Peptide Antagonists for P-selectin Discriminate between Sulfatide-Dependent Platelet Aggregation and PSGL-1-Mediated Cell Adhesion.

Background: Membrane-exposed sulfatides are proposed to contribute to P-selectin-dependent platelet aggregation. Here, we demonstrated that P-selectin-mediated platelet aggregation on a collagen-coated surface under flow indeed depended on sulfatides and that this interaction differed considerably from the interaction of P-selectin with P-selectin Glycoprotein Ligand-1 (PSGL-1), which underlies leukocyte-endothelium adhesion.

Methods And Results: Upon platelet activation, sulfatides were translocated to the platelet surface to form focal hot-spots.

Is a pillow a risk factor for glaucoma?

Purpose: To study whether a clinically significant increase in intraocular pressure (IOP) occurs during simulated sleep conditions with the subject's head turned comfortably into a pillow (the simulated sleep position) and the effect of protective glasses on any such IOP rise.

Methods: A specially developed electronic epipalpebral pressure (EPP) sensor was attached to an eyelid of the right eye of all participants: 11 patients with primary open-angle glaucoma and 11 healthy volunteers. During calibration, mechanical pressure was applied to the EPP sensor taped to the lower eyelid and the IOP was measured simultaneously at the slit lamp by Goldmann applanation tonometry.

Postoperative aqueous humour flare as a surrogate marker for proliferative vitreoretinopathy development.

Purpose: As some surgical procedures have been shown to increase postoperative flare values and thus contribute to blood-ocular barrier breakdown, retinal reattachment surgery might influence the risk of developing proliferative vitreoretinopathy (PVR). Therefore, we investigated whether postoperative aqueous flare values are a surrogate marker for the development of postoperative PVR.

Methods: We prospectively included 195 patients with primary rhegmatogenous retinal detachment (RRD) and measured aqueous laser flare preoperatively, and at 2 and 6 weeks postoperatively.

Splenic autonomic denervation increases inflammatory status but does not aggravate atherosclerotic lesion development.

Unlabelled: The brain plays a prominent role in the regulation of inflammation. Immune cells are under control of the so-called cholinergic anti-inflammatory reflex, mainly acting via autonomic innervation of the spleen. Activation of this reflex inhibits the secretion of proinflammatory cytokines and may reduce the development of atherosclerosis.

Hematopoietic α7 nicotinic acetylcholine receptor deficiency increases inflammation and platelet activation status, but does not aggravate atherosclerosis.

Background: The autonomic nervous system attenuates inflammation through activation of the α7 nicotinic acetylcholine receptor (α7nAChR), a pathway termed the cholinergic anti-inflammatory reflex. Interestingly, α7nAChR is expressed on immune cells and platelets, both of which play a crucial role in the development of atherosclerosis.

Objective: To investigate the role of hematopoietic α7nAChR in inflammation and platelet function in atherosclerotic ldlr(-/-) mice and to identify its consequences for atherosclerotic lesion development.

Inhibition of the central melanocortin system decreases brown adipose tissue activity.

The melanocortin system is an important regulator of energy balance, and melanocortin 4 receptor (MC4R) deficiency is the most common monogenic cause of obesity. We investigated whether the relationship between melanocortin system activity and energy expenditure (EE) is mediated by brown adipose tissue (BAT) activity. Therefore, female APOE*3-Leiden.

Sympathetic nervous system control of triglyceride metabolism: novel concepts derived from recent studies.

Important players in triglyceride (TG) metabolism include the liver (production), white adipose tissue (WAT) (storage), heart and skeletal muscle (combustion to generate ATP), and brown adipose tissue (BAT) (combustion toward heat), the collective action of which determine plasma TG levels. Interestingly, recent evidence points to a prominent role of the hypothalamus in TG metabolism through innervating the liver, WAT, and BAT mainly via sympathetic branches of the autonomic nervous system. Here, we review the recent findings in the area of sympathetic control of TG metabolism.

Macrophage ABCA2 deletion modulates intracellular cholesterol deposition, affects macrophage apoptosis, and decreases early atherosclerosis in LDL receptor knockout mice.

Objective: The ABCA2 transporter shares high structural homology to ABCA1, which is crucial for the removal of excess cholesterol from macrophages and, by extension, in atherosclerosis. It has been suggested that ABCA2 sequesters cholesterol inside the lysosomes, however, little is known of the macrophage-specific role of ABCA2 in regulating lipid homeostasis in vivo and in modulating susceptibility to atherosclerosis.

Methods: Chimeras with dysfunctional macrophage ABCA2 were generated by transplantation of bone marrow from ABCA2 knockout (KO) mice into irradiated LDL receptor (LDLr) KO mice.

Effects of deletion of macrophage ABCA7 on lipid metabolism and the development of atherosclerosis in the presence and absence of ABCA1.

ABCA7, a close relative of ABCA1 which facilitates cholesterol efflux to lipid-poor apoproteins, has been implicated in macrophage lipid efflux and clearance of apoptotic cells in in vitro studies. In the current study, we investigated the in vivo effects of macrophage ABCA7 deficiency on lipid metabolism and atherosclerosis. Chimeras with dysfunctional ABCA7 in macrophages and other blood cells were generated by transplantation of bone marrow from ABCA7 knockout (KO) mice into irradiated low-density lipoprotein receptor (LDLr) KO mice.

The effect of ABCG1 deficiency on atherosclerotic lesion development in LDL receptor knockout mice depends on the stage of atherogenesis.

Objective: As ABCG1 plays a role in cholesterol efflux, macrophage ABCG1 expression has been suggested to protect against atherosclerosis. However, we and others observed varying effects of ABCG1 deficiency on atherosclerotic lesion size. The objective of this study was to define the effect of ABCG1 deficiency during atherosclerotic lesion progression in LDL receptor knockout (LDLr(-/-)) mice.

Augmented atherogenesis in LDL receptor deficient mice lacking both macrophage ABCA1 and ApoE.

Aim: ABCA1 protects against atherosclerosis by facilitating cholesterol efflux from macrophage foam cells in the arterial wall to extracellular apolipoprotein (apo) A-I. In contrast to apoA-I, apoE is secreted by macrophages and can, like apoA-I, induce ABCA1-mediated cholesterol efflux. Yet, the combined effect of macrophage ABCA1 and apoE on lesion development is unexplored.

Genetic variant of the scavenger receptor BI in humans.

Background: In mice, the scavenger receptor class B type I (SR-BI) is essential for the delivery of high-density lipoprotein (HDL) cholesterol to the liver and steroidogenic organs. Paradoxically, elevated HDL cholesterol levels are associated with increased atherosclerosis in SR-BI-knockout mice. It is unclear what role SR-BI plays in human metabolism.

Deletion of the high-density lipoprotein receptor scavenger receptor BI in mice modulates thrombosis susceptibility and indirectly affects platelet function by elevation of plasma free cholesterol.

Objective: Scavenger receptor BI (SR-BI) is a cell surface receptor that promotes the selective uptake of cholesteryl esters from high-density lipoprotein (HDL) by the liver. In mice, SR-BI deficiency results in increased plasma HDL cholesterol levels and enhanced susceptibility to atherosclerosis. The aim of this study was to investigate the role of SR-BI deficiency on platelet function.

ATP-binding cassette transporters A1 and G1, HDL metabolism, cholesterol efflux, and inflammation: important targets for the treatment of atherosclerosis.

Atherosclerosis has been characterized as a chronic inflammatory response to cholesterol deposition in arteries. Plasma high density lipoprotein (HDL) levels bear a strong independent inverse relationship with atherosclerotic cardiovascular disease. One central antiatherogenic role of HDL is believed to be its ability to remove excessive peripheral cholesterol back to the liver for subsequent catabolism and excretion, a physiologic process termed reverse cholesterol transport (RCT).

Macrophage adipose triglyceride lipase deficiency attenuates atherosclerotic lesion development in low-density lipoprotein receptor knockout mice.

Objective: The consequences of macrophage triglyceride (TG) accumulation on atherosclerosis have not been studied in detail so far. Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme for the initial step in TG hydrolysis. Because ATGL knockout (KO) mice exhibit massive TG accumulation in macrophages, we used ATGL KO mice to study the effects of macrophage TG accumulation on atherogenesis.

Children's problems predict adults' DSM-IV disorders across 24 years.

Objective: The goal of this study was to determine continuities of a broad range of psychopathology from childhood into middle adulthood in a general population sample across a 24-year follow-up.

Method: In 1983, parent ratings of children's problems were collected with the Child Behavior Checklist (CBCL) in a general population sample of 2,076 children and young adolescents aged 4 to 16 years. In 2007, 24 years later, 1,339 of these individuals were reassessed with the CIDI, a standardized DSM-IV interview.

Developmental trajectories of child to adolescent externalizing behavior and adult DSM-IV disorder: results of a 24-year longitudinal study.

Objective: Childhood externalizing behavior is found to be relatively persistent. Developmental pathways within types of externalizing behavior have been recognized from childhood to adolescence. We aimed to describe the prediction of adult DSM-IV disorders from developmental trajectories of externalizing behavior over a period of 24 years on a longitudinal multiple birth cohort study of 2,076 children.

Restoration of high-density lipoprotein levels by cholesteryl ester transfer protein expression in scavenger receptor class B type I (SR-BI) knockout mice does not normalize pathologies associated with SR-BI deficiency.

Objective: Disruption of scavenger receptor class B type I (SR-BI) in mice impairs high-density lipoprotein (HDL)-cholesterol (HDL-C) delivery to the liver and induces susceptibility to atherosclerosis. In this study, it was investigated whether introduction of cholesteryl ester transfer protein (CETP) can normalize HDL-C transport to the liver and reduce atherosclerosis in SR-BI knockout (KO) mice.

Methods And Results: Expression of human CETP in SR-BI(KO) mice resulted in decreased plasma HDL-C levels, both on chow diet (1.

Macrophage ABCA5 deficiency influences cellular cholesterol efflux and increases susceptibility to atherosclerosis in female LDLr knockout mice.

Objectives: To determine the role of macrophage ATP-binding cassette transporter A5 (ABCA5) in cellular cholesterol homeostasis and atherosclerotic lesion development.

Methods And Results: Chimeras with dysfunctional macrophage ABCA5 (ABCA5(-M/-M)) were generated by transplantation of bone marrow from ABCA5 knockout (ABCA5(-/-)) mice into irradiated LDLr(-/-) mice. In vitro, bone marrow-derived macrophages from ABCA5(-M/-M) chimeras exhibited a 29% (P<0.

High-density lipoprotein: key molecule in cholesterol efflux and the prevention of atherosclerosis.

Accumulation of cholesterol by macrophages, leading to their transformation into foam cells is a key event in the initiation of atherosclerosis. As maintenance of cholesterol homeostasis in macrophages is essential to prevent foam cell formation, mechanisms by which macrophages export cellular cholesterol have been intensively investigated in recent years. Several epidemiological studies have shown that plasma levels of high-density lipoprotein (HDL) cholesterol are inversely correlated with the risk of atherosclerosis.

Predicting adult emotional and behavioral problems from externalizing problem trajectories in a 24-year longitudinal study.

The aim of this study was to examine the prediction of adult behavioral and emotional problems from developmental trajectories of externalizing behavior in a 24-years longitudinal population-based study of 2,076 children. The adult psychiatric outcome of these trajectories has not yet been examined. Trajectories of the four externalizing behavior types: aggression, opposition, property violations and status violations were determined separately through latent class growth analysis using data of five waves, covering ages 4-18 years.

Child to adult continuities of psychopathology: a 24-year follow-up.

Objective: To determine continuities of mental health problems of children across a 24-year follow-up period.

Method: In 1983, parent ratings of emotional and behavioral problems were collected with the Child Behavior Checklist (CBCL) in a general population sample of 2076 children. Twenty-four years later, 1365 participants completed Adult Self-Reports (ASR) to assess emotional and behavioral problems.

Independent protective roles for macrophage Abcg1 and Apoe in the atherosclerotic lesion development.

Objective: ATP-binding cassette transporter G1 (Abcg1) and apolipoprotein E (Apoe) play a role in macrophage cholesterol efflux and consequently the development of atherosclerosis. A possible interaction between Abcg1 and Apoe in cholesterol efflux was postulated, but the potential combined action of these proteins on atherosclerotic lesion formation is unclear.

Methods: LDL receptor knockout (KO) mice were transplanted with bone marrow from Abcg1/Apoe double KO (dKO) mice, their respective single knockouts, and wild-type (WT) controls and challenged with a high-fat/high-cholesterol diet for 6 weeks to induce atherosclerosis.