No abstract

During craniofacial development, cranial neural crest (CNC) cells migrate into the developing face and form bone through intramembranous ossification. Loss of JAGGED1 (JAG1) signaling in the CNC cells is associated with maxillary hypoplasia or maxillary bone deficiency (MBD) in mice and recapitulates the MBD seen in humans with Alagille syndrome. JAGGED1, a membranebound NOTCH ligand, is required for normal craniofacial development, and Jaggedl mutations in humans are known to cause Alagille Syndrome, which is associated with cardiac, biliary, and bone phenotypes and these children experience increased bony fractures. Previously, we demonstrated deficient maxillary osteogenesis in Wnt1-cre;Jagged f/f (Jag1CKO) mice by conditional deletion of Jagged1 in maxillary CNC cells. In this study, we investigated the JAG1 signaling pathways in a CNC cell line. Treatment with JAG1 induced osteoblast differentiation and maturation markers, Runx2 and Ocn, respectively, Alkaline Phosphatase (ALP) production, as well as classic NOTCH1 targets, Hes1 and Hey1. While JAG1-induced Hes1 and Hey1 expression levels were predictably

Objectives:To determine the frequency of obstructive sleep apnea (OSA), insomnia, restless legs, and other sleep symptoms in patients with cardiovascular disease and the association of these sleep disorders with quantitative cardiovascular measures.Methods: Study design was a cross-sectional survey and retrospective chart review. A questionnaire containing validated sleep symptoms was distributed to 202 patients with cardiovascular disease at a tertiary referral cardiology clinic. Following a focused review of these patients' medical charts, their questionnaire responses were examined for associations with clinical cardiovascular parameters.Results: Twenty-one percent of patients reported a prior diagnosis of OSA. A total of 115 patients (60%) had at least one additional sleep symptom. Clinically significant insomnia was significantly associated with heart disease (relative risk [RR] = 1.5, confidence interval [CI] = 1.1 to 2.1), prior myocardial infarction or cerebrovascular accident (RR = 2.1, CI = 1.2 to 3.6), and heart failure (RR = 2.2, CI = 1.3 to 3.8). Left ventricular ejection fraction was significantly associated with insomnia by Insomnia Severity Index (β = −0.52, CI = −0.89 to −0.13).Conclusion: The frequency of OSA in patients in this tertiary cardiology clinic was higher than the general population in the United States, with the majority of patients experiencing at least one sleep symptom. Insomnia symptoms were shown to be associated with multiple cardiovascular measures, including left ventricular ejection fraction. These findings imply an interwoven relationship between cardiovascular and sleep symptoms as captured by validated sleep questionnaires.

During craniofacial development, cranial neural crest (CNC) cells migrate into the developing face and form bone through intramembranous ossification. Loss of JAGGED1 (JAG1) signaling in the CNC cells is associated with maxillary hypoplasia or maxillary bone deficiency (MBD) in mice and recapitulates the MBD seen in humans with Alagille syndrome. JAGGED1, a membrane-bound NOTCH ligand, is required for normal craniofacial development, and Jagged1 mutations in humans are known to cause Alagille Syndrome, which is associated with cardiac, biliary, and bone phenotypes and these children experience increased bony fractures. Previously, we demonstrated deficient maxillary osteogenesis in Wnt1-cre;Jagged1 f/f (Jag1CKO) mice by conditional deletion of Jagged1 in maxillary CNC cells. In this study, we investigated the JAG1 signaling pathways in a CNC cell line. Treatment with JAG1 induced osteoblast differentiation and maturation markers, Runx2 and Ocn, respectively, Alkaline Phosphatase (ALP) production, as well as classic NOTCH1 targets, Hes1 and Hey1. While JAG1-induced Hes1 and Hey1 expression levels were predictably decreased after DAPT (NOTCH inhibitor) treatment, JAG1-induced Runx2 and Ocn levels were surprisingly constant in the presence of DAPT, indicating that JAG1 effects in the CNC cells are independent of the canonical NOTCH pathway. JAG1 treatment of CNC cells increased Janus Kinase 2 (JAK2) phosphorylation, which was refractory to DAPT treatment, highlighting the importance of the non-canonical NOTCH pathway during CNC cells osteoblast commitment. Pharmacologic inhibition of JAK2 phosphorylation, with and without DAPT treatment, upon JAG1 induction reduced ALP production and, Runx2 and Ocn gene expression.Collectively, these data suggest that JAK2 is an essential component downstream of a non-canonical JAG1-NOTCH1 pathway through which JAG1 stimulates expression of osteoblast-specific gene targets in CNC cells that contribute to osteoblast differentiation and bone mineralization.

The majority of aqueous SLIT patients perceived their compliance to be excellent, although, based on a previous study, these patients did not reach excellent compliance benchmarks. Inconvenience of clinic visits and cost of therapy were found to be the most common barriers to care. Despite what providers perceived as less-than-excellent compliance, 82% of patients reported symptom improvement with SLIT.