Cyclosporin A and prednisolone do not inhibit the expression of high-affinity receptors for interleukin 2

To elucidate the mechanisms of action of cyclosporin A (CyA) and prednisolone (pred), we investigated the effects of these immunosuppressive drugs on the expression of receptors for interleukin 2 (IL-2) as well as the effect of exogenous IL-2 on CyA-inhibited and pred-inhibited responses. Pred-induced inhibition of T cell proliferative responses could be reversed by addition of exogenous IL-2. In contrast, exogenous IL-2 could not overcome CyA-mediated inhibition of T cell proliferation. Receptors for IL-2, as measured by the expression of Tac antigen, were slightly decreased by CyA and pred. However, expression of the biologically active, high-affinity IL-2 receptors was not diminished. These data suggest that pred-mediated inhibition occurs at the level of the IL-2 system, whereas CyA affects the proliferative mechanism of the T cell itself

Cyclosporine A does not prevent expression of biologically active IL 2 receptors in vitro

In this study, we show that CsA does not affect the expression of IL 2 receptors. Moreover, these IL 2 receptors are capable of transducing signals, as measured by a rise in intracellular pH

Prednisolone and cyclosporin a exert differential inhibitory effects on T-cell proliferation in vitro

To elucidate the mechanisms of action of prednisolone (pred) and cyclosporin A (CyA), we have investigated the effects of these immunosuppressive drugs on the proliferative response of human peripheral blood lymphocytes (PBMN) induced by various stimulants, well defined with regard to their monocyte dependence. We found that pred-induced inhibition of monocyte-dependent proliferative responses could be reversed by the addition of exogenous interleukin 2 (IL-2). Monocyte-independent proliferative responses were not affected by pred. These findings suggest that pred inhibits IL-2 production and subsequent lymphocyte proliferation at the level of the signal derived from the monocyte. In contrast, CyA inhibited monocyte-dependent as well as monocyte-independent proliferative responses of human PBMN. This inhibition could not be reversed by the addition of exogenous IL-2. We have previously demonstrated that CyA does not affect the expression of receptors for IL-2. Taken together, these data indicate that CyA-mediated inhibition does not primarily occur at the level of the IL-2 system, but rather affects the proliferative mechanism of the T cell itself. These data clearly demonstrate that pred and CyA act at distinct sites of the triggering process

The influence of immunosuppressive treatment on immune responsiveness in vivo in kidney transplant recipients

In this study, we have compared the influence of CsA and pred/aza on the immunocompetence in man. Therefore, kidney-transplant recipients were tested for their primary keyhole limpet hemocyanin and secondary (tetanus and KLH) humoral immune responses and their primary dinitrochlorobenzene and secondary (recall antigens) cellular immune responses. We demonstrate that primary immune responses are inhibited by CsA, whereas secondary immune responses are relatively résistant. Pred/aza therapy seems to inhibit all cellular immune responses, as we demonstrated before, as well as the primary humoral immune responses. Secondary humoral immune responses are only slightly affected by pred/aza. Our results provide a strong argument for starting immunosuppression with CsA, either with or without a low-dose pred

Endothelium-associated biomarkers mid-regional proadrenomedullin and C-terminal proendothelin-1 have good ability to predict 28-day mortality in critically ill patients with SARS-CoV-2 pneumonia: A prospective cohort study

PURPOSE: We assessed the ability of mid-regional proadrenomedullin (MR-proADM) and C-terminal proendothelin-1 (CT-proET-1) to predict 28-day mortality in critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia. METHODS: Biomarkers were collected during the first seven days in this prospective observational cohort study. We investigated the relationship between biomarkers and mortality in a multivariable Cox regression model adjusted for age and SOFA score. RESULTS: In 105 critically ill patients with confirmed SARS-CoV-2 pneumonia 28-day mortality was 28.6%. MR-proADM and CT-proET-1 were significantly higher in 28-day non-survivors at baseline and over time. ROC curves revealed high accuracy to identify non-survivors for baseline MR-proADM and CT-proET-1, AUC 0.84, (95% CI 0.76–0.92), p < 0.001 and 0.79, (95% CI 0.69–0.89), p < 0.001, respectively. The AUC for prediction of 28-day mortality for MR-proADM and CT-proET-1 remained high over time. MR-proADM ≥1.57 nmol/L and CT-proET-1 ≥ 111 pmol/L at baseline were significant predictors for 28-day mortality (HR 6.80, 95% CI 3.12–14.84, p < 0.001 and HR 3.72, 95% CI 1.71–8.08, p 0.01). CONCLUSION: Baseline and serial MR-proADM and CT-proET-1 had good ability to predict 28-day mortality in critically ill patients with SARS-CoV-2 pneumonia. TRIAL REGISTRATION: NEDERLANDS TRIAL REGISTER, NL8460

Data from: A high-density SNP chip for genotyping great tit (Parus major) populations and its application to studying the genetic architecture of exploration behaviour

High density SNP microarrays (‘SNP chips’) are a rapid, accurate and efficient method for genotyping several hundred thousand polymorphisms in large numbers of individuals. While SNP chips are routinely used in human genetics and in animal and plant breeding, they are less widely used in evolutionary and ecological research. In this paper we describe the development and application of a high density Affymetrix Axiom chip with around 500 000 SNPs, designed to perform genomics studies of great tit (Parus major) populations. We demonstrate that the per-SNP genotype error rate is well below 1% and that the chip can also be used to identify structural or copy number variation (CNVs). The chip is used to explore the genetic architecture of exploration behaviour (EB), a personality trait that has been widely studied in great tits and other species. No SNPs reached genome-wide significance, including at DRD4, a candidate gene. However, EB is heritable and appears to have a polygenic architecture. Researchers developing similar SNP chips may note: (i) SNPs previously typed on alternative platforms are more likely to be converted to working assays, (ii) detecting SNPs by more than one pipeline, and in independent datasets, ensures a high proportion of working assays, (iii) allele frequency ascertainment bias is minimised by performing SNP discovery in individuals from multiple populations and (iv) samples with the lowest call rates tend to also have the greatest genotyping error rates