Lyve1-Driven Nras Causes Edema, Enlarged Lymphatic Vessels, and Hepatic Vascular Defects in Embryonic Mice.

Background: Kaposiform lymphangiomatosis (KLA) is a complex lymphatic anomaly associated with a somatic activating NRAS p.Q61R (NRAS) mutation. KLA is characterized by malformed lymphatic vessels that can lead to effusions and coagulopathy.

Comparison of American and European Guideline Recommendations for Diagnostic Workup and Secondary Prevention of Ischemic Stroke and Transient Ischemic Attack.

Guidelines help to facilitate treatment decisions based on available evidence, and also to provide recommendations in areas of uncertainty. In this paper, we compare the recommendations for stroke workup and secondary prevention of ischemic stroke and transient ischemic attack of the American Heart Association (AHA)/American Stroke Association (ASA) with the European Stroke Organization (ESO) guidelines. The primary aim of this paper is to offer clinicians guidance by identifying areas where there is consensus and where consensus is lacking, in the absence or presence of high-level evidence.

NRAS mutation drives elevated angiopoietin-2 expression in human endothelial cells and a genetic mouse model.

Background: Angiopoietin-2 (Ang-2) is increased in the blood of patients with kaposiform lymphangiomatosis (KLA) and kaposiform hemangioendothelioma (KHE). While the genetic causes of KHE are not clear, a somatic activating NRAS mutation has been found in the lesions of KLA patients.

Procedure: Our study tested the hypothesis that the NRAS mutation drives elevated Ang-2 expression in endothelial cells.

Performance of a Diagnostic Model for the Presence of Unruptured Intracranial Aneurysms in the General Population.

Introduction: The prevalence of unruptured intracranial aneurysms (UIAs) in the general population is 3%. Aneurysmal subarachnoid hemorrhage can be prevented by screening for UIAs followed by monitoring and, if needed, preventive neurosurgical or endovascular treatment of identified UIAs. Therefore, we developed a diagnostic model for the presence of UIAs in the general population to help identify persons at high risk of having UIAs.

Kaposiform lymphangiomatosis: Diagnosis, pathogenesis, and treatment.

Kaposiform lymphangiomatosis (KLA) is a life-threatening rare disease that can cause substantial morbidity, mortality, and social burdens for patients and their families. Diagnosis often occurs long after initial symptoms, and there are few centers in the world with the expertise to diagnose and care for patients with the disease. KLA is a lymphatic anomaly and significant advancements have been made in understanding its pathogenesis and etiology since its first description in 2014.

Surveillance of Unruptured Intracranial Aneurysms: Cost-Effectiveness Analysis for 3 Countries.

Background And Objectives: No consensus exists on adequate surveillance of conservatively managed unruptured intracranial aneurysms (UIAs). We aimed to determine optimal MRI surveillance strategies for the growth of UIAs using cost-effectiveness analysis. A secondary aim was to develop a clinical tool for personalizing UIA surveillance.

NRAS mutation in human endothelial cells causes vascular malformations.

Somatic mutations in NRAS drive the pathogenesis of melanoma and other cancers but their role in vascular anomalies and specifically human endothelial cells is unclear. The goals of this study were to determine whether the somatic-activating NRAS mutation in human endothelial cells induces abnormal angiogenesis and to develop in vitro and in vivo models to identify disease-causing pathways and test inhibitors. Here, we used mutant NRAS and wild-type NRAS (NRAS) expressing human endothelial cells in in vitro and in vivo angiogenesis models.

Kaposiform lymphangiomatosis treated with multimodal therapy improves coagulopathy and reduces blood angiopoietin-2 levels.

Kaposiform lymphangiomatosis (KLA) is a rare, life-threatening congenital lymphatic malformation. Diagnosis is often delayed due to complex indistinct symptoms. Blood angiopoietin-2 (ANG2) levels are elevated in KLA and may be useful as a biomarker to monitor disease status.

Determinants of the Presence and Size of Intracranial Aneurysms in the General Population: The Rotterdam Study.

Background And Purpose: The prevalence of unruptured intracranial aneurysms (UIAs) in the adult population is ≈3%. Rupture of an intracranial aneurysm can have devastating consequences, which emphasizes the importance of identification of potentially modifiable determinants for the presence and size of UIAs. Our aim was to study the association of a broad spectrum of potential determinants with the presence and size of UIAs in a general adult population.

Constitutively active PIK3CA mutations are expressed by lymphatic and vascular endothelial cells in capillary lymphatic venous malformation.

Capillary lymphatic venous malformations (CLVM) are complex vascular anomalies characterized by aberrant and enlarged lymphatic and blood vessels. CLVM appear during fetal development and enlarge after birth, causing life-long complications such as coagulopathy, pulmonary embolism, chronic pain, and disfigurement. Treatment includes surgical debulking, amputation, and recurrent sclerotherapy.

Cellular and molecular mechanisms of PIK3CA-related vascular anomalies.

The phosphoinositide 3-kinase (PI3K) pathway is a major mediator of growth factor signaling, cell proliferation and metabolism. Somatic gain-of-function mutations in , the catalytic subunit of PI3K, have recently been discovered in a number of vascular anomalies. The timing and origin of these mutations remain unclear although they are believed to occur during embryogenesis.

Signaling pathways and inhibitors of cells from patients with kaposiform lymphangiomatosis.

Background: Kaposiform lymphangiomatosis (KLA) is a rare lymphatic anomaly with significant morbidity and mortality. KLA is characterized by diffuse multifocal lesions comprised of focal areas of "kaposiform" spindled cells accompanying malformed lymphatic channels. The goal of this study was to identify activated signaling pathways in cells isolated from three KLA patients for the purpose of testing new therapies.

Ponatinib Combined With Rapamycin Causes Regression of Murine Venous Malformation.

Objective- Venous malformations (VMs) arise from developmental defects of the vasculature and are characterized by massively enlarged and tortuous venous channels. VMs grow commensurately leading to deformity, obstruction of vital structures, bleeding, and pain. Most VMs are associated with the activating mutation L914F in the endothelial cell (EC) tyrosine kinase receptor TIE2.

Hypoxia-induced Pulmonary Hypertension in Different Mouse Strains: Relation to Transcriptome.

Patients with pulmonary arterial hypertension (PAH) can harbor mutations in several genes, most commonly in BMPR2. However, disease penetrance in patients with BMPR2 mutations is low. In addition, most patients do not carry known PAH gene mutations, suggesting that other factors determine susceptibility to PAH.

Independent and combined effects of airway remodelling and allergy on airway responsiveness.

Airway remodelling and allergic inflammation are key features of airway hyperresponsiveness (AHR) in asthma; however, their interrelationships are unclear. The present study investigated the separate and combined effects of increased airway smooth muscle (ASM) layer thickness and allergy on AHR. We integrated a protocol of ovalbumin (OVA)-induced allergy into a non-inflammatory mouse model of ASM remodelling induced by conditional and airway-specific expression of transforming growth factor-α (TGF-α) in early growth response-1 (Egr-1)-deficient transgenic mice, which produced thickening of the ASM layer following ingestion of doxycycline.

Optical coherence tomography-based contact indentation for diaphragm mechanics in a mouse model of transforming growth factor alpha induced lung disease.

This study tested the utility of optical coherence tomography (OCT)-based indentation to assess mechanical properties of respiratory tissues in disease. Using OCT-based indentation, the elastic modulus of mouse diaphragm was measured from changes in diaphragm thickness in response to an applied force provided by an indenter. We used a transgenic mouse model of chronic lung disease induced by the overexpression of transforming growth factor-alpha (TGF-α), established by the presence of pleural and peribronchial fibrosis and impaired lung mechanics determined by the forced oscillation technique and plethysmography.

Angiopoietins as serum biomarkers for lymphatic anomalies.

Vascular anomalies can cause significant morbidity and mortality. Advances in diagnosis will be improved if noninvasive biomarkers can be identified, as obtaining a tissue biopsy can worsen the disease and precipitate complications. The goal of this study was to identify biomarkers for vascular anomaly patients to aid diagnosis and potentially give insights into pathogenesis.

Placenta growth factor augments airway hyperresponsiveness via leukotrienes and IL-13.

Airway hyperresponsiveness (AHR) affects 55%-77% of children with sickle cell disease (SCD) and occurs even in the absence of asthma. While asthma increases SCD morbidity and mortality, the mechanisms underlying the high AHR prevalence in a hemoglobinopathy remain unknown. We hypothesized that placenta growth factor (PlGF), an erythroblast-secreted factor that is elevated in SCD, mediates AHR.

Epidermal growth factor receptor signalling regulates granulocyte-macrophage colony-stimulating factor production by airway epithelial cells and established allergic airway disease.

Background: Airway epithelial cells (AEC) are increasingly recognized as a major signalling centre in the pathogenesis of allergic asthma. A previous study demonstrated that epithelial growth factor receptor (EGFR) signalling in AEC regulated key features of allergic airway disease. However, it is unclear what mediators are regulated by EGFR signalling in AEC, although the production of the pro-inflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is EGFR dependent in keratinocytes.

Diesel exhaust particle exposure increases severity of allergic asthma in young mice.

Background: Epidemiologic studies have reported an association between diesel exhaust particle (DEP) exposure, allergic sensitization, and childhood wheezing, although the mechanisms remain unclear. While DEP is known to augment allergic responses in adult animal models, its effects on sensitization and asthma severity in young animals is unknown.

Objective: To examine the impact of different doses of DEP and allergen co-exposure on allergic sensitization and asthma characteristics in young mice, and whether Th17 as well as Th2 responses are induced.