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Item Cardiac arrest after induction of anesthesia in a 2-month-old infant with undiagnosed Williams syndrome(Wolters Kluwer, 2019) Dunlap, Julie D.; Green, Morton C.; Shah, Aali M.; Kibby, Brandon T.; Billmire, Deobrah F.; Pediatrics, School of MedicineA 2-month-old male infant presented for elective repair of inguinal hernias. His preoperative medical history and physical examination were unremarkable. During induction of anesthesia, the infant sustained an adverse cardiac event. The event was characterized by tachycardia, hypotension, and massive ST-segment elevation. Despite vigorous resuscitation, spontaneous hemodynamic stability could not be achieved and extracorporeal membrane oxygenation was required. A transthoracic echocardiogram revealed severe hypoplasia of the ascending aorta. As effective cardiac function did not recover and there was evidence of diffuse ischemic brain injury, life support was withdrawn. Genetic testing performed postoperatively was definitive for Williams syndrome.Item Influence of Staphylococcus aureus Strain Background on Sa3int Phage Life Cycle Switches(MDPI, 2022) Rohmer, Carina; Dobritz, Ronja; Tuncbilek-Dere, Dilek; Lehmann, Esther; Gerlach, David; George, Shilpa Elizabeth; Bae, Taeok; Nieselt, Kay; Wolz, Christiane; Microbiology and Immunology, School of MedicineStaphylococcus aureus asymptomatically colonizes the nasal cavity of mammals, but it is also a leading cause of life-threatening infections. Most human nasal isolates carry Sa3 phages, which integrate into the bacterial hlb gene encoding a sphingomyelinase. The virulence factor-encoding genes carried by the Sa3-phages are highly human-specific, and most animal strains are Sa3 negative. Thus, both insertion and excision of the prophage could potentially confer a fitness advantage to S. aureus. Here, we analyzed the phage life cycle of two Sa3 phages, Φ13 and ΦN315, in different phage-cured S. aureus strains. Based on phage transfer experiments, strains could be classified into low (8325-4, SH1000, and USA300c) and high (MW2c and Newman-c) transfer strains. High-transfer strains promoted the replication of phages, whereas phage adsorption, integration, excision, or recA transcription was not significantly different between strains. RNASeq analyses of replication-deficient lysogens revealed no strain-specific differences in the CI/Mor regulatory switch. However, lytic genes were significantly upregulated in the high transfer strain MW2c Φ13 compared to strain 8325-4 Φ13. By transcriptional start site prediction, new promoter regions within the lytic modules were identified, which are likely targeted by specific host factors. Such host-phage interaction probably accounts for the strain-specific differences in phage replication and transfer frequency. Thus, the genetic makeup of the host strains may determine the rate of phage mobilization, a feature that might impact the speed at which certain strains can achieve host adaptation.Item Rifampin enhances cytochrome P450 (CYP) 2B6-mediated efavirenz 8-hydroxylation in healthy volunteers(Elsevier, 2016-04) Cho, Doo-Yeoun; Shen, Joan H.Q.; Lemler, Suzanne M.; Skaar, Todd C.; Li, Lang; Blievernicht, Julia; Zanger, Ulrich M.; Kim, Kwon-Bok; Shin, Jae-Gook; Flockhart, David A.; Desta, Zeruesenay; Department of Medicine, IU School of MedicineThe effect of rifampin on the in vivo metabolism of the antiretroviral drug efavirenz was evaluated in healthy volunteers. In a cross-over placebo control trial, healthy subjects (n = 20) were administered a single 600 mg oral dose of efavirenz after pretreatment with placebo or rifampin (600 mg/day for 10 days). Plasma and urine concentrations of efavirenz, 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz were measured by LC-MS/MS. Compared to placebo treatment, rifampin increased the oral clearance (by ∼2.5-fold) and decreased maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC0-∞) of efavirenz (by ∼1.6- and ∼2.5-fold respectively) (p < 0.001). Rifampin treatment substantially increased the Cmax and AUC0-12h of 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz, metabolic ratio (AUC0-72h of metabolites to AUC0-72h efavirenz) and the amount of metabolites excreted in urine (Ae0-12hr) (all, p < 0.01). Female subjects had longer elimination half-life (1.6-2.2-fold) and larger weight-adjusted distribution volume (1.6-1.9-fold) of efavirenz than male subjects (p < 0.05) in placebo and rifampin treated groups respectively. In conclusion, rifampin enhances CYP2B6-mediated efavirenz 8-hydroxylation in vivo. The metabolism of a single oral dose of efavirenz may be a suitable in vivo marker of CYP2B6 activity to evaluate induction drug interactions involving this enzyme.Item Supplementing provider counseling with an educational video prior to scheduled induction of labor(Springer Nature, 2024-10-18) Pape, Kelsey J.; Froehlich, Sierra A.; Haas, David M.; Obstetrics and Gynecology, School of MedicineBackground: Induction of labor (IOL) is common with one in four labors being induced in the United States (US). IOL has been associated with lower birth satisfaction. Video education can address gaps in education and promote anticipatory guidance. Prior studies in obstetrics have focused on randomized designs in English-speaking patients, leaving opportunities to explore how these tools perform in a pragmatic fashion with diverse patient populations. Our objective was to evaluate the effects of a video education tool on patient satisfaction and knowledge of IOL experience in English and Spanish-speaking patients scheduled for IOL at a tertiary care hospital. Methods: This was a single site pragmatic implementation of a quality improvement measure at an academic hospital. A bilingual survey was developed to evaluate the impact of an educational video on birth satisfaction and knowledge of IOL procedures. The video is freely available in English and Spanish. Baseline postpartum surveys were collected from June to July 2021. The video was subsequently recommended by providers when scheduling IOLs. Post-intervention surveys were collected from September to November 2021 after an implementation period. Groups were compared using t-tests for satisfaction scores and chi-square analyses for categorical variables. Results: Thirty-two participants completed the baseline survey and 72 completed the post-implementation survey with response rates of 88.9% and 91.1%, respectively. There were no statistically significant changes between mean total satisfaction scores (26.9 vs 28.0 out of 40.0, p = 0.290). 61 participants were English speaking (58%) and 43 Spanish (42%). Thirty (42%) patients reported watching the video. Correct identification of amniotomy use improved in the post-intervention group (p = 0.002). No changes were seen in anticipated duration of labor nor in whether patients would choose to be induced again. Conclusions: Recommendation of video education before scheduled IOL was associated with little improvement in knowledge about IOL, but no significant improvement in patient satisfaction. While video education has improved these measures in randomized trials, our study demonstrated that real-world implementation and patient uptake may be initially difficult. This study may help providers emphasize direct education and counseling and promote optimal implementation of innovative educational media.Item Targeted Induction of Lung Endothelial Cell Apoptosis Causes Emphysema-like Changes in the Mouse(American Society for Biochemistry and Molecular Biology, 2008-08-21) Giordano, Ricardo J.; Lahdenranta, Johanna; Zhen, Lijie; Chukwueke, Ugonma; Petrache, Irina; Langley, Robert R.; Fidler, Isaiah J.; Pasqualini, Renata; Tuder, Rubin M.; Arap, Wadih; Biochemistry and Molecular Biology, School of MedicinePulmonary gas exchange relies on a rich capillary network, which, together with alveolar epithelial type I and II cells, form alveolar septa, the functional units in the lung. Alveolar capillary endothelial cells are critical in maintaining alveolar structure, because disruption of endothelial cell integrity underlies several lung diseases. Here we show that targeted ablation of lung capillary endothelial cells recapitulates the cellular events involved in cigarette smoke-induced emphysema, one of the most prevalent nonneoplastic lung diseases. Based on phage library screening on an immortalized lung endothelial cell line, we identified a lung endothelial cell-binding peptide, which preferentially homes to lung blood vessels. This peptide fused to a proapoptotic motif specifically induced programmed cell death of lung endothelial cells in vitro as well as targeted apoptosis of the lung microcirculation in vivo. As early as 4 days following peptide administration, mice developed air space enlargement associated with enhanced oxidative stress, influx of macrophages, and up-regulation of ceramide. Given that these are all critical elements of the corresponding human emphysema caused by cigarette smoke, these data provide evidence for a central role for the alveolar endothelial cells in the maintenance of lung structure and of endothelial cell apoptosis in the pathogenesis of emphysema-like changes. Thus, our data enable the generation of a convenient mouse model of human emphysema. Finally, combinatorial screenings on immortalized cells followed by in vivo targeting establishes an experimental framework for discovery and validation of additional ligand-directed pharmacodelivery systems.