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1.
Liver Int ; 44(4): 966-978, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38293761

ABSTRACT

BACKGROUND & AIMS: Fibrosis stage is a strong predictor of nonalcoholic steatohepatitis (NASH) outcomes. Two blinded studies evaluated the pharmacokinetics, pharmacodynamics and safety of obeticholic acid (OCA) in subjects with staged NASH fibrosis or cirrhosis. METHODS: Study 747-117 randomized 51 subjects with NASH (fibrosis stages F1-F4) to daily placebo, OCA 10 or OCA 25 mg (1:2:2) for 85 days. Study 747-118 randomized 24 subjects with NASH cirrhosis (F4; Child-Pugh [CP]-A) and normal liver control subjects matched for similar body weight to daily OCA 10 or OCA 25 mg (1:1) for 28 days. Individual and combined study data were analysed. RESULTS: No severe or serious adverse events (AEs) or AEs leading to discontinuation or death occurred. Pruritus was the most frequent AE. Plasma OCA exposure (dose-normalized area under the curve) increased with fibrosis stage but was a relatively poor predictor of hepatic OCA exposure (primary site of action), which remained constant across fibrosis stages F1-F3 and increased 1.8-fold compared with F1 in subjects with cirrhosis due to NASH. Both cohorts showed robust changes in farnesoid X receptor activation markers with OCA treatment and marked decreases in alanine transaminase, aspartate transaminase and gamma-glutamyltransferase. CONCLUSIONS: Despite higher drug exposures in subjects with NASH cirrhosis, short-term daily treatment with OCA 10 or 25 mg was generally safe and well tolerated in subjects with NASH fibrosis or NASH CP-A cirrhosis. Both cohorts experienced improvements in nonhistologic pharmacodynamic markers consistent with previously conducted OCA phase 2 and phase 3 studies in NASH fibrosis.


Subject(s)
Chenodeoxycholic Acid/analogs & derivatives , Non-alcoholic Fatty Liver Disease , Humans , Non-alcoholic Fatty Liver Disease/complications , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/pathology , Liver Cirrhosis/drug therapy , Liver Cirrhosis/pathology , Chenodeoxycholic Acid/adverse effects
2.
Anesthesiology ; 134(1): 35-51, 2021 01 01.
Article in English | MEDLINE | ID: mdl-33064833

ABSTRACT

BACKGROUND: γ-Aminobutyric acid type A (GABAA) receptor agonists are known to cause involuntary muscle movements. The mechanism of these movements is not known, and its relationship to depth of anesthesia monitoring is unclear. We have explored the effect of involuntary muscle movement on the pharmacokinetic-pharmacodynamic model for the GABAA receptor agonist ABP-700 and its effects on the Bispectral Index (BIS) as well as the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scores. METHODS: Observations from 350 individuals (220 men, 130 women) were analyzed, comprising 6,312 ABP-700 concentrations, 5,658 ABP-700 metabolite (CPM-acid) concentrations, 25,745 filtered BIS values, and 6,249 MOAA/S scores, and a recirculatory model developed. Various subject covariates and pretreatment with an opioid or a benzodiazepine were explored as covariates. Relationships between BIS and MOAA/S models and involuntary muscle movements were examined. RESULTS: The final model shows that the pharmacokinetics of ABP-700 are characterized by small compartmental volumes and rapid clearance. The BIS model incorporates an effect-site for BIS suppression and a secondary excitatory/disinhibitory effect-site associated with a risk of involuntary muscle movements. The secondary effect-site has a threshold that decreases with age. The MOAA/S model did not show excitatory effects. CONCLUSIONS: The GABAA receptor agonist ABP-700 shows the expected suppressive effects for BIS and MOAA/S, but also disinhibitory effects for BIS associated with involuntary muscle movements and reduced by pretreatment. Our model provides information about involuntary muscle movements that may be useful to improve depth of anesthesia monitoring for GABAA receptor agonists.


Subject(s)
Anesthesia , Consciousness Monitors , Etomidate/analogs & derivatives , GABA-A Receptor Agonists/pharmacology , Imidazoles/pharmacology , Adult , Algorithms , Analgesics, Opioid , Benzodiazepines , Conscious Sedation , Etomidate/pharmacokinetics , Female , GABA-A Receptor Agonists/pharmacokinetics , Humans , Imidazoles/pharmacokinetics , Male , Monitoring, Intraoperative , Muscle, Smooth/drug effects , Preanesthetic Medication
4.
Lancet ; 394(10215): 2184-2196, 2019 12 14.
Article in English | MEDLINE | ID: mdl-31813633

ABSTRACT

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. METHODS: In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. FINDINGS: Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). INTERPRETATION: Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes. FUNDING: Intercept Pharmaceuticals.


Subject(s)
Chenodeoxycholic Acid/analogs & derivatives , Non-alcoholic Fatty Liver Disease/drug therapy , Administration, Oral , Biomarkers/analysis , Biopsy , Chenodeoxycholic Acid/administration & dosage , Chenodeoxycholic Acid/therapeutic use , Double-Blind Method , Female , Humans , Liver Function Tests , Male , Middle Aged
5.
Anesthesiology ; 127(1): 20-35, 2017 07.
Article in English | MEDLINE | ID: mdl-28459733

ABSTRACT

BACKGROUND: Cyclopropyl-methoxycarbonylmetomidate (ABP-700) is a new "soft" etomidate analog. The primary objectives of this first-in-human study were to describe the safety and efficacy of ABP-700 and to determine its maximum tolerated dose. Secondary objectives were to characterize the pharmacokinetics of ABP-700 and its primary metabolite (cyclopropyl-methoxycarbonyl acid), to assess the clinical effects of ABP-700, and to investigate the dose-response and pharmacokinetic/pharmacodynamic relationships. METHODS: Sixty subjects were divided into 10 cohorts and received an increasing, single bolus of either ABP-700 or placebo. Safety was assessed by clinical laboratory evaluations, infusion-site reactions, continuous monitoring of vital signs, physical examination, adverse event monitoring, and adrenocorticotropic hormone stimulation testing. Clinical effects were assessed with modified observer's assessment of alertness/sedation and Bispectral Index monitoring. Pharmacokinetic parameters were calculated. RESULTS: Stopping criteria were met at 1.00 mg/kg dose. No serious adverse events were reported. Adverse events were dose-dependent and comprised involuntary muscle movement, tachycardia, and ventilatory effects. Adrenocorticotropic hormone stimulation evoked a physiologic cortisol response in all subjects, no different from placebo. Pharmacokinetics were dose-proportional. A three-compartment pharmacokinetic model described the data well. A rapid onset of anesthesia/sedation after bolus administration and also a rapid recovery were observed. A quantitative concentration-effect relationship was described for the modified observer's assessment of alertness/sedation and Bispectral Index. CONCLUSIONS: This first-in-human study of ABP-700 shows that ABP-700 was safe and well tolerated after single-bolus injections up to 1.00 mg/kg. Bolus doses of 0.25 and 0.35 mg/kg were found to provide the most beneficial clinical effect versus side-effect profile.


Subject(s)
Etomidate/analogs & derivatives , Etomidate/pharmacology , Hypnotics and Sedatives/pharmacology , Adolescent , Adult , Dose-Response Relationship, Drug , Double-Blind Method , Etomidate/administration & dosage , Female , Humans , Hypnotics and Sedatives/administration & dosage , Infusions, Intravenous , Male , Maximum Tolerated Dose , Middle Aged , Reference Values , Young Adult
6.
J Cardiothorac Vasc Anesth ; 30(6): 1562-1570, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27554236

ABSTRACT

OBJECTIVES: Gaps and uncertainty exist regarding the understanding of optimal clinical goals for perioperative (ie, preoperative, intraoperative, and postoperative) blood pressure (BP) management in patients undergoing cardiac surgery and the consequences of achieving or failing to achieve those goals. In this setting, it is understood that preoperative hypertension is predictive of poor postoperative outcomes, with a growing appreciation that current, clinically acceptable changes in intraoperative BP also may be associated independently with adverse short- and long-term outcomes. In contrast, the impact of postoperative BP on outcomes after cardiac surgery remains less clear. DESIGN: This study was a retrospective outcome analysis. SETTING: The study included all cardiac surgery patients cared for at a single institution over a 7-year period. Consequences of the success or failure of meeting postoperative BP targets on medical outcomes and health resource utilization were evaluated. RESULTS: The study comprised 5,225 patients. Hypertensive postoperative patients experienced a higher in-hospital mortality rate compared with matched-case normotensive patients (4.97% v 1.32%, p<0.001) and a longer hospital stay (p = 0.024). In hypertensive patients, serum creatinine levels from postoperative day 1 through postoperative day 7 were increased compared with baseline and postoperative renal dysfunction according to the Kidney Disease: Improving Global Outcomes criteria occurred significantly more often (25.3% v 19.7%, p = 0.027). CONCLUSIONS: Postoperative hypertension is associated with compromised outcome as reflected by higher mortality, longer length of stay, and higher incidence of renal dysfunction.


Subject(s)
Acute Kidney Injury/epidemiology , Cardiac Surgical Procedures , Hospital Mortality , Hypertension/epidemiology , Postoperative Complications/epidemiology , Aged , Comorbidity , Female , Humans , Length of Stay/statistics & numerical data , Male , Retrospective Studies , Risk Factors
7.
EBioMedicine ; 10: 291-7, 2016 Aug.
Article in English | MEDLINE | ID: mdl-27349457

ABSTRACT

Clevidipine, a dihydropyridine (DHP) analogue, lowers blood pressure (BP) by inhibiting l-type calcium channels (CaV1.2; gene CACNA1C) predominantly located in vascular smooth muscle (VSM). However, clinical observations suggest that clevidipine acts by a more complex mechanism. Clevidipine more potently reduces pulmonary vascular resistance (PVR) than systemic vascular resistance and its spectrum of effects on PVR are not shared by other DHPs. Clevidipine has potent spasmolytic effects in peripheral arteries at doses that are sub-clinical for BP lowering and, in hypertensive acute heart failure, clevidipine, but not other DHPs, provides dyspnea relief, partially independent of BP reduction. These observations suggest that a molecular variation in CaV1.2 may exist which confers unique pharmacology to different DHPs. We sequenced CACNA1C transcripts from human lungs and measured their affinity for clevidipine. Human lung tissue contains CACNA1C mRNA with many different splice variations. CaV1.2 channels with a specific combination of variable exons showed higher affinity for clevidipine, well below the concentration associated with BP reduction. Co-expression with pannexin 1 further increased the clevidipine affinity for this CaV1.2 splice variant. A high-affinity splice variant of CaV1.2 in combination with pannexin 1 could underlie the selective effects of clevidipine on pulmonary arterial pressure and on dyspnea. RESEARCH IN CONTEXT: Clevidipine lowers blood pressure by inhibiting calcium channels in vascular smooth muscle. In patients with acute heart failure, clevidipine was shown to relieve breathing problems. This was only partially related to the blood pressure lowering actions of clevidipine and not conferred by another calcium channel inhibitor. We here found calcium channel variants in human lung that are more selectively inhibited by clevidipine, especially when associated with pannexin channels. This study gives a possible mechanism for clevidipine's relief of breathing problems and supports future clinical trials testing the role of clevidipine in the treatment of acute heart failure.


Subject(s)
Alternative Splicing , Calcium Channels, L-Type/genetics , Connexins/genetics , Lung/metabolism , Acute Disease , Blood Pressure/drug effects , Blood Pressure/genetics , Calcium Channel Blockers/pharmacology , Calcium Channel Blockers/therapeutic use , Calcium Channels, L-Type/metabolism , Connexins/metabolism , Dyspnea/drug therapy , Dyspnea/etiology , Gene Expression Regulation/drug effects , Heart Failure/complications , Heart Failure/drug therapy , Heart Failure/genetics , Humans , Lung/drug effects , Protein Binding , Pyridines/pharmacology , Pyridines/therapeutic use
8.
Anesthesiology ; 121(6): 1203-16, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25170571

ABSTRACT

BACKGROUND: Cyclopropyl-methoxycarbonyl metomidate (CPMM, also known as ABP-700) is a second-generation "soft" (i.e., metabolically labile) etomidate analogue. The purpose of this study was to characterize CPMM's pharmacology in beagle dogs in preparation for potential first in human phase 1 clinical trials. METHODS: CPMM's and etomidate's hypnotic activity and duration of action were assessed using loss of righting reflex and anesthesia score assays in three or four dogs. Their pharmacokinetics were defined after single bolus administration and single bolus followed by 2-h infusion. Adrenocortical recovery times after single bolus followed by 2-h infusion of CPMM, propofol, etomidate, and vehicle were measured using an adrenocorticotropic hormone stimulation test. RESULTS: Compared with etomidate, CPMM was half as potent as a hypnotic (ED50 approximately 0.8 mg/kg), was more rapidly metabolized, and had a shorter duration of sedative-hypnotic action. Recovery times after CPMM administration were also independent of infusion duration. After hypnotic infusion, adrenocorticotropic hormone-stimulated plasma cortisol concentrations were 4- to 27-fold higher in dogs that received CPMM versus etomidate. Adrenocortical recovery was faster in dogs after CPMM infusion versus etomidate infusion (half-time: 215 vs. 1,623 min, respectively). Adrenocortical responsiveness assessed 90 min after CPMM infusion was not significantly different from that after propofol infusion. CONCLUSION: The studies in dogs confirm that CPMM has hypnotic and adrenocortical recovery profiles that are superior than those of etomidate, supporting the continued development of CPMM as a clinical sedative-hypnotic to be used as a single bolus and by continuous infusion to induce and maintain general anesthesia or procedural sedation.


Subject(s)
Anesthetics, Intravenous/pharmacology , Anesthetics, Intravenous/pharmacokinetics , Etomidate/analogs & derivatives , Etomidate/pharmacology , Etomidate/pharmacokinetics , Hypnotics and Sedatives/pharmacology , Hypnotics and Sedatives/pharmacokinetics , Adrenal Cortex/drug effects , Anesthesia , Animals , Area Under Curve , Behavior, Animal/drug effects , Chemistry, Pharmaceutical , Dogs , Male , Models, Statistical , Propofol/pharmacokinetics , Propofol/pharmacology
9.
J Exp Pharmacol ; 6: 11-4, 2014.
Article in English | MEDLINE | ID: mdl-27186138

ABSTRACT

Various factors may be responsible for blood pressure alterations during perioperative care. When these physiologic alterations require treatment, several therapeutic options are available. Clevidipine is an ultrashort-acting, intravenous L-type calcium channel antagonist of the dihydropyridine class. Anecdotal experience has demonstrated its efficacy in various clinical scenarios in the pediatric population. We report apparent resistance to the vasodilatory effects of clevidipine in a 13-year-old girl who presented for anesthetic care during posterior spinal fusion for neuromuscular scoliosis whose chronic medication regimen included aripiprazole and methylphenidate for the treatment of depression and attention-deficit/hyperactivity disorder. We discuss the potential interaction of aripiprazole and methylphenidate with the calcium channel antagonists and cellular mechanisms responsible for the resistance to the vasodilatory effects of clevidipine.

10.
Curr Opin Anaesthesiol ; 22(2): 237-41, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19390251

ABSTRACT

PURPOSE OF REVIEW: External quality assessment programs in the form of pay for performance, report cards and national rankings are rapidly overtaking more traditional, internal quality assessment efforts and external clinical practice guidelines. Although such initiatives are designed to improve healthcare quality by promoting competition and increasing transparency, review of their efficacy and unintended effects is just coming to the national spotlight. RECENT FINDINGS: Critical evaluation of external quality assessment programs remains limited despite their scope, speed and breadth of implementation. Recent publications, however, suggest that external quality assessment efforts may have major unintended consequences. These include effects on patient decision-making, the 'dynamic equilibrium' of patient care, healthcare disparities, medical innovation and practice patterns. SUMMARY: In their early years of implementation, external quality assessment programs have already had significant consequences in the healthcare system. As new tools become available, their full impact on care and caregivers must be thoroughly evaluated. Careful consideration of clinical practice implications and an understanding of the risks are critical before accepting and implementing new assessment paradigms. The substantial and widespread effects of these programs should prompt further evaluation from the medical community.


Subject(s)
Delivery of Health Care , Program Evaluation/methods , Quality Assurance, Health Care/methods , Quality Assurance, Health Care/standards , Authorship , Guidelines as Topic , Humans , Outcome and Process Assessment, Health Care , Program Evaluation/standards , Quality of Health Care/economics , Risk Management , Task Performance and Analysis
11.
Anesthesiology ; 105(3): 627-8; author reply 628, 629-30, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16932003
13.
Nat Genet ; 38(5): 531-9, 2006 May.
Article in English | MEDLINE | ID: mdl-16604073

ABSTRACT

Hepcidin is a key regulator of systemic iron homeostasis. Hepcidin deficiency induces iron overload, whereas hepcidin excess induces anemia. Mutations in the gene encoding hemojuvelin (HFE2, also known as HJV) cause severe iron overload and correlate with low hepcidin levels, suggesting that hemojuvelin positively regulates hepcidin expression. Hemojuvelin is a member of the repulsive guidance molecule (RGM) family, which also includes the bone morphogenetic protein (BMP) coreceptors RGMA and DRAGON (RGMB). Here, we report that hemojuvelin is a BMP coreceptor and that hemojuvelin mutants associated with hemochromatosis have impaired BMP signaling ability. Furthermore, BMP upregulates hepatocyte hepcidin expression, a process enhanced by hemojuvelin and blunted in Hfe2-/- hepatocytes. Our data suggest a mechanism by which HFE2 mutations cause hemochromatosis: hemojuvelin dysfunction decreases BMP signaling, thereby lowering hepcidin expression.


Subject(s)
Antimicrobial Cationic Peptides/genetics , Bone Morphogenetic Proteins/metabolism , Gene Expression Regulation/physiology , Membrane Proteins/physiology , Signal Transduction/physiology , Transforming Growth Factor beta/metabolism , Amino Acid Sequence , Animals , Bone Morphogenetic Protein 2 , CHO Cells , Cricetinae , GPI-Linked Proteins , Hemochromatosis Protein , Hepcidins , Humans , Liver/cytology , Liver/metabolism , Membrane Proteins/genetics , Molecular Sequence Data , Mutation , Polymerase Chain Reaction
14.
Best Pract Res Clin Anaesthesiol ; 19(3): 349-64, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16013686

ABSTRACT

Despite the widespread presence of clinical anesthesiology in medical practice, the mechanism by which diverse inhalational agents result in the state of general anesthesia remains unknown. Over recent decades, our understanding of general anesthetic mechanisms has evolved dramatically from early unitary hypotheses, largely due to the development and influence of a myriad of scientific disciplines ranging from molecular biology to cognitive neuroscience. These discoveries have led to a renaissance of investigation into the mechanisms of general anesthetics and have generated both novel answers and questions. In this chapter, we review the major hypotheses of general anesthetic mechanisms of action and present an expanded overview of current investigation into those mechanisms. We also present a framework to aid in thinking about the actions of these agents, highlighting the relationship between putative targets at the molecular level and the more integrated functional changes in behavior and consciousness.


Subject(s)
Anesthesia, General , Anesthetics, Inhalation/pharmacology , Brain Chemistry/drug effects , Brain/drug effects , Animals , Brain Chemistry/genetics , Humans
16.
J Biol Chem ; 280(33): 29820-7, 2005 Aug 19.
Article in English | MEDLINE | ID: mdl-15975920

ABSTRACT

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor beta (TGF-beta) superfamily of ligands, which regulate many mammalian physiologic and pathophysiologic processes. BMPs exert their effects through type I and type II serine/threonine kinase receptors and the Smad intracellular signaling pathway. Recently, the glycosylphosphatidylinositol (GPI)-anchored protein DRAGON was identified as a co-receptor for BMP signaling. Here, we investigate whether a homologue of DRAGON, repulsive guidance molecule (RGMa), is similarly involved in the BMP signaling pathway. We show that RGMa enhances BMP, but not TGF-beta, signals in a ligand-dependent manner in cell culture. The soluble extracellular domain of RGMa fused to human Fc (RGMa.Fc) forms a complex with BMP type I receptors and binds directly and selectively to radiolabeled BMP-2 and BMP-4. RGMa mediates BMP signaling through the classical BMP signaling pathway involving Smad1, 5, and 8, and it up-regulates endogenous inhibitor of differentiation (Id1) protein, an important downstream target of BMP signals. Finally, we demonstrate that BMP signaling occurs in neurons that express RGMa in vivo. These data are consistent with a role for RGMa as a BMP co-receptor.


Subject(s)
Nerve Tissue Proteins/physiology , Receptors, Growth Factor/physiology , Amino Acid Sequence , Animals , Bone Morphogenetic Protein Receptors , Bone Morphogenetic Proteins/physiology , Cells, Cultured , DNA-Binding Proteins/physiology , GPI-Linked Proteins , Humans , Mice , Molecular Sequence Data , Phosphoproteins/physiology , Rats , Signal Transduction , Smad Proteins , Smad1 Protein , Smad5 Protein , Smad8 Protein , Spinal Cord/metabolism , Trans-Activators/physiology , Transforming Growth Factor beta/physiology
17.
Anesth Analg ; 100(4): 1062-1064, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15781523

ABSTRACT

Most surgical fires involve the airway but they can also occur in the surgical field. Herein, we report an intraoperative fire in the surgical field during repair of a bronchoesophageal fistula. During the portion of the surgery after the fistula was divided and the bronchus was open to atmosphere, continuous positive airway pressure was applied to the nondependent lung, and in conjunction with the use of electrocautery and dry sponges in the field, resulted in a fire. Anesthesia for thoracic surgery carries unique risks of fire because these patients frequently require large oxygen concentrations, special interventions for improving oxygenation, and have variable degrees of airway disruption. This report highlights unique safety concerns during anesthesia for thoracic surgery, and addresses more general safety issues relating to fire risk in all surgical patients.


Subject(s)
Bronchial Fistula/surgery , Fires , Intraoperative Period , Operating Rooms , Tracheoesophageal Fistula/surgery , Aged , Anesthesia, Inhalation , Humans , Male , Oxygen Inhalation Therapy
18.
J Biol Chem ; 280(14): 14122-9, 2005 Apr 08.
Article in English | MEDLINE | ID: mdl-15671031

ABSTRACT

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor (TGF)beta superfamily of ligands that regulate many crucial aspects of embryonic development and organogenesis. Unlike other TGFbeta ligands, co-receptors for BMP ligands have not been described. Here we show that DRAGON, a glycosylphosphatidylinositol-anchored member of the repulsive guidance molecule family, which is expressed early in the developing nervous system, enhances BMP but not TGFbeta signaling. DRAGON binds directly to BMP2 and BMP4 but not to BMP7 or other TGFbeta ligands. The enhancing action of DRAGON on BMP signaling is also reduced by administration of Noggin, a soluble BMP antagonist, indicating that the action of DRAGON is ligand-dependent. DRAGON associates directly with BMP type I (ALK2, ALK3, and ALK6) and type II (ActRII and ActRIIB) receptors, and its signaling is reduced by dominant negative Smad1 and ALK3 or -6 receptors. In the Xenopus embryo, DRAGON both reduces the threshold of the ability of Smad1 to induce mesodermal and endodermal markers and alters neuronal and neural crest patterning. The direct interaction of DRAGON with BMP ligands and receptors indicates that it is a BMP co-receptor that potentiates BMP signaling.


Subject(s)
Bone Morphogenetic Proteins/metabolism , Nerve Tissue Proteins/metabolism , Neural Cell Adhesion Molecules/metabolism , Signal Transduction/physiology , Animals , Body Patterning , Bone Morphogenetic Protein Receptors , Bone Morphogenetic Proteins/genetics , Carrier Proteins , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Embryo, Mammalian/anatomy & histology , Embryo, Mammalian/physiology , Embryo, Nonmammalian , Female , Genes, Reporter , Humans , Mice , Morphogenesis/physiology , Nerve Tissue Proteins/genetics , Nervous System/anatomy & histology , Nervous System/embryology , Neural Cell Adhesion Molecules/genetics , Protein Binding , Protein Isoforms/genetics , Protein Isoforms/metabolism , Proteins/metabolism , Receptors, Growth Factor/genetics , Receptors, Growth Factor/metabolism , Smad Proteins , Smad1 Protein , Trans-Activators/genetics , Trans-Activators/metabolism , Transforming Growth Factor beta/metabolism , Xenopus Proteins , Xenopus laevis/embryology , Xenopus laevis/metabolism
19.
J Neurosci ; 24(8): 2027-36, 2004 Feb 25.
Article in English | MEDLINE | ID: mdl-14985445

ABSTRACT

DRG11, a transcription factor expressed in embryonic dorsal root ganglion (DRG) and dorsal horn neurons, has a role in the development of sensory circuits. We have used a genomic binding strategy to screen for the promoter region of genes regulated by DRG11. One gene with a promoter region binding to the DNA binding domain of DRG11 encodes a novel membrane-associated [glycosyl-phosphatidylinositol (GPI)-anchored] protein that we call DRAGON. DRAGON expression is transcriptionally regulated by DRG11, and it is coexpressed with DRG11 in embryonic DRG and spinal cord. DRAGON expression in these areas is reduced in DRG11 null mutants. DRAGON is expressed, however, in the neural tube before DRG11, and unlike DRG11 it is expressed in the brain and therefore must be regulated by other transcriptional regulatory elements. DRAGON shares high sequence homology with two other GPI-anchored membrane proteins: the mouse ortholog of chick repulsive guidance molecule (mRGM), which is expressed in the mouse nervous system in areas complementary to DRAGON, and DRAGON-like muscle (DL-M), the expression of which is restricted to skeletal and cardiac muscle. A comparative genomic analysis indicates that the family of RGM-related genes--mRGM, DRAGON, and DL-M--are highly conserved among mammals, zebrafish, chick, and Caenorhabditis elegans but not Drosophila. DRAGON, RGM, and DL-M mRNA expression in the zebrafish embryo is similar to that in the mouse. Neuronal cell adhesion assays indicate that DRAGON promotes and mRGM reduces adhesion of mouse DRG neurons. We show that DRAGON interacts with itself homophilically. The dynamic expression, ordered spatial localization, and adhesive properties of the RGM-related family of membrane-associated proteins are compatible with specific roles in development.


Subject(s)
Homeodomain Proteins/metabolism , Membrane Proteins/metabolism , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neural Cell Adhesion Molecules/metabolism , Transcription Factors/metabolism , Amino Acid Sequence , Animals , Base Sequence , Brain/embryology , Brain/metabolism , Cell Line , Cloning, Molecular , Conserved Sequence/genetics , GPI-Linked Proteins , Ganglia, Spinal/embryology , Ganglia, Spinal/metabolism , Gene Expression Regulation, Developmental , Glycosylphosphatidylinositols/metabolism , Homeodomain Proteins/genetics , Humans , Membrane Proteins/genetics , Mice , Molecular Sequence Data , Multigene Family/genetics , Muscle Proteins/genetics , Muscle Proteins/metabolism , Nerve Tissue Proteins/biosynthesis , Neural Cell Adhesion Molecules/genetics , Neurons/cytology , Neurons/metabolism , Organ Specificity , RNA, Messenger/metabolism , Sequence Homology, Amino Acid , Spinal Cord/embryology , Spinal Cord/metabolism , Transcription Factors/genetics , Zebrafish
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