Treatment of pediatric heterozygous familial hypercholesterolemia 7 years after the EAS recommendations: Real-world results from a large French cohort.

Background: Heterozygous familial hypercholesterolemia (HeFH) predisposes to premature cardiovascular diseases. Since 2015, the European Atherosclerosis Society has advocated initiation of statins at 8-10 years of age and a low-density lipoprotein cholesterol (LDL-C) target of <135 mg/dL. Longitudinal data from large databases on pharmacological management of pediatric HeFH are lacking.

ROCK2 interacts with p22phox to phosphorylate p47phox and to control NADPH oxidase activation in human monocytes.

Monocytes play a key role in innate immunity by eliminating pathogens, releasing high levels of cytokines, and differentiating into several cell types, including macrophages and dendritic cells. Similar to other phagocytes, monocytes produce superoxide anions through the NADPH oxidase complex, which is composed of two membrane proteins (p22phox and gp91phox/NOX2) and four cytosolic proteins (p47phox, p67phox, p40phox and Rac1). The pathways involved in NADPH oxidase activation in monocytes are less known than those in neutrophils.

Circulating PCSK9 Linked to Dyslipidemia in Lebanese Schoolchildren.

In adults, elevated levels of circulating Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) have been associated with increased Low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and worse cardiovascular outcomes. However, few studies analyzed the relation between PCSK9 and lipid parameters in pediatric populations. The aim of our study is to evaluate the distribution and the correlation of serum PCSK9 levels with lipid parameters in a sample of Lebanese school children.

Aortic Root Anatomy Is Related to the Bicuspid Aortic Valve Phenotype.

Background: Bicuspid aortic valve (BAV) is associated with an asymmetric (not circular) aortic root, resulting in variability in the aortic root diameter measurements obtained using different techniques. The objective of this study was to describe aortic root asymmetry, including its orientation in the thorax, in relation to the various phenotypes of BAV and its impact on aortic root diameter measurements obtained using transthoracic echocardiography.

Methods: Aortic root asymmetry, orientation of the largest root diameter, and orientation of the valve opening were studied using computed tomographic scans of patients with BAV without significant aortic valve dysfunction referred for evaluation of a thoracic aortic aneurysm.

Identification of a Variant in Gene as a Major Cause of Hypobetalipoproteinemia in Lebanese Families.

Familial hypobetalipoproteinemia (FHBL) is a codominant genetic disorder characterized by reduced plasma levels of low-density lipoprotein cholesterol and apolipoprotein B. To our knowledge, no study on FHBL in Lebanon and the Middle East region has been reported. Therefore, we conducted genetic studies in unrelated families and probands of Lebanese origin presenting with FHBL, in order to identify the causes of this disease.

A Giant Abdominal Aortic Aneurysm Revealing a Marfan Syndrome With a New FBN1 Mutation.

Marfan syndrome is a connective tissue disease that rarely presents first with peripheral aortic aneurysms. We highlight the case of a young man with Marfan syndrome presenting with an abdominal aortic aneurysm due to a heterozygous fibrillin-1 gene mutation.

APOE gene variants in primary dyslipidemia.

Apolipoprotein E (apoE) is a major apolipoprotein involved in lipoprotein metabolism. It is a polymorphic protein and different isoforms are associated with variations in lipid and lipoprotein levels and thus cardiovascular risk. The isoform apoE4 is associated with an increase in LDL-cholesterol levels and thus a higher cardiovascular risk compared to apoE3.

Pathogenic variants in THSD4, encoding the ADAMTS-like 6 protein, predispose to inherited thoracic aortic aneurysm.

Purpose: Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease with often unrecognized inherited forms. We sought to identify novel pathogenic variants associated with autosomal dominant inheritance of TAAD.

Methods: We analyzed exome sequencing data from 35 French TAAD families and performed next-generation sequencing capture panel of genes in 1114 unrelated TAAD patients.

Apocynin prevents GM-CSF-induced-ERK1/2 activation and -neutrophil survival independently of its inhibitory effect on the phagocyte NADPH oxidase NOX2.

Neutrophils are key cells in innate immunity and inflammation. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is known to enhance many neutrophil functions such as reactive oxygen species (ROS) production, degranulation and cell survival via the activation of the ERK1/2 pathway. ERK1/2 pathway activation is redox sensitive and could be modulated by ROS.

A new mutational hotspot in the SKI gene in the context of MFS/TAA molecular diagnosis.

SKI pathogenic variations are associated with Shprintzen-Goldberg Syndrome (SGS), a rare systemic connective tissue disorder characterized by craniofacial, skeletal and cardiovascular features. So far, the clinical description, including intellectual disability, has been relatively homogeneous, and the known pathogenic variations were located in two different hotspots of the SKI gene. In the course of diagnosing Marfan syndrome and related disorders, we identified nine sporadic probands (aged 2-47 years) carrying three different likely pathogenic or pathogenic variants in the SKI gene affecting the same amino acid (Thr180).

The Prolyl Isomerase Pin1 Controls Lipopolysaccharide-Induced Priming of NADPH Oxidase in Human Neutrophils.

Production of superoxide anion and other reactive oxygen species (ROS) by neutrophils has a vital role in host defense against microbes. However, over-production can induce cell injury participating to inflammation. Superoxide anion is produced by the phagocyte NADPH oxidase/NOX2, a multicomponent enzyme system consisting of six proteins: two trans-membrane proteins (gp91 and p22 ) and four soluble cytosolic proteins (p40 , p67 , p47 , and the small G-proteins, Rac1/2).

[Fenestration of a spontaneous coronary hematoma with life-threatening dissection: A case of recurrent and multivessel spontaneous coronary artery dissections in a young female].

The fenestration of a coronary artery hematoma is a therapeutic option in case of a life-threatening spontaneous coronary artery dissection, if the conservative treatment is not feasible. Here we present the case of a 34-year-old woman who presented three spontaneous coronary artery dissections, on three different arteries, over a period of twenty-one months. The diagnosis was confirmed by endovascular imaging.

Reference Expression Profile of Three Transcript Isoforms and Their Association with Clinical Variability in Marfan Syndrome.

Marfan syndrome (MFS) is a rare connective tissue disorder mainly due to mutations in the gene. Great phenotypic variability is notable for age of onset, the presence and absence, and the number and the severity of the symptoms. Our team showed that gene expression level was a good surrogate endpoint for severity of some MFS clinical features.

[ST-elevation myocardial infarction (STEMI) in the elderly].

Admission in cardiology departments of patients over 80 years old, even nonagenarians, for ST-segment elevation myocardial infarction (STEMI) is not uncommon in 2018. The management of these high risk and polypathological patients, with atypical clinical presentation, is not based on international guidelines or randomized studies, but rather on retrospective studies, expert consensus, and common sense. Each decision has to be individualized to the patient's situation.

Marfan Syndrome Variability: Investigation of the Roles of Sarcolipin and Calcium as Potential Transregulator of FBN1 Expression.

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder that displays a great clinical variability. Previous work in our laboratory showed that fibrillin-1 () messenger RNA (mRNA) expression is a surrogate endpoint for MFS severity. Therefore, an expression quantitative trait loci (eQTL) analysis was performed to identify trans-acting regulators of expression, and a significant signal reached genome-wide significant threshold on chromosome 11.

Association of modifiers and other genetic factors explain Marfan syndrome clinical variability.

Marfan syndrome (MFS) is a rare autosomal dominant connective tissue disorder related to variants in the FBN1 gene. Prognosis is related to aortic risk of dissection following aneurysm. MFS clinical variability is notable, for age of onset as well as severity and number of clinical manifestations.

Phagocyte NADPH oxidase: a multicomponent enzyme essential for host defenses.

Phagocytes such as neutrophils and monocytes play an essential role in host defenses against microbial pathogens. Reactive oxygen species (ROS), such as superoxide anion, hydrogen peroxide, the hydroxyl radical, and hypochlorous acid, together with microbicidal peptides and proteases, constitute their antimicrobial arsenal. The enzyme responsible for superoxide anion production and, consequently, ROS generation, is called NADPH oxidase or respiratory burst oxidase.

Vitamin E uncouples joint destruction and clinical inflammation in a transgenic mouse model of rheumatoid arthritis.

Objective: Reactive oxygen species are thought to play a role in rheumatoid arthritis (RA) in humans. We postulated that antioxidant treatment could have a beneficial effect in this disease. We therefore investigated the effects of vitamin E in the transgenic KRN/NOD mouse model of RA.

Presence of estrogen receptor beta in the human endometrium through the cycle: expression in glandular, stromal, and vascular cells.

The recent discovery of a new isoform of estrogen receptor (ER) beta has prompted the reexamination of estrogen action on target organs. Here, we describe the endometrial expression of human ERbeta and compare its distribution with that of ERalpha in the endometrial functional zone. Using immunocytochemistry with well characterized polyclonal antibodies against ERbeta, we have detected specific ERbeta expression in all endometrial compartments (glandular, stromal, and vascular); the specificity of the immunostaining is confirmed by lack of staining of the uterine sections with anti-ERbeta antibodies previously incubated with peptide preparation.

Suppression of arthritis and protection from bone destruction by treatment with TNP-470/AGM-1470 in a transgenic mouse model of rheumatoid arthritis.

Objective: We assessed the clinical and histologic features of angiogenesis inhibition in a transgenic mouse model of arthritis that closely resembles rheumatoid arthritis (RA) in humans.

Methods: KRN/NOD mice, which spontaneously develop arthritis, were treated with TNP-470, an angiogenesis inhibitor. Disease was monitored by use of clinical indices and histologic examinations; circulating blood levels of vascular endothelial growth factor were determined by enzyme-linked immunosorbent assay.

Anti-proteinase-3 (PR3) antibodies (C-ANCA) recognize various targets on the human umbilical vein endothelial cell (HUVEC) membrane.

Numerous studies suggest that C-ANCA are directly pathogenic in vasculitis by activating leucocytes (oxidative burst, enzyme release, endothelial cytotoxicity, etc.). We and others have shown that C-ANCA can also directly activate HUVEC, but the precise target on HUVEC is unknown.

Induction of interleukin-1 and subsequent tissue factor expression by anti-proteinase 3 antibodies in human umbilical vein endothelial cells.

Objective: To assess the ability of anti-proteinase 3 (anti-PR3) classic antineutrophil cytoplasmic antibodies (cANCA) to stimulate endothelial expression of tissue factor (TF), which is the main initiator of the coagulation cascade that can lead to endothelial injury and thrombosis in patients with Wegener's granulomatosis.

Methods: Human umbilical vein endothelial cells (HUVEC) were grown to confluence and stimulated with affinity-purified anti-PR3 antibodies, Igs from healthy subjects, and endotoxin (lipopolysaccharide) as positive control.

Results: TF activity was generated in anti-PR3-stimulated cells, as shown by a chromogenic test.

Antibodies to proteinase-3 mediate expression of intercellular adhesion molecule-1 (ICAM-1, CD 54).

We investigated the role of intercellular adhesion molecule-1 (ICAM-1) in the adhesion of polymorphonuclear neutrophils (PMN) to classic antineutrophil cytoplasmic antibody (C-ANCA)-treated endothelial cells, independently of cytokines. Human umbilical vein endothelial cells (HUVEC) grown to confluence in cytokine-free conditions were stimulated with C-ANCA sera and affinity-purified anti-proteinase 3 antibodies (PR3) from Wegener's granulomatosis (WG) patients. Non-activated PMN were added to treated HUVEC and adhesion was measured.