ABSTRACT
The ductus arteriosus (DA) is a unique fetal vascular shunt, which allows blood to bypass the developing lungs in utero. After birth, changes in complex signaling pathways lead to constriction and permanent closure of the DA. The persistent patency of the DA (PDA) is a common disorder in preterm infants, yet the underlying causes of PDA are not fully defined. Although limits on the availability of human DA tissues prevent comprehensive studies on the mechanisms of DA function, mouse models have been developed that reveal critical pathways in DA regulation. Over 20 different transgenic models of PDA in mice have been described, with implications for human DA biology. Similarly, we enumerate 224 human single-gene syndromes that are associated with PDA, including a small subset that consistently feature PDA as a prominent phenotype. Comparison and functional analyses of these genes provide insight into DA development and identify key regulatory pathways that may serve as potential therapeutic targets for the management of PDA.
Subject(s)
Ductus Arteriosus, Patent , Ductus Arteriosus , Animals , Disease Models, Animal , Ductus Arteriosus/metabolism , Ductus Arteriosus, Patent/drug therapy , Ductus Arteriosus, Patent/etiology , Humans , Infant, Newborn , Infant, Premature , MiceABSTRACT
BACKGROUND: Indomethacin treatment for patent ductus arteriosus (PDA) is associated with acute kidney injury (AKI). Fenoldopam, a dopamine (DA) DA1-like receptor agonist dilates the renal vasculature and may preserve renal function during indomethacin treatment. However, limited information exists on DA receptor-mediated signaling in the ductus and fenoldopam may prevent ductus closure given its vasodilatory nature. METHODS: DA receptor expression in CD-1 mouse vessels was analyzed by qPCR and immunohistochemistry. Concentration-response curves were established using pressure myography. Pretreatment with SCH23390 (DA1-like receptor antagonist), phentolamine (α -adrenergic receptor antagonist) or indomethacin addressed mechanisms for DA-induced changes. Fenoldopam's effects on postnatal ductus closure were evaluated in vivo. RESULTS: DA1 receptors were expressed equally in ductus and aorta. High-dose DA induced modest vasoconstriction under newborn O2 conditions. Phentolamine inhibited DA-induced constriction, while SCH23390 augmented constriction, consistent with a vasodilatory role for DA1 receptors. Despite this, fenoldopam had little effect on ductus tone nor indomethacin- or O2-induced constriction and did not impair postnatal closure in vivo. CONCLUSION(S): DA receptors are present in the ductus but have limited physiologic effects. DA-induced ductus vasoconstriction is mediated via α-adrenergic pathways. The absence of DA1-mediated impairment of ductus closure supports the study of potential role for fenoldopam during PDA treatment.
Subject(s)
Dopamine Agonists/pharmacology , Dopamine/metabolism , Ductus Arteriosus, Patent/drug therapy , Ductus Arteriosus/drug effects , Fenoldopam/pharmacology , Receptors, Dopamine D1/agonists , Vasoconstriction/drug effects , Vasodilation/drug effects , Vasodilator Agents/pharmacology , Animals , Ductus Arteriosus/metabolism , Ductus Arteriosus/physiopathology , Ductus Arteriosus, Patent/metabolism , Ductus Arteriosus, Patent/physiopathology , Female , Indomethacin/toxicity , Mice , Oxygen/toxicity , Pregnancy , Receptors, Dopamine D1/metabolism , Signal TransductionABSTRACT
BACKGROUND: Hepatitis C (HCV) affects over 2.2 million people in the United States and is associated with liver cirrhosis and gallstone formation. However, cholecystectomy outcomes of HCV patients compared to non-HCV patients are not well studied. This study aims to examine differences in cholecystectomy outcomes among patients with untreated, treated, and no HCV history. STUDY DESIGN: A retrospective cohort study was conducted at a single institution including data over a 12-year period. Patients were excluded if they had a prior chronic hepatitis B or HIV diagnosis. Non-HCV patients were matched to HCV patients based on age, sex, and race/ethnicity. RESULTS: We identified 66 patients with untreated HCV and 33 patients with treated HCV. 324 non-HCV patients were matched to the HCV cohort. The overall postoperative complication rate was 10.9%. There was no statistically significant difference in postoperative complication rates between groups (p=0.71). There was no significant difference in the level of intervention required to treat these complications based on the Clavien-Dindo classification (p=0.97), postoperative ICU admission (p=0.43), or reoperation rate (p=0.45). CONCLUSION: Despite having a longer average length of stay and increased risk for intraoperative blood product transfusion, both untreated and treated HCV patients have similar rates of postoperative complications and complication severity compared to controls. These findings suggest that HCV patients tolerate cholecystectomy at a comparable level to non-HCV patients. The lack of difference in postoperative complication rates between untreated and treated HCV patients indicates that lack of antiviral treatment should not delay cholecystectomy.