vitro in murine spleen T cells with CCR6 deficiency. The ability of CCR6 to act as CCL18 receptor was confirmed in vivo in an inflammation model, where subcutaneous CCL18 injection induced profound focal skin inflammation in WT but not in CCR6−/− mice. This inflammation featured edema and marked infiltration of various leukocyte subsets, including T cells with a Th17 signature, supporting CCR6’s role as a Th17 chemotactic receptor. Notably, focal overexpression of CCL18 in plaques was associated with an increased presence of CCR6+ (T) cells.DiscussionOur studies are the first to identify the CCL18/CCR6 axis as a regulator of immune responses in advanced murine and human atherosclerosis

CCL18 aggravates atherosclerosis by inducing CCR6-dependent T-cell influx and polarization

INTRODUCTION: The CC chemokine ligand 18 (CCL18) is a chemokine highly expressed in chronic inflammation in humans. Recent observations of elevated CCL18 plasma levels in patients with acute cardiovascular syndromes prompted an investigation into the role of CCL18 in the pathogenesis of human and mouse atherosclerosis. METHODS AND RESULTS: CCL18 was profoundly upregulated in ruptured human atherosclerotic plaque, particularly within macrophages. Repeated administration of CCL18 in Western-type diet-fed ApoE -/- mice or PCSK9 mut-overexpressing wild type (WT) mice led to increased plaque burden, enriched in CD3 + T cells. In subsequent experimental and molecular modeling studies, we identified CCR6 as a functional receptor mediating CCL18 chemotaxis, intracellular Ca 2+ flux, and downstream signaling in human Jurkat and mouse T cells. CCL18 failed to induce these effects in vitro in murine spleen T cells with CCR6 deficiency. The ability of CCR6 to act as CCL18 receptor was confirmed in vivo in an inflammation model, where subcutaneous CCL18 injection induced profound focal skin inflammation in WT but not in CCR6 -/- mice. This inflammation featured edema and marked infiltration of various leukocyte subsets, including T cells with a Th17 signature, supporting CCR6's role as a Th17 chemotactic receptor. Notably, focal overexpression of CCL18 in plaques was associated with an increased presence of CCR6 + (T) cells. DISCUSSION: Our studies are the first to identify the CCL18/CCR6 axis as a regulator of immune responses in advanced murine and human atherosclerosis

Clinical and virological characteristics of hospitalised COVID-19 patients in a German tertiary care centre during the first wave of the SARS-CoV-2 pandemic: a prospective observational study

Purpose: Adequate patient allocation is pivotal for optimal resource management in strained healthcare systems, and requires detailed knowledge of clinical and virological disease trajectories. The purpose of this work was to identify risk factors associated with need for invasive mechanical ventilation (IMV), to analyse viral kinetics in patients with and without IMV and to provide a comprehensive description of clinical course. Methods: A cohort of 168 hospitalised adult COVID-19 patients enrolled in a prospective observational study at a large European tertiary care centre was analysed. Results: Forty-four per cent (71/161) of patients required invasive mechanical ventilation (IMV). Shorter duration of symptoms before admission (aOR 1.22 per day less, 95% CI 1.10-1.37, p < 0.01) and history of hypertension (aOR 5.55, 95% CI 2.00-16.82, p < 0.01) were associated with need for IMV. Patients on IMV had higher maximal concentrations, slower decline rates, and longer shedding of SARS-CoV-2 than non-IMV patients (33 days, IQR 26-46.75, vs 18 days, IQR 16-46.75, respectively, p < 0.01). Median duration of hospitalisation was 9 days (IQR 6-15.5) for non-IMV and 49.5 days (IQR 36.8-82.5) for IMV patients. Conclusions: Our results indicate a short duration of symptoms before admission as a risk factor for severe disease that merits further investigation and different viral load kinetics in severely affected patients. Median duration of hospitalisation of IMV patients was longer than described for acute respiratory distress syndrome unrelated to COVID-19

Essays on economics and demography

Chapter 1 indicates the relevancy of the share of national income concentrated among a country's richest 20% for health outcomes of the lowest three quintiles of the income distribution independent of their personal absolute income. A comparison of 93 countries suggests that the income distance between an individual and the people the individual directly observes at work or in the neighborhood might not be the only form of relative deprivation, but that the distance to the wealthy might matter as well. The results are not caused by the distribution of absolute income: previous research has shown that the level of GDP per capita is the single most important determinant of health outcomes (see Prichett and Summers, 1996), which our results confirm. The chapter discusses possible explanations for the link between income distribution and health outcomes. Suggestions for two explanations are found: public disinvestment in human capital in countries where income is unequally distributed and relative deprivation, i.e. social comparison resulting in stress, risk taking behavior, or unwise consumption expenditure. Chapter 2 investigates the relative efficiency of public and private health care spending in reducing infant and child mortality using cross-national data for 163 countries. The analysis shows that an increase in public funds is both, significantly correlated with lower mortality rates and significantly more efficient in reducing mortality than private health care expenditure. The results indicate that an increase in private health care expenditure might even be associated with higher, not lower, mortality. Although some of the estimated difference in the efficiency of public and private health care expenditure can be explained by geographies and socioeconomic factors, chapter 1 concludes that the indications for such difference are robust

Income Distribution, Infant Mortality, and Health Care Expenditure

Do health outcomes depend on relative income as well as on an individual?s absolute level of income? We use infant mortality as a health status indicator and ?nd a signi?cant and positive link between infant mortality and income inequality using cross-national data for 98 countries. Holding constant the income of each of the three poorest quintiles of a country's population, we ?nd that an increase in the income of the upper 20% of the income distribution is associated with higher, not lower infant mortality. Our results imply that a one percentage point decrease in the income share of the richest quintile correlates with a decrease in infant mortality by nearly two percent. The surprisingly positive coe¢cient becomes insignificant when we control for public health care expenditure. Low public expenditure on health care seems to translate into limited access to health care for the poor.

Synthesis and Pharmacological Properties of Silicon-Containing 1,4-Dihydropyridine Derivatives: Calcium Channel Antagonists and α₁ Adrenoceptor Antagonists of the Sila-niguldipine Type

Racemic 3-(4,4-diphenyl-4-silapiperidin-1-yl)propyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (rac-sila-niguldipine, rac-1b), a sila analogue of the calcium antagonist rac-niguldipine (rac-1a), and the sila-niguldipine derivatives rac-2b−rac-4b were synthesized in multistep syntheses, starting from dichlorodiphenylsilane. The silicon compounds rac-1b−rac-4b contain a 4,4-diphenyl-4-silapiperidin-1-yl group instead of the 4,4-diphenylpiperidin-1-yl moiety in the parent carbon compound rac-1a. rac-Sila-niguldipine and the precursor 3-(4,4-diphenyl-4-silapiperidin-1-yl)propanol (11) were structurally characterized by single-crystal X-ray diffraction. The pharmacological profiles of rac-1b−rac-4b were compared with that of rac-1a across a range of receptor binding assays (radioligand binding studies at α1A and α2 adrenoceptors, the L-type Ca2+ channel, and the serotonin 5-HT receptor). The silicon compounds rac-2b−rac-4b exhibit a profile similar to that of SNAP 5089 and therefore may be of potential benefit in the treatment of diseases such as benign prostatic hyperplasia (BPH)

Sila-haloperidol: A Silicon Analogue of the Dopamine (D₂) Receptor Antagonist Haloperidol^§

Haloperidol (1a), a dopamine (D2) receptor antagonist, is in clinical use as an antipsychotic agent. Carbon/silicon exchange (sila-substitution) at the 4-position of the piperidine ring of 1a (R3COH → R3SiOH) leads to sila-haloperidol (1b). Sila-haloperidol was synthesized in a multistep synthesis, starting from tetramethoxysilane, and was isolated as the hydrochloride 1b·HCl. ESI-MS studies of aqueous solutions of the silanol 1b and the corresponding disiloxane 10 at different pH values revealed a remarkable stability of 1b. The C/Si analogues 1a·HCl and 1b·HCl were structurally characterized by single-crystal X-ray diffraction and solution ([D6]DMSO) NMR spectroscopy. Analogous chair conformations of the piperidinium (1a·HCl) and 4-silapiperidinium (1b·HCl) skeleton were observed in the crystal, and two analogous chair conformations of the cations were detected in solution, the molar ratios of these two conformers differing substantially (1a·HCl, 13:1; 1b·HCl, 2:1). In radioligand binding studies, the C/Si analogues 1a and 1b displayed similar potencies at recombinant human dopamine hD1, hD4, and hD5 receptors, whereas the silicon compound 1b was 4.7-fold more potent at hD2 receptors than its carbon analogue 1a; i.e., sila-substitution of haloperidol has changed the receptor selectivity profile