Friedrich Hayek and his visits to Chile

F. A. Hayek took two trips to Chile, the first in 1977, the second in 1981. The visits were controversial. On the first trip he met with General Augusto Pinochet, who had led a coup that overthrew Salvador Allende in 1973. During his 1981 visit, Hayek gave interviews that were published in the Chilean newspaper El Mercurio and in which he discussed authoritarian regimes and the problem of unlimited democracy. After each trip, he complained that the western press had painted an unfair picture of the economic situation under the Pinochet regime. Drawing on archival material, interviews, and past research, we provide a full account of this controversial episode in Hayek’s life

Electron-Donating Phenolic and Electron-Accepting Quinone Moieties in Peat Dissolved Organic Matter: Quantities and Redox Transformations in the Context of Peat Biogeochemistry

ISSN:0013-936XISSN:1520-585

Immunoglobulin M-enriched intravenous immunoglobulin inhibits classical pathway complement activation, but not bactericidal activity of human serum

Acute or even hyperacute humoral graft rejection, mediated by classical pathway complement activation, occurs in allo- and xenotransplantation due to preformed anti-graft antibodies. Intravenous immunoglobulin (IVIg) preparations can prevent complement-mediated tissue injury and delay hyperacute xenograft rejection. It is known that IgM-enriched IVIg (IVIgM) has a higher capacity to block complement than IVIgG. Different IVIgs were therefore tested for specificity of complement inhibition and effect on anti-bacterial activity of human serum. IVIgM-I (Pentaglobin), 12% IgM), IVIgM-II (IgM-fraction of IVIgM-I, 60% IgM), and three different IVIgG (all >95% IgG) were used. The known complement inhibitor dextran sulfate was used as control. Hemolytic assays were performed to analyze pathway-specificity of complement inhibition. Effects of IVIg on complement deposition on pig cells and Escherichia coli were assessed by flow cytometry and cytotoxicity as well as bactericidal assays. Complement inhibition by IVIgM was specific for the classical pathway, with IC50 values of 0.8 mg/ml for IVIgM-II and 1.7 mg/ml for IVIgM-I in the CH50 assay. Only minimal inhibition of the lectin pathway was seen with IVIgM-II (IC50 15.5 mg/ml); no alternative pathway inhibition was observed. IVIgG did not inhibit complement in any hemolytic assay. Classical pathway complement inhibition by IVIgM was confirmed in an in vitro xenotransplantation model with PK15 cells. In contrast, IVIgM did not inhibit (mainly alternative pathway mediated) killing of E. coli by human serum. In conclusion, IgM-enriched IVIg is a specific inhibitor of the classical complement pathway, leaving the alternative pathway intact, which is an important natural anti-bacterial defense, especially for immunosuppressed patients

Controlling Factors in the Rates of Oxidation of Anilines and Phenols by Triplet Methylene Blue in Aqueous Solution

Anilines and phenols are structurally similar compound classes that both are susceptible to oxidation by excited state triplet sensitizers but undergo oxidation by different mechanisms. To gain an understanding of the factors that control the rate of oxidation of anilines and phenols by triplet excited states, a kinetic study was performed on the oxidation of substituted anilines and phenols by methylene blue. The rate constants of one-electron transfer from anilines to triplet state methylene blue and their dependence on the reaction free energy are well fit to a SandrosBoltzmann model. The observed rate constants are also well modeled when aniline oxidation potentials derived computationally are used. For phenols, the proton-coupled electron transfer rate constants were found to correlate primarily with O-H bond dissociation free energy and secondarily with phenol pK(a center dot) Rate constants for phenols could be modeled using computed bond dissociation free energies. These results provide a basis for predicting aniline and phenol oxidation rates, which could be valuable, for example, in assessing the likely persistence and fate of aniline- and phenol-based aqueous environmental pollutants

Nuclear PIM1 confers resistance to rapamycin-impaired endothelial proliferation

The PIM serine/threonine kinases and the mTOR/AKT pathway integrate growth factor signaling and promote cell proliferation and survival. They both share phosphorylation targets and have overlapping functions, which can partially substitute for each other. In cancer cells PIM kinases have been reported to produce resistance to mTOR inhibition by rapamycin. Tumor growth depends highly on blood vessel infiltration into the malignant tissue and therefore on endothelial cell proliferation. We therefore investigated how the PIM1 kinase modulates growth inhibitory effects of rapamycin in mouse aortic endothelial cells (MAEC). We found that proliferation of MAEC lacking Pim1 was significantly more sensitive to rapamycin inhibition, compared to wildtype cells. Inhibition of mTOR and AKT in normal MAEC resulted in significantly elevated PIM1 protein levels in the cytosol and in the nucleus. We observed that truncation of the C-terminal part of Pim1 beyond Ser 276 resulted in almost exclusive nuclear localization of the protein. Re-expression of this Pim1 deletion mutant significantly increased the proliferation of Pim1(-/-) cells when compared to expression of the wildtype Pim1 cDNA. Finally, overexpression of the nuclear localization mutant and the wildtype Pim1 resulted in complete resistance to growth inhibition by rapamycin. Thus, mTOR inhibition-induced nuclear accumulation of PIM1 or expression of a nuclear C-terminal PIM1 truncation mutant is sufficient to increase endothelial cell proliferation, suggesting that nuclear localization of PIM1 is important for resistance of MAEC to rapamycin inhibition of proliferation

Electron-Donating Phenolic and Electron-Accepting Quinone Moieties in Peat Dissolved Organic Matter: Quantities and Redox Transformations in the Context of Peat Biogeochemistry

Electron-donating phenolic and electron-accepting quinone moieties in peat dissolved organic matter (DOM) are considered to play key roles in processes defining carbon cycling in northern peatlands. This work advances a flow-injection analysis system coupled to chronoamperometric detection to allow for the simultaneous and highly sensitive determination of these moieties in dilute DOM samples. Analysis of anoxic pore water and oxic pool water samples collected across an ombrotrophic bog in Sweden demonstrated the presence of both phenolic and quinone moieties in peat DOM. The pore water DOM had higher quantities of phenolic but not quinone moieties compared with commonly used model aquatic and terrestrial DOM isolates. Significantly lower phenol content in DOM from oxic pools than DOM from anoxic pore waters indicated oxidative DOM processing in the pools. Consistently, treatment of peat DOM with laccase, a phenol-oxidase, under oxic conditions resulted in an irreversible removal of phenols and reversible oxidation of hydroquinones to quinones. Electron transfer to peat DOM was fully reversible over an electrochemical reduction and subsequent O₂-reoxidation cycle, supporting that quinones in peat DOM serve as regenerable microbial electron acceptors in peatlands. The results advance our understanding of redox processes involving phenolic and quinone DOM moieties and their roles in northern peatland carbon cycling

Multimeric tyrosine sulfate acts as an endothelial cell protectant and prevents complement activation in xenotransplantation models

BACKGROUND: Activation of endothelial cells (EC) in xenotransplantation is mostly induced through binding of antibodies (Ab) and activation of the complement system. Activated EC lose their heparan sulfate proteoglycan (HSPG) layer and exhibit a procoagulant and pro-inflammatory cell surface. We have recently shown that the semi-synthetic proteoglycan analog dextran sulfate (DXS, MW 5000) blocks activation of the complement cascade and acts as an EC-protectant both in vitro and in vivo. However, DXS is a strong anticoagulant and systemic use of this substance in a clinical setting might therefore be compromised. It was the aim of this study to investigate a novel, fully synthetic EC-protectant with reduced inhibition of the coagulation system. METHOD: By screening with standard complement (CH50) and coagulation assays (activated partial thromboplastin time, aPTT), a conjugate of tyrosine sulfate to a polymer-backbone (sTyr-PAA) was identified as a candidate EC-protectant. The pathway-specificity of complement inhibition by sTyr-PAA was tested in hemolytic assays. To further characterize the substance, the effects of sTyr-PAA and DXS on complement deposition on pig cells were compared by flow cytometry and cytotoxicity assays. Using fluorescein-labeled sTyr-PAA (sTyr-PAA-Fluo), the binding of sTyr-PAA to cell surfaces was also investigated. RESULTS: Of all tested compounds, sTyr-PAA was the most effective substance in inhibiting all three pathways of complement activation. Its capacity to inhibit the coagulation cascade was significantly reduced as compared with DXS. sTyr-PAA also dose-dependently inhibited deposition of human complement on pig cells and this inhibition correlated with the binding of sTyr-PAA to the cells. Moreover, we were able to demonstrate that sTyr-PAA binds preferentially and dose-dependently to damaged EC. CONCLUSIONS: We could show that sTyr-PAA acts as an EC-protectant by binding to the cells and protecting them from complement-mediated damage. It has less effect on the coagulation system than DXS and may therefore have potential for in vivo application

Pruritus in Hemodialysis Patients: Longitudinal Associations With Clinical and Patient-Reported Outcomes

RATIONALE & OBJECTIVE: Cross-sectional studies have reported an association of chronic kidney disease-associated pruritus (CKD-aP) with adverse clinical events and patient-reported outcomes (PROs). We studied the longitudinal associations between changes in CKD-aP and clinical outcomes among patients receiving maintenance hemodialysis. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 7,976 hemodialysis recipients across 21 countries in phases 4-6 (2009-2018) of the Dialysis Outcomes and Practice Patterns Study (DOPPS) who had 2 CKD-aP assessments approximately 12 months apart. EXPOSURES: Exposure status was based on the assessment of pruritis initially and again approximately 1 year later. Four groups were identified, including those with moderate or more severe pruritis only at the initial assessment (resolved), only at the second assessment (incident), at neither assessment (absent), or at both assessments (persistent). OUTCOMES: Laboratory values and PROs ascertained at the initial assessment of pruritis and 1 year later. ANALYTICAL APPROACH: Linear mixed model to investigate changes in laboratory values and PROs over the 1-year study period across the 4 exposure groups. RESULTS: 51% of patients had moderate to severe CKD-aP symptoms at either assessment (22% at both). The prevalences of depression, restless sleep, and feeling drained increased over the study period (+13%,+10%, and+14%, respectively) among patients with incident pruritus and decreased (-5%, -8%, and -12%, respectively) among patients with resolved pruritus. Minimal changes in PROs over time were observed for the absent and persistent groups. Changes over time in laboratory values (phosphorus, Kt/V) were not detected for either of these groups. Compared with patients with absent CKD-aP, the adjusted HRs for patients with persistent CKD-aP were 1.29 (95% CI, 1.09-1.53) for all-cause mortality, 1.17 (1.07-1.28) for all-cause hospitalization, and 1.48 (1.26-1.74) for cardiovascular events. LIMITATIONS: No interim evaluation of CKD-aP symptoms between the 2 assessments; potential selection bias from patients who died or were otherwise lost to follow-up before the second assessment. CONCLUSIONS: CKD-aP symptoms are chronic, and these findings highlight the potential value of repeated assessment of this symptom using standardized approaches. Future research should systematically investigate potential causes of CKD-aP and options for its effective treatment. PLAIN-LANGUAGE SUMMARY: Previous research has studied itching and its consequences in hemodialysis recipients only at a single time point. We surveyed 7,976 patients receiving maintenance hemodialysis to assess itching over a period of 1 year. We found that, among those experiencing itching at the initial assessment, more than half had persistent symptoms 1 year later. Those in whom itching developed during follow-up were more likely to experience depression, poor sleep, long recovery times after dialysis, and feeling faint or drained. These patients also rated their quality of life as poorer than those who did not experience itching. These findings emphasize the potential value of clinical detection of itching and the pursuit of effective treatments for patients receiving dialysis experiencing these symptoms