Low density lipoprotein oxidized under lysosomal conditions decreases arterial vasodilatation.

Endothelial dysfunction is a risk factor for atherosclerosis and includes impaired endothelium-dependent vasodilatation. We have shown previously that low density lipoprotein (LDL) can be oxidized by iron in the lysosomes of macrophages. Macrophage lysis in atherosclerotic lesions might expose endothelial cells to this oxidized LDL and adversely affect their function.

Incidence of SARS-CoV-2 seropositivity in pediatric healthcare workers prior to widespread vaccination: A 5-month longitudinal cohort study.

Objectives: Determine SARS-CoV-2 IgG antibody incidence over time in unvaccinated pediatric healthcare workers (pHCWs).

Design: A prospective longitudinal cohort of unvaccinated pHCWs measuring the incidence of new infection after initial prevalence was established at 4.1% with seropositive predominance in emergency department (ED)-based pHCWs.

Sickle Cell Disease Treatment with Arginine Therapy (STArT): study protocol for a phase 3 randomized controlled trial.

Background: Despite substantial illness burden and healthcare utilization conferred by pain from vaso-occlusive episodes (VOE) in children with sickle cell disease (SCD), disease-modifying therapies to effectively treat SCD-VOE are lacking. The aim of the Sickle Cell Disease Treatment with Arginine Therapy (STArT) Trial is to provide definitive evidence regarding the efficacy of intravenous arginine as a treatment for acute SCD-VOE among children, adolescents, and young adults.

Methods: STArT is a double-blind, placebo-controlled, randomized, phase 3, multicenter trial of intravenous arginine therapy in 360 children, adolescents, and young adults who present with SCD-VOE.

Tracing Slow Phenoptosis to the Prenatal Stage in Social Vertebrates.

Vladimir Skulachev's coining of the term "phenoptosis" 25 years ago (Skulachev, V. P., Biochemistry (Moscow), 62, 1997) highlighted the theoretical possibility that aging is a programmed process to speed the exit of individuals posing some danger to their social group.

Monocytic Cell Adhesion to Oxidised Ligands: Relevance to Cardiovascular Disease.

Atherosclerosis, the major cause of vascular disease, is an inflammatory process driven by entry of blood monocytes into the arterial wall. LDL normally enters the wall, and stimulates monocyte adhesion by forming oxidation products such as oxidised phospholipids (oxPLs) and malondialdehyde. Adhesion molecules that bind monocytes to the wall permit traffic of these cells.

Effects of lysosomal low-density lipoprotein oxidation by ferritin on macrophage function.

We have previously demonstrated that low-density lipoprotein (LDL) can be oxidized by iron in the lysosomes of macrophages. Some of the iron content of lysosomes might be delivered through autophagy of ferritin (the main iron-storage protein in the body). We have now investigated the effects of ferritin-mediated LDL oxidation on macrophage function.

Workplace inequality is associated with status-signaling expenditure.

Regional inequality is known to magnify sensitivity to social rank. This, in turn, is shown to increase people’s propensity to acquire luxury goods as a means to elevate their perceived social status. Yet existing research has focused on broad, aggregated datasets, and little is known about how individual-level measures of income interact with inequality within peer groups to affect status signaling.

Cysteamine Decreases Low-Density Lipoprotein Oxidation, Causes Regression of Atherosclerosis, and Improves Liver and Muscle Function in Low-Density Lipoprotein Receptor-Deficient Mice.

Background We have shown previously that low-density lipoprotein (LDL) can be oxidized in the lysosomes of macrophages, that this oxidation can be inhibited by cysteamine, an antioxidant that accumulates in lysosomes, and that this drug decreases atherosclerosis in LDL receptor-deficient mice fed a high-fat diet. We have now performed a regression study with cysteamine, which is of more relevance to the treatment of human disease. Methods and Results LDL receptor-deficient mice were fed a high-fat diet to induce atherosclerotic lesions.

Pro-Inflammatory Implications of 2-Hydroxypropyl-β-cyclodextrin Treatment.

Lifestyle- and genetically induced disorders related to disturbances in cholesterol metabolism have shown the detrimental impact of excessive cholesterol levels on a plethora of pathological processes such as inflammation. In this context, two-hydroxypropyl-β-cyclodextrin (CD) is increasingly considered as a novel pharmacological compound to decrease cellular cholesterol levels due to its ability to increase cholesterol solubility. However, recent findings have reported contra-indicating events after the use of CD questioning the clinical applicability of this compound.

Vitamins E and C do not effectively inhibit low density lipoprotein oxidation by ferritin at lysosomal pH.

Low density lipoprotein (LDL) might be oxidized by iron in the lysosomes of macrophages in atherosclerotic lesions. We have shown previously that the iron-storage proteinferritin can oxidize LDL at lysosomal pH. We have now investigated the roles of the most important antioxidant contained in LDL, α-tocopherol (the main form of vitamin E) and of ascorbate (vitamin C), a major water-soluble antioxidant, on LDL oxidation by ferritin at lysosomal pH (pH 4.

Prevalence of SARS-CoV-2 antibodies in pediatric healthcare workers.

Objectives: To determine SARS-CoV-2-antibody prevalence in pediatric healthcare workers (pHCWs).

Design: Baseline prevalence of anti-SARS-CoV-2-IgG was assessed in a prospective cohort study from a large pediatric healthcare facility. Prior SARS-CoV-2 testing history, potential risk factors and anxiety level about COVID-19 were determined.

The association between gambling and financial, social and health outcomes in big financial data.

Gambling is an ordinary pastime for some people, but is associated with addiction and harmful outcomes for others. Evidence of these harms is limited to small-sample, cross-sectional self-reports, such as prevalence surveys. We examine the association between gambling as a proportion of monthly income and 31 financial, social and health outcomes using anonymous data provided by a UK retail bank, aggregated for up to 6.

Effect of vitamin E on low density lipoprotein oxidation at lysosomal pH.

Many cholesterol-laden foam cells in atherosclerotic lesions are macrophages and much of their cholesterol is present in their lysosomes and derived from low density lipoprotein (LDL). LDL oxidation has been proposed to be involved in the pathogenesis of atherosclerosis. We have shown previously that LDL can be oxidised in the lysosomes of macrophages.

Studying biological science does not lead to adoption of a healthy lifestyle.

Aims: The lifestyle and physical activity (PA) habits of young people play a key role in the prevention of cardiovascular and metabolic diseases at older ages. The current generation of biological science students at university holds promise for better future medicine and medical technology. However, their physical fitness and lifestyle are often ignored.

Cysteamine inhibits lysosomal oxidation of low density lipoprotein in human macrophages and reduces atherosclerosis in mice.

Background And Aims: We have shown previously that low density lipoprotein (LDL) aggregated by vortexing is internalised by macrophages and oxidised by iron in lysosomes to form the advanced lipid/protein oxidation product ceroid. We have now used sphingomyelinase-aggregated LDL, a more pathophysiological form of aggregated LDL, to study lysosomal oxidation of LDL and its inhibition by antioxidants, including cysteamine (2-aminoethanethiol), which concentrates in lysosomes by several orders of magnitude. We have also investigated the effect of cysteamine on atherosclerosis in mice.

Lysosomal oxidation of LDL alters lysosomal pH, induces senescence, and increases secretion of pro-inflammatory cytokines in human macrophages.

We have shown that aggregated LDL is internalized by macrophages and oxidized in lysosomes by redox-active iron. We have now investigated to determine whether the lysosomal oxidation of LDL impairs lysosomal function and whether a lysosomotropic antioxidant can prevent these alterations. LDL aggregated by SMase (SMase-LDL) caused increased lysosomal lipid peroxidation in human monocyte-derived macrophages or THP-1 macrophage-like cells, as shown by a fluorescent probe, Foam-LPO.

Low density lipoprotein oxidation by ferritin at lysosomal pH.

Oxidation of low density lipoprotein (LDL) has been proposed to be involved in the pathogenesis of atherosclerosis. We have previously shown that LDL can be oxidised by iron in lysosomes. As the iron-storage protein ferritin might enter lysosomes by autophagy, we have investigated the ability of ferritin to catalyse LDL oxidation at lysosomal pH.

The synthetic glycolipid-based TLR4 antagonist FP7 negatively regulates in vitro and in vivo haematopoietic and non-haematopoietic vascular TLR4 signalling.

TLRs, including TLR4, have been shown to play a crucial role in cardiovascular inflammatory-based diseases. The main goal of this study was to determine the potential of FP7, a synthetic glycolipid active as a TLR4 antagonist, to modulate haematopoietic and non-haematopoietic vascular TLR4 pro-inflammatory signalling. HUVEC, human THP-1 monocytes, THP-1-derived macrophages, mouse RAW-264.

Antioxidants inhibit low density lipoprotein oxidation less at lysosomal pH: A possible explanation as to why the clinical trials of antioxidants might have failed.

Oxidised low density lipoprotein (LDL) was considered to be important in the pathogenesis of atherosclerosis, but the large clinical trials of antioxidants, including the first one using probucol (the PQRST Trial), failed to show benefit and have cast doubt on the importance of oxidised LDL. We have shown previously that LDL oxidation can be catalysed by iron in the lysosomes of macrophages. The aim of this study was therefore to investigate the effectiveness of antioxidants in preventing LDL oxidation at lysosomal pH and also establish the possible mechanism of oxidation.

Adams-Oliver Syndrome Type 2 in Association with Compound Heterozygous DOCK6 Mutations.

Adams-Oliver syndrome (AOS) is a multiple congenital anomaly syndrome characterized by aplasia cutis congenita (ACC) and transverse terminal limb defects (TTLDs). We present a case of type 2 autosomal recessive AOS associated with heterozygous mutations in the dedicator of cytokinesis 6 (DOCK6) gene, with characteristic findings of ACC, TTLD, intracerebral periventricular calcifications, and polymicrogyria.