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1.
J Clin Med ; 10(4)2021 Feb 11.
Article in English | MEDLINE | ID: mdl-33670210

ABSTRACT

Cardiac surgery employing cardiopulmonary bypass exposes infants to a high risk of morbidity and mortality. The objective of this study was to assess the utility of clinical and laboratory variables to predict the development of low cardiac output syndrome, a frequent complication following cardiac surgery in infants. We performed a prospective observational study in the pediatric cardiovascular ICU in an academic children's hospital. Thirty-one patients with congenital heart disease were included. Serum levels of nucleosomes and a panel of 20 cytokines were measured at six time points in the perioperative period. Cardiopulmonary bypass patients were characterized by increased levels of interleukin-10, -6, and -1α upon admission to the ICU compared to non-bypass cardiac patients. Patients developing low cardiac output syndrome endured longer aortic cross-clamp time and required greater inotropic support at 12 h postoperatively compared to bypass patients not developing the condition. Higher preoperative interleukin-10 levels and 24 h postoperative interleukin-8 levels were associated with low cardiac output syndrome. Receiver operating characteristic curve analysis demonstrated a moderate capability of aortic cross-clamp duration to predict low cardiac output syndrome but not IL-8. In conclusion, low cardiac output syndrome was best predicted in our patient population by the surgical metric of aortic cross-clamp duration.

2.
Orphanet J Rare Dis ; 11(1): 149, 2016 11 05.
Article in English | MEDLINE | ID: mdl-27816064

ABSTRACT

BACKGROUND: Schimke immuno-osseous dysplasia (SIOD) is a multisystemic disorder caused by biallelic mutations in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) gene. Changes in gene expression underlie the arteriosclerosis and T-cell immunodeficiency of SIOD; therefore, we hypothesized that SMARCAL1 deficiency causes the focal segmental glomerulosclerosis (FSGS) of SIOD by altering renal gene expression. We tested this hypothesis by gene expression analysis of an SIOD patient kidney and verified these findings through immunofluorescent analysis in additional SIOD patients and a genetic interaction analysis in Drosophila. RESULTS: We found increased expression of components and targets of the Wnt and Notch signaling pathways in the SIOD patient kidney, increased levels of unphosphorylated ß-catenin and Notch1 intracellular domain in the glomeruli of most SIOD patient kidneys, and genetic interaction between the Drosophila SMARCAL1 homologue Marcal1 and genes of the Wnt and Notch signaling pathways. CONCLUSIONS: We conclude that increased Wnt and Notch activity result from SMARCAL1 deficiency and, as established causes of FSGS, contribute to the renal disease of most SIOD patients. This further clarifies the pathogenesis of SIOD and will hopefully direct potential therapeutic approaches for SIOD patients.


Subject(s)
Arteriosclerosis/metabolism , Glomerulosclerosis, Focal Segmental/metabolism , Immunologic Deficiency Syndromes/metabolism , Kidney Diseases/metabolism , Nephrotic Syndrome/metabolism , Osteochondrodysplasias/metabolism , Pulmonary Embolism/metabolism , Receptors, Notch/metabolism , Wnt Proteins/metabolism , Animals , Arteriosclerosis/genetics , Child , Child, Preschool , DNA Helicases/genetics , DNA Helicases/metabolism , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Fluorescent Antibody Technique, Indirect , Glomerulosclerosis, Focal Segmental/genetics , Humans , Immunologic Deficiency Syndromes/genetics , Kidney Diseases/genetics , Male , Nephrotic Syndrome/genetics , Osteochondrodysplasias/genetics , Primary Immunodeficiency Diseases , Pulmonary Embolism/genetics , Wnt Proteins/genetics
3.
Pediatr Res ; 78(6): 609-17, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26309238

ABSTRACT

BACKGROUND: Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive disorder caused by mutations in SMARCAL1. A frequent complication is arteriosclerosis associated with reduced elastin expression; however, the mechanism underlying the reduced elastin expression remains unknown. METHODS: Expression of transcriptional regulators of elastin (ELN) and microRNA (miRNA) regulators of ELN messenger RNA (mRNA), ELN promoter methylation, and ELN mRNA poly(A) tail length were assessed by quantitative RT-PCR, bisulfite Sanger sequencing, and the Poly(A) Tail Length Assay Kit, respectively, in unaffected developing human aortae and in an SIOD aorta. RESULTS: Comparing unaffected fetal and adult aortae, ELN precursor mRNA (pre-mRNA) levels remained nearly constant, whereas mRNA levels declined by ~10(2)-fold. This corresponded with a reduction in poly(A) tail length but not with changes in the other parameters. In contrast, compared to the unaffected fetal aortae, the SIOD aorta had 18-fold less ELN pre-mRNA and 10(4)-fold less mRNA. This corresponded with increased expression of miRNA regulators and shorter ELN mRNA poly(A) tail lengths but not with altered expression of ELN transcriptional regulators or ELN promoter methylation. CONCLUSION: Posttranscriptional mechanisms account for the reduction in ELN mRNA levels in unaffected aortae, whereas transcriptional and posttranscriptional mechanisms reduce elastin expression in SIOD aorta and predispose to arteriosclerosis.


Subject(s)
Aorta/metabolism , Arteriosclerosis/genetics , Elastin/genetics , Immunologic Deficiency Syndromes/genetics , Nephrotic Syndrome/genetics , Osteochondrodysplasias/genetics , Pulmonary Embolism/genetics , RNA Precursors/genetics , RNA Processing, Post-Transcriptional , RNA, Messenger/genetics , Transcription, Genetic , Adolescent , Adult , Aorta/embryology , Aorta/pathology , Arteriosclerosis/embryology , Arteriosclerosis/metabolism , Arteriosclerosis/pathology , Case-Control Studies , Cells, Cultured , Child , Child, Preschool , DNA Methylation , Down-Regulation , Elastin/metabolism , Female , Gestational Age , Humans , Immunologic Deficiency Syndromes/embryology , Immunologic Deficiency Syndromes/metabolism , Immunologic Deficiency Syndromes/pathology , Male , MicroRNAs/genetics , MicroRNAs/metabolism , Middle Aged , Nephrotic Syndrome/embryology , Nephrotic Syndrome/metabolism , Nephrotic Syndrome/pathology , Osteochondrodysplasias/embryology , Osteochondrodysplasias/metabolism , Osteochondrodysplasias/pathology , Primary Immunodeficiency Diseases , Promoter Regions, Genetic , Pulmonary Embolism/embryology , Pulmonary Embolism/metabolism , Pulmonary Embolism/pathology , RNA Precursors/metabolism , RNA, Messenger/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism
4.
Orphanet J Rare Dis ; 7: 70, 2012 Sep 22.
Article in English | MEDLINE | ID: mdl-22998683

ABSTRACT

BACKGROUND: Arteriosclerosis and emphysema develop in individuals with Schimke immuno-osseous dysplasia (SIOD), a multisystem disorder caused by biallelic mutations in SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1). However, the mechanism by which the vascular and pulmonary disease arises in SIOD remains unknown. METHODS: We reviewed the records of 65 patients with SMARCAL1 mutations. Molecular and immunohistochemical analyses were conducted on autopsy tissue from 4 SIOD patients. RESULTS: Thirty-two of 63 patients had signs of arteriosclerosis and 3 of 51 had signs of emphysema. The arteriosclerosis was characterized by intimal and medial hyperplasia, smooth muscle cell hyperplasia and fragmented and disorganized elastin fibers, and the pulmonary disease was characterized by panlobular enlargement of air spaces. Consistent with a cell autonomous disorder, SMARCAL1 was expressed in arterial and lung tissue, and both the aorta and lung of SIOD patients had reduced expression of elastin and alterations in the expression of regulators of elastin gene expression. CONCLUSIONS: This first comprehensive study of the vascular and pulmonary complications of SIOD shows that these commonly cause morbidity and mortality and might arise from impaired elastogenesis. Additionally, the effect of SMARCAL1 deficiency on elastin expression provides a model for understanding other features of SIOD.


Subject(s)
Arteriosclerosis/physiopathology , Emphysema/physiopathology , Immunologic Deficiency Syndromes/physiopathology , Nephrotic Syndrome/physiopathology , Osteochondrodysplasias/physiopathology , Pulmonary Embolism/physiopathology , Adult , Arteriosclerosis/genetics , Autopsy , Child , Child, Preschool , DNA Helicases/genetics , Emphysema/genetics , Female , Humans , Immunohistochemistry , Immunologic Deficiency Syndromes/genetics , Male , Nephrotic Syndrome/genetics , Osteochondrodysplasias/genetics , Primary Immunodeficiency Diseases , Pulmonary Embolism/genetics
5.
Pharmacotherapy ; 31(6): 609-20, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21923445

ABSTRACT

Neuromuscular blocking agents (NMBAs) are often administered as a prolonged (> 24 hrs) continuous infusion in infants and children in the intensive care unit for a variety of reasons including facilitation of oxygenation and ventilation. No guidelines on the use of NMBAs in pediatric patients are available yet in the United States; however, pediatric guidelines are available in the United Kingdom. Based on a 2007 U.S. survey, the most commonly used nondepolarizing NMBAs for sustained neuromuscular blockade in critically ill children are pancuronium and vecuronium. Recent national drug shortages involving NMBAs have been reported for atracurium, cisatracurium, pancuronium, rocuronium, and vecuronium. Therefore, to explore alternative options for neuromuscular blockade, we conducted a literature search to identify articles evaluating prolonged use (> 24 hrs) of NMBAs administered by continuous infusion. The search was limited to English-language articles in the MEDLINE (1950-August 2010), EMBASE (1988-August 2010), International Pharmaceutical Abstracts (1970-August 2010), and Cochrane Library (1996-August 2010) databases. Relevant abstracts, reference citations, and manufacturers' product information were also reviewed. A total of 13 reports representing 208 children were included in the analysis. Many of the reports described wide interpatient variability in dosing for the specific NMBAs evaluated. Selection of the most appropriate NMBA should be based on the patient's clinical status, potential adverse effects, and pharmacoeconomics. All patients receiving sustained neuromuscular blockade should be monitored routinely to ensure that dosing is appropriate in order to obtain the desired level of blockade. The goal is to use the lowest dose possible in an effort to limit adverse effects or prolonged blockade.


Subject(s)
Critical Care/methods , Neuromuscular Blocking Agents/therapeutic use , Practice Guidelines as Topic , Child , Child, Preschool , Critical Illness , Dose-Response Relationship, Drug , Humans , Infant , Infant, Newborn , Infusions, Intravenous , Neuromuscular Blocking Agents/administration & dosage , Neuromuscular Blocking Agents/adverse effects , United Kingdom , United States
6.
J Pediatr Pharmacol Ther ; 16(1): 39-46, 2011 Jan.
Article in English | MEDLINE | ID: mdl-22477823

ABSTRACT

OBJECTIVES: The purpose of this study was to assess the appropriateness of weight-based dosing of continuous intravenous infusion of fentanyl in overweight/obese versus normal-weight children admitted to the pediatric intensive care unit (PICU). METHODS: This retrospective, pilot study included 5- to 12-year-old children admitted to the PICU over a 2-year period who received continuous intravenous infusion fentanyl for ≥ 4 days. The overweight/obese group included children with a body mass index (BMI) ≥ 85th percentile, while the control group included children with BMI < 85th percentile. The primary objective was to compare the number of fentanyl continuous intravenous infusion dosage changes required per day to achieve adequate sedation between groups. Secondarily, opioid withdrawal symptoms following the discontinuation of fentanyl and concomitant sedative/analgesic regimens were analyzed between groups. Student t tests and chi-square analyses were performed as appropriate, with an a priori alpha of p≤0.05. RESULTS: Sixteen normal-weight and 15 overweight/obese patients with 18 and 16 individual infusions were identified, respectively. No statistical difference was found between groups for the number of dosage changes per day, 0.92 versus 0.69 (p=0.16). Five patients in each group experienced withdrawal (p=0.71). The total number of concomitant bolus doses received was greater in the overweight/obese group but did not reach statistical significance. CONCLUSIONS: There was a numerical, but statistically nonsignificant difference in the number of sedative/analgesic bolus doses and dosing changes per day between groups. Larger studies are warranted to determine the optimal dosing strategy for continuous intravenous infusion fentanyl in overweight/obese children.

7.
J Pediatr Pharmacol Ther ; 15(1): 30-7, 2010 Jan.
Article in English | MEDLINE | ID: mdl-22477790

ABSTRACT

OBJECTIVES: Dexmedetomidine is an α(2)-adrenergic receptor agonist with sedative and analgesic effects in mechanically ventilated adults and children. Safety and efficacy data are limited in children. The purpose of this study is to retrospectively identify the incidence and types of adverse events noted in children receiving continuous infusions of dexmedetomidine and evaluate potential risk factors for adverse events. METHODS: Between July 1, 2006, and July 31, 2007, data were collected on all children (< 18 years) who received continuous infusions of dexmedetomidine. Data collection included demographics, dexmedetomidine regimen, and type/number of adverse events. The primary endpoint was the total number of adverse events noted, including: transient hypertension, hypotension, neurological manifestations, apnea, and bradycardia. Secondary endpoints included categorization of each type of adverse event and an assessment of risk factors. A logistic regression model was used to assess the relationship of adverse events with independent variables including length of ICU stay, cumulative dose, peak infusion rate, duration of therapy, PRISM III score, and bolus dose. RESULTS: Thirty-six patients received dexmedetomidine representing 41 infusions. The median age was 16 months (range, 0.1-204 months) and median PRISM III score was 2 (range, 0-18). Eighteen (43.9%) patients received a bolus dose of dexmedetomidine. The median cumulative dose (mcg/kg) and peak dose (mcg/kg/hr) were 8.5 (range, 2.2-193.7) and 0.5 (range, 0.2-0.7), respectively. Dexmedetomidine was continued for a median of 20 (range, 3-263) hours. Six (14.6%) patients were slowly tapered off the continuous infusions. Twenty-one adverse events were noted in 17 patients, including 4 neurologic manifestations. Fourteen patients required interventions for adverse events. ICU length of stay was the only independent risk factor (p=0.036) for development of adverse events. CONCLUSIONS: Several potential adverse events were noted with dexmedetomidine continuous infusions including possible neurological manifestations. Further studies are needed looking at adverse events associated with dexmedetomidine use in the pediatric population.

9.
Nat Med ; 13(10): 1185-92, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17873880

ABSTRACT

The cardioprotective effects of estrogen are mediated by receptors expressed in vascular cells. Here we show that 27-hydroxycholesterol (27HC), an abundant cholesterol metabolite that is elevated with hypercholesterolemia and found in atherosclerotic lesions, is a competitive antagonist of estrogen receptor action in the vasculature. 27HC inhibited both the transcription-mediated and the non-transcription-mediated estrogen-dependent production of nitric oxide by vascular cells, resulting in reduced estrogen-induced vasorelaxation of rat aorta. Furthermore, increasing 27HC levels in mice by diet-induced hypercholesterolemia, pharmacologic administration or genetic manipulation (by knocking out the gene encoding the catabolic enzyme CYP7B1) decreased estrogen-dependent expression of vascular nitric oxide synthase and repressed carotid artery reendothelialization. As well as antiestrogenic effects, there were proestrogenic actions of 27HC that were cell-type specific, indicating that 27HC functions as an endogenous selective estrogen receptor modulator (SERM). Taken together, these studies point to 27HC as a contributing factor in the loss of estrogen protection from vascular disease.


Subject(s)
Cardiotonic Agents/antagonists & inhibitors , Cardiotonic Agents/pharmacology , Estrogens/pharmacology , Hydroxycholesterols/pharmacology , Selective Estrogen Receptor Modulators/pharmacology , Animals , Aorta, Thoracic/drug effects , Binding, Competitive/drug effects , Cardiotonic Agents/metabolism , Cell Culture Techniques , Cell Line , Cells, Cultured , Cholesterol, Dietary/administration & dosage , DNA, Complementary , Dose-Response Relationship, Drug , Drug Administration Schedule , Estrogens/metabolism , Female , Glutathione Transferase/metabolism , Humans , Hydroxycholesterols/administration & dosage , Hydroxycholesterols/blood , Inhibitory Concentration 50 , Injections, Subcutaneous , Kidney/cytology , Kinetics , Male , Mice , Mice, Knockout , Nitric Oxide/antagonists & inhibitors , Nitric Oxide Synthase Type II/antagonists & inhibitors , Nitric Oxide Synthase Type III , RNA, Messenger/metabolism , Receptors, Estrogen/antagonists & inhibitors , Receptors, Estrogen/genetics , Recombinant Fusion Proteins/antagonists & inhibitors , Selective Estrogen Receptor Modulators/administration & dosage , Selective Estrogen Receptor Modulators/blood , Vasodilation/drug effects
10.
Circ Res ; 100(10): 1452-9, 2007 May 25.
Article in English | MEDLINE | ID: mdl-17446434

ABSTRACT

C-reactive protein (CRP) is an acute-phase reactant that is positively associated with cardiovascular disease risk and endothelial dysfunction. In cell culture, CRP decreases the expression of endothelial NO synthase (eNOS), which regulates diverse endothelial cell (EC) functions including migration. To determine whether CRP alters EC gene expression and phenotype in vivo, we studied CF1 transgenic mice expressing rabbit CRP (CF1-CRP) regulated by the phosphoenolpyruvate carboxykinase promoter such that levels could be altered by changing carbohydrate intake. Compared with CF1 controls with CRP of <1 microg/mL, carotid artery reendothelialization after perivascular electric injury was blunted in CF1-CRP mice, with CRP levels as low as 9 microg/mL. eNOS mRNA and enzyme abundance in carotid arteries was also blunted by CRP at 9 microg/mL in vivo, and ex vivo studies of isolated arteries showed that this occurs via direct action on the endothelium. The impaired reendothelialization with CRP was mimicked by NOS antagonism in CF1 mice; conversely, in cultured ECs CRP attenuation of migration was prevented by exogenous NO. Studies of EC transfected with human eNOS 5' flanking sequence fused to luciferase indicated that CRP decreases eNOS gene transcription. Both mutagenesis and electrophoretic mobility shift assays further revealed that CRP-responsive elements reside within the first 79 bp of the eNOS promoter. Thus, CRP downregulates eNOS and attenuates reendothelialization in vivo in mice, and this action of CRP on eNOS is mediated at the level of gene transcription.


Subject(s)
C-Reactive Protein/physiology , Endothelial Cells/physiology , Nitric Oxide Synthase Type III/antagonists & inhibitors , Animals , Carotid Arteries/physiology , Cattle , Cell Movement , Cells, Cultured , Down-Regulation , Humans , Mice , Mice, Inbred C57BL , Mice, Transgenic , Nitric Oxide Synthase Type III/genetics , Promoter Regions, Genetic , RNA, Messenger/analysis
11.
Circ Res ; 98(1): 63-72, 2006 Jan 06.
Article in English | MEDLINE | ID: mdl-16339487

ABSTRACT

Vascular disease risk is inversely related to circulating levels of high-density lipoprotein (HDL) cholesterol. However, the mechanisms by which HDL provides vascular protection are unclear. The disruption of endothelial monolayer integrity is an important contributing factor in multiple vascular disorders, and vascular lesion severity is tempered by enhanced endothelial repair. Here, we show that HDL stimulates endothelial cell migration in vitro in a nitric oxide-independent manner via scavenger receptor B type I (SR-BI)-mediated activation of Rac GTPase. This process does not require HDL cargo molecules, and it is dependent on the activation of Src kinases, phosphatidylinositol 3-kinase, and p44/42 mitogen-activated protein kinases. Rapid initial stimulation of lamellipodia formation by HDL via SR-BI, Src kinases, and Rac is also demonstrable. Paralleling the in vitro findings, carotid artery reendothelialization after perivascular electric injury is blunted in apolipoprotein A-I(-/-) mice, and reconstitution of apolipoprotein A-I expression rescues normal reendothelialization. Furthermore, reendothelialization is impaired in SR-BI(-/-) mice. Thus, HDL stimulates endothelial cell migration via SR-BI-initiated signaling, and these mechanisms promote endothelial monolayer integrity in vivo.


Subject(s)
Endothelial Cells/drug effects , Lipoproteins, HDL/pharmacology , Scavenger Receptors, Class B/physiology , Animals , Apolipoprotein A-I/physiology , Cattle , Cell Movement/drug effects , Cells, Cultured , Endothelial Cells/cytology , Male , Mice , Mice, Inbred C57BL , Nitric Oxide Synthase Type III/physiology , rac GTP-Binding Proteins/physiology , src-Family Kinases/physiology
12.
Circ Res ; 97(11): 1124-31, 2005 Nov 25.
Article in English | MEDLINE | ID: mdl-16269657

ABSTRACT

C-reactive protein (CRP) is an acute-phase reactant that is positively correlated with cardiovascular disease risk and endothelial dysfunction. Whether CRP has direct actions on endothelium and the mechanisms underlying such actions are unknown. Here we show in cultured endothelium that CRP prevents endothelial NO synthase (eNOS) activation by diverse agonists, resulting in the promotion of monocyte adhesion. CRP antagonism of eNOS occurs nongenomically and is attributable to blunted eNOS phosphorylation at Ser1179. Okadaic acid or knockdown of PP2A by short-interference RNA reverses CRP antagonism of eNOS, indicating a key role for the phosphatase. Aggregated IgG, the known ligand for Fcgamma receptors, causes parallel okadaic acid-sensitive loss of eNOS function, FcgammaRIIB expression is demonstrable in endothelium, and heterologous expression studies reveal that CRP antagonism of eNOS requires FcgammaRIIB. In FcgammaRIIB(+/+) mice, CRP blunts acetylcholine-induced increases in carotid artery vascular conductance; in contrast, CRP enhances acetylcholine responses in FcgammaRIIB(-/-) mice. Thus FcgammaRIIB mediates CRP inhibition of eNOS via PP2A, providing a mechanistic link between CRP and endothelial dysfunction.


Subject(s)
C-Reactive Protein/pharmacology , Nitric Oxide Synthase Type III/antagonists & inhibitors , Receptors, IgG/physiology , Acetylcholine/pharmacology , Animals , Cattle , Cells, Cultured , Humans , Male , Mice , Mice, Inbred C57BL , Nitric Oxide/biosynthesis , Phosphoprotein Phosphatases/physiology , Phosphorylation , Serum Amyloid P-Component/pharmacology , U937 Cells
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