Circulating molecules reflect imaging biomarkers of hemorrhage in cerebral cavernous malformations.

Increases in mean lesional iron content by quantitative susceptibility mapping (QSM) by ≥6% and/or vascular permeability by dynamic contrast enhanced quantitative perfusion (DCEQP) by ≥40% on MRI have been associated with new symptomatic hemorrhage (SH) in cerebral cavernous malformations (CCMs). It is not known if plasma biomarkers can reflect these changes within the lesion proper. This cohort study enrolled 46 CCM patients with SH in the prior year.

Isolated Optic Nerve Relapse in a Pediatric Patient With T-Cell Lymphoblastic Leukemia: A Brief Report.

Isolated optic nerve (ON) relapse is a rare occurrence in lymphoblastic leukemia (LBL). A 10-year-old boy with T-LBL presented 8 months after diagnosis with blurred vision and thickening of right ON on magnetic resonance imaging consistent with relapse. Cerebrospinal fluid and bone marrow were negative for leukemia.

Mild Hypoxia Accelerates Cerebral Cavernous Malformation Disease Through CX3CR1-CX3CL1 Signaling.

Background: Heterogeneity in the severity of cerebral cavernous malformations (CCMs) disease, including brain bleedings and thrombosis that cause neurological disabilities in patients, suggests that environmental, genetic, or biological factors act as disease modifiers. Still, the underlying mechanisms are not entirely understood. Here, we report that mild hypoxia accelerates CCM disease by promoting angiogenesis, neuroinflammation, and vascular thrombosis in the brains of CCM mouse models.

Transcriptomic signatures of individual cell types in cerebral cavernous malformation.

Cerebral cavernous malformation (CCM) is a hemorrhagic neurovascular disease with no currently available therapeutics. Prior evidence suggests that different cell types may play a role in CCM pathogenesis. The contribution of each cell type to the dysfunctional cellular crosstalk remains unclear.

Trial Readiness of Cavernous Malformations With Symptomatic Hemorrhage, Part I: Event Rates and Clinical Outcome.

Background: Cerebral cavernous malformation with symptomatic hemorrhage (SH) are targets for novel therapies. A multisite trial-readiness project (https://www.clinicaltrials.

Trial Readiness of Cavernous Malformations With Symptomatic Hemorrhage, Part II: Biomarkers and Trial Modeling.

Background: Quantitative susceptibility mapping (QSM) and dynamic contrast-enhanced quantitative perfusion (DCEQP) magnetic resonance imaging sequences assessing iron deposition and vascular permeability were previously correlated with new hemorrhage in cerebral cavernous malformations. We assessed their prospective changes in a multisite trial-readiness project.

Methods: Patients with cavernous malformation and symptomatic hemorrhage (SH) in the prior year, without prior or planned lesion resection or irradiation were enrolled.

Inflammatory Mechanisms in a Neurovascular Disease: Cerebral Cavernous Malformation.

Cerebral cavernous malformation (CCM) is a common cerebrovascular malformation causing intracranial hemorrhage, seizures, and focal neurologic deficits. A unique CCM lesional inflammatory microenvironment has been shown to influence the clinical course of the disease. This review addresses the inflammatory cell infiltrate in the CCM lesion and the role of a defined antigen-driven immune response in pathogenicity.

mTORC1 Inhibitor Rapamycin Inhibits Growth of Cerebral Cavernous Malformation in Adult Mice.

Background: Cerebral cavernous malformations (CCMs) are vascular malformations that frequently cause stroke. CCMs arise due to loss of function in one of the genes that encode the CCM complex, a negative regulator of MEKK3-KLF2/4 signaling in vascular endothelial cells. Gain-of-function mutations in (encoding the enzymatic subunit of the PI3K (phosphoinositide 3-kinase) pathway associated with cell growth) synergize with CCM gene loss-of-function to generate rapidly growing lesions.

Cavernous Angioma Symptomatic Hemorrhage (CASH) Trial Readiness II: Imaging Biomarkers and Trial Modeling.

Background: Quantitative susceptibility mapping (QSM) and dynamic contrast enhanced quantitative perfusion (DCEQP) MRI sequences assessing iron deposition and vascular permeability were previously correlated with new hemorrhage in cavernous angiomas. We assessed their prospective changes in cavernous angiomas with symptomatic hemorrhage (CASH) in a multisite trial readiness project ( clinicaltrials.gov NCT03652181 ).

Impact of socioeconomics and race on clinical follow-up and trial enrollment and adherence in cerebral cavernous malformation.

Cerebral cavernous malformation (CCM) affects more than a million Americans but advanced care for symptomatic lesions and access to research studies is largely limited to referral academic centers MATERIALS AND METHODS: A cohort of CCM patients screened for research studies at an accredited center of excellence for CCM was analyzed. Demographics, lesion location, history of hemorrhage, insurance type and area of deprivation index (ADI) were collected. Primary outcomes were clinical follow-up within a year from initial evaluation, and enrollment and adherence in clinical trials among eligible subjects RESULTS: A majority (52.

Multidisciplinary coordinated care of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease).

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu disease, is a rare disorder with a case prevalence as high as one in 5000, causing arteriovenous malformations in multiple organ systems. HHT is familial with autosomal dominant inheritance, with genetic testing allowing confirmation of the diagnosis in asymptomatic kindreds. Common clinical manifestations are epistaxis and intestinal lesions causing anemia and requiring transfusions.

Plasma metabolites with mechanistic and clinical links to the neurovascular disease cavernous angioma.

Background: Cavernous angiomas (CAs) affect 0.5% of the population, predisposing to serious neurologic sequelae from brain bleeding. A leaky gut epithelium associated with a permissive gut microbiome, was identified in patients who develop CAs, favoring lipid polysaccharide producing bacterial species.

β1 integrin monoclonal antibody treatment ameliorates cerebral cavernous malformations.

β1 integrins are important in blood vessel formation and function, finely tuning the adhesion of endothelial cells to each other and to the extracellular matrix. The role of integrins in the vascular disease, cerebral cavernous malformation (CCM) has yet to be explored in vivo. Endothelial loss of the gene KRIT1 leads to brain microvascular defects, resulting in debilitating and often fatal consequences.

Circulating Plasma miRNA Homologs in Mice and Humans Reflect Familial Cerebral Cavernous Malformation Disease.

Patients with familial cerebral cavernous malformation (CCM) inherit germline loss of function mutations and are susceptible to progressive development of brain lesions and neurological sequelae during their lifetime. To date, no homologous circulating molecules have been identified that can reflect the presence of germ line pathogenetic CCM mutations, either in animal models or patients. We hypothesize that homologous differentially expressed (DE) plasma miRNAs can reflect the CCM germline mutation in preclinical murine models and patients.

Rapamycin in Cerebral Cavernous Malformations: What Doses to Test in Mice and Humans.

Cerebral cavernous malformations (CCMs) are hemorrhagic neurovascular lesions that affect more than 1 million people in the United States. Rapamycin inhibits CCM development and bleeding in murine models. The appropriate dosage to modify disease phenotype remains unknown.

Perfusion and Permeability MRI Predicts Future Cavernous Angioma Hemorrhage and Growth.

Background: Cerebral cavernous angioma (CA) is a capillary vasculopathy affecting more than a million Americans with a small fraction of cases demonstrating lesional bleed or growth with major clinical sequelae. Perfusion and permeability are fundamental features of CA pathophysiology, but their role as prognostic biomarkers is unclear.

Purpose: To investigate whether perfusion or permeability lesional descriptors derived from dynamic contrast-enhanced quantitative perfusion (DCEQP) magnetic resonance imaging (MRI) can predict subsequent lesional bleed/growth in the year following imaging.

Astrocytes propel neurovascular dysfunction during cerebral cavernous malformation lesion formation.

Cerebral cavernous malformations (CCMs) are common neurovascular lesions caused by loss-of-function mutations in 1 of 3 genes, including KRIT1 (CCM1), CCM2, and PDCD10 (CCM3), and generally regarded as an endothelial cell-autonomous disease. Here we reported that proliferative astrocytes played a critical role in CCM pathogenesis by serving as a major source of VEGF during CCM lesion formation. An increase in astrocyte VEGF synthesis is driven by endothelial nitric oxide (NO) generated as a consequence of KLF2- and KLF4-dependent elevation of eNOS in CCM endothelium.

Perfusion and permeability as diagnostic biomarkers of cavernous angioma with symptomatic hemorrhage.

Cavernous angiomas with symptomatic hemorrhage (CASH) have a high risk of rebleeding, and hence an accurate diagnosis is needed. With blood flow and vascular leak as established mechanisms, we analyzed perfusion and permeability derivations of dynamic contrast-enhanced quantitative perfusion (DCEQP) MRI in 745 lesions of 205 consecutive patients. Thirteen respective derivations of lesional perfusion and permeability were compared between lesions that bled within a year prior to imaging (N = 86), versus non-CASH (N = 659) using machine learning and univariate analyses.

The last frontier of globalization: Trade and foreign direct investment in healthcare.

Internationalizing far later than other sectors, healthcare has seen trade and foreign direct investment (FDI) grow in recent years. While part of the service economy, healthcare has unique features that distinguish it from other service sectors and imprint on its globalization and spillover patterns. In this paper, we review the trends in healthcare internationalization, its drivers, and the obstacles standing in the way.