Prescription psychostimulant use, admissions and treatment initiation and retention in pregnant people with opioid use disorder.

While attention deficit hyperactivity disorder is common among people with addiction, the risks and benefits of attention deficit hyperactivity disorder medication in pregnant people with opioid use disorder are poorly understood. Here, using US multistate administrative data, we examined 3,247 pregnant people initiating opioid use disorder treatment, of whom 5% received psychostimulants. Compared to peers not receiving psychostimulants, the psychostimulant cohort had greater buprenorphine (adjusted relative risk 1.

Colony stimulating factor 1 receptor (Csf1r) expressing cell ablation in mafia (macrophage-specific Fas-induced apoptosis) mice alters monocyte landscape and atherosclerotic lesion characteristics.

Macrophage infiltration and accumulation in the atherosclerotic lesion are associated with plaque progression and instability. Depletion of macrophages from the lesion might provide valuable insights into plaque stabilization processes. Therefore, we assessed the effects of systemic and local macrophage depletion on atherogenesis.

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.

Perspective: Hepatocyte-Directed Base Editing as Novel Treatment for Human Dyslipidemia-Current Status and Remaining Challenges.

Hyperlipidemia is a major risk factor for the development of atherosclerotic cardiovascular disease. Lipid-lowering drug therapies therefore still form the heart of the ongoing battle against the occurrence of cardiovascular events. However, in light of the important improvements in gene interference and editing that have been made during the last 2 decades, gene therapy-the genetic modification of cells to produce a permanent therapeutic effect-is currently employed to relief hypercholesterolemic subjects from their potential (chronic) cardiovascular disease burden.

Genetic Analysis Reveals a Distinct Lineage of Hog Deer (Axis porcinus) in Kratie Province, Cambodia.

The hog deer (Axis porcinus) is an endangered cervid with drastic population declines. There are 2 recognized subspecies of hog deer: A. p.

Magnetic resonance imaging contrast-enhancement with superparamagnetic iron oxide nanoparticles amplifies macrophage foam cell apoptosis in human and murine atherosclerosis.

Aims: (Ultra) Small superparamagnetic iron oxide nanoparticles, (U)SPIO, are widely used as magnetic resonance imaging contrast media and assumed to be safe for clinical applications in cardiovascular disease. As safety tests largely relied on normolipidaemic models, not fully representative of the clinical setting, we investigated the impact of (U)SPIOs on disease-relevant endpoints in hyperlipidaemic models of atherosclerosis.

Methods And Results: RAW264.

N-Acetyl Galactosamine Targeting: Paving the Way for Clinical Application of Nucleotide Medicines in Cardiovascular Diseases.

While the promise of oligonucleotide therapeutics, such as (chemically modified) ASO (antisense oligonucleotides) and short interfering RNAs, is undisputed from their introduction onwards, their unfavorable pharmacokinetics and intrinsic capacity to mobilize innate immune responses, were limiting widespread clinical use. However, these major setbacks have been tackled by breakthroughs in chemistry, stability and delivery. When aiming an intervention hepatic targets, such as lipid and sugar metabolism, coagulation, not to mention cancer and virus infection, introduction of N-acetylgalactosamine aided targeting technology has advanced the field profoundly and by now a dozen of N-acetylgalactosamine therapeutics for these indications have been approved for clinical use or have progressed to clinical trial stage 2 to 3 testing.

Impact of bone marrow ATP-binding cassette transporter A1 deficiency on atherogenesis is independent of the presence of the low-density lipoprotein receptor.

Background And Aims: There is extensive evidence from bone marrow transplantation studies that hematopoietic ATP binding cassette A1 (Abca1) is atheroprotective in low-density lipoprotein receptor (Ldlr) deficient mice. In contrast, studies using lysosyme M promoter-driven deletion of Abca1 in Ldlr deficient mice failed to show similar effects. It was hypothesized that the discrepancy between these studies might be due to the presence of Ldlr in bone marrow-derived cells in the transplantation model.

Disruption of Phospholipid Transfer Protein-Mediated High-Density Lipoprotein Maturation Reduces Scavenger Receptor BI Deficiency-Driven Atherosclerosis Susceptibility Despite Unexpected Metabolic Complications.

Objective: We tested the hypothesis that enlarged, dysfunctional HDL (high-density lipoprotein) particles contribute to the augmented atherosclerosis susceptibility associated with SR-BI (scavenger receptor BI) deficiency in mice. Approach and Results: We eliminated the ability of HDL particles to fully mature by targeting PLTP (phospholipid transfer protein) functionality. Particle size of the HDL population was almost fully normalized in male and female SR-BI×PLTP double knockout mice.

Empowering medical students as agents of curricular change: a value-added approach to student engagement in medical education.

One area in which medical students can add significant value is medical education, and involving them as key stakeholders in their education can have a profound impact on students and the institutions that serve them. However, detailed descriptions of the structure, implementation and quality of programs facilitating student engagement are lacking. We describe the structure of a novel student engagement program at the University of Illinois College of Medicine-Chicago (UICOM-Chicago) known as the Student Curricular Board (SCB).

Low human and murine Mcl-1 expression leads to a pro-apoptotic plaque phenotype enriched in giant-cells.

The anti-apoptotic protein myeloid cell leukemia 1 (Mcl-1) plays an important role in survival and differentiation of leukocytes, more specifically of neutrophils. Here, we investigated the impact of myeloid Mcl-1 deletion in atherosclerosis. Western type diet fed LDL receptor-deficient mice were transplanted with either wild-type (WT) or LysMCre Mcl-1 (Mcl-1) bone marrow.

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.

Essential Role of Histone Methyltransferase G9a in Rapid Tolerance to the Anxiolytic Effects of Ethanol.

Background: Tolerance to ethanol-induced anxiolysis promotes alcohol intake, thus contributing to alcohol use disorder development. Recent studies implicate histone deacetylase-mediated histone H3K9 deacetylation in regulating neuropeptide Y expression during rapid ethanol tolerance to the anxiolytic effects of ethanol. Furthermore, the histone methyltransferase, G9a, and G9a-mediated H3K9 dimethylation (H3K9me2) have recently emerged as regulators of addiction and anxiety; however, their role in rapid ethanol tolerance is unknown.

Removal of urea by electro-oxidation in a miniature dialysis device: a study in awake goats.

The key to success in developing a wearable dialysis device is a technique to safely and efficiently regenerate and reuse a small volume of dialysate in a closed-loop system. In a hemodialysis model in goats, we explored whether urea removal by electro-oxidation (EO) could be effectively and safely applied in vivo. A miniature dialysis device was built, containing 1 or 2 "EO units," each with 10 graphite electrodes, with a cumulative electrode surface of 585 cm per unit.

Evaluation of GalNAc-siRNA Conjugate Activity in Pre-clinical Animal Models with Reduced Asialoglycoprotein Receptor Expression.

The hepatocyte-specific asialoglycoprotein receptor (ASGPR) is an ideal candidate for targeted drug delivery to the liver due to its high capacity for substrate clearance from circulation together with its well-conserved expression and function across species. The development of GalNAc-siRNA conjugates, in which a synthetic triantennary N-acetylgalactosamine-based ligand is conjugated to chemically modified siRNA, has enabled efficient, ASGPR-mediated delivery to hepatocytes. To investigate the potential impact of variations in receptor expression on the efficiency of GalNAc-siRNA conjugate delivery, we evaluated the pharmacokinetics and pharmacodynamics of GalNAc-siRNA conjugates in multiple pre-clinical models with reduced receptor expression.

Leukocyte Bim deficiency does not impact atherogenesis in ldlr mice, despite a pronounced induction of autoimmune inflammation.

Proapoptotic Bcl-2 family member Bim is particularly relevant for deletion of autoreactive and activated T and B cells, implicating Bim in autoimmunity. As atherosclerosis is a chronic inflammatory process with features of autoimmune disease, we investigated the impact of hematopoietic Bim deficiency on plaque formation and parameters of plaque stability. Bim or wild type bone marrow transplanted ldlr mice were fed a Western type diet (WTD) for 5 or 10 weeks, after which they were immunophenotyped and atherosclerotic lesions were analyzed.

Emerging Role of Epigenetic Mechanisms in Alcohol Addiction.

Alcohol use disorder (AUD) is a complex brain disorder with an array of persistent behavioral and neurochemical manifestations. Both genetic and environmental factors are known to contribute to the development of AUD, and recent studies on alcohol exposure and subsequent changes in gene expression suggest the importance of epigenetic mechanisms. In particular, histone modifications and DNA methylation have emerged as important regulators of gene expression and associated phenotypes of AUD.

Hematopoietic arginase 1 deficiency results in decreased leukocytosis and increased foam cell formation but does not affect atherosclerosis.

Background And Aims: Arginase1 (Arg1), an M2 macrophage marker, plays a critical role in a number of immunological functions in macrophages, which are the main cell type facilitating atherosclerotic lesion development. Arg1 uses the substrate l-arginine to create l-ornithine, a precursor molecule required for collagen formation and vascular smooth muscle cell differentiation. By reducing l-arginine availability, Arg1 limits the production of nitric oxide (NO), a pro-atherogenic factor in macrophages.

Abca1 deficiency protects the heart against myocardial infarction-induced injury.

Background And Aims: We explored the role of ATP-binding cassette transporter A1 (Abca1), in post-myocardial infarction (MI) cardiac injury.

Methods: In Abca1(-/-) mice, wild type (WT) mice, and WT mice transplanted with Abca1(-/-) or WT bone marrow, an MI was induced in vivo. Furthermore, an ex vivo MI was induced in isolated Abca1(-/-) and WT hearts.

Hck/Fgr Kinase Deficiency Reduces Plaque Growth and Stability by Blunting Monocyte Recruitment and Intraplaque Motility.

Background: Leukocyte migration is critical for the infiltration of monocytes and accumulation of monocyte-derived macrophages in inflammation. Considering that Hck and Fgr are instrumental in this process, their impact on atherosclerosis and on lesion inflammation and stability was evaluated.

Methods And Results: Hematopoietic Hck/Fgr-deficient, LDLr(-/-) chimeras, obtained by bone marrow transplantation, had smaller but, paradoxically, less stable lesions with reduced macrophage content, overt cap thinning, and necrotic core expansion as the most prominent features.

Orp8 deficiency in bone marrow-derived cells reduces atherosclerotic lesion progression in LDL receptor knockout mice.

Introduction: Oxysterol binding protein Related Proteins (ORPs) mediate intracellular lipid transport and homeostatic regulation. ORP8 downregulates ABCA1 expression in macrophages and cellular cholesterol efflux to apolipoprotein A-I. In line, ORP8 knockout mice display increased amounts of HDL cholesterol in blood.

The epigenetic landscape of alcoholism.

Alcoholism is a complex psychiatric disorder that has a multifactorial etiology. Epigenetic mechanisms are uniquely capable of accounting for the multifactorial nature of the disease in that they are highly stable and are affected by environmental factors, including alcohol itself. Chromatin remodeling causes changes in gene expression in specific brain regions contributing to the endophenotypes of alcoholism such as tolerance and dependence.

Diet-induced (epigenetic) changes in bone marrow augment atherosclerosis.

Alterations in DNA methylation patterns in peripheral blood leukocytes precede atherosclerotic lesion development in mouse models of atherosclerosis and have been linked to cardiovascular death in patients. The aim of this study is to investigate the long-term changes induced by WTD feeding on BM cells and the consequences for atherosclerosis susceptibility. Hereto, WTD BM or Chow BM was transplanted into LDLR KO mice on chow.