Generation and characterization of a delta F508 cystic fibrosis mouse model.

We have generated mice carrying the most common mutation in cystic fibrosis (CF), delta F508, within the cystic fibrosis (Cftr) gene. Mutant animals show pathological and electrophysiological changes consistent with a CF phenotype. delta F508-/- mice die from peritonitis and show deficiencies in cAMP-activated electrogenic Cl- transport. These mice produce delta F508 transcripts and show the temperature-dependent trafficking defect first described for the human delta F508 CFTR protein. A functional CFTR Cl- channel not demonstrated by null CF mice or present at 37 degrees C was detected following incubation of epithelial cells at 27 degrees C. Thus, these mice are an accurate delta F508 model and will be valuable for testing drugs aimed at overcoming the delta F508 trafficking defect.

Heart rate and QRS duration as biomarkers predict the immediate outcome from pulseless electrical activity.

INTRODUCTION: Pulseless electrical activity (PEA) is commonly observed in in-hospital cardiac arrest (IHCA). Universally available ECG characteristics such as QRS duration (QRSd) and heart rate (HR) may develop differently in patients who obtain ROSC or not. The aim of this study was to assess prospectively how QRSd and HR as biomarkers predict the immediate outcome of patients with PEA. METHOD: We investigated 327 episodes of IHCA in 298 patients at two US and one Norwegian hospital. We assessed the ECG in 559 segments of PEA nested within episodes, measuring QRSd and HR during pauses of compressions, and noted the clinical state that immediately followed PEA. We investigated the development of HR, QRSd, and transitions to ROSC or no-ROSC (VF/VT, asystole or death) in a joint longitudinal and competing risks statistical model. RESULTS: Higher HR, and a rising HR, reflect a higher transition intensity ("hazard") to ROSC (p < 0.001), but HR was not associated with the transition intensity to no-ROSC. A lower QRSd and a shrinking QRSd reflect an increased transition intensity to ROSC (p = 0.023) and a reduced transition intensity to no-ROSC (p = 0.002). CONCLUSION: HR and QRSd convey information of the immediateoutcome during resuscitation from PEA. These universally available and promising biomarkers may guide the emergency team in tailoring individual treatment.

Pulseless electrical activity in in-hospital cardiac arrest - A crossroad for decisions.

BACKGROUND: PEA is often seen during resuscitation, either as the presenting clinical state in cardiac arrest or as a secondary rhythm following transient return of spontaneous circulation (ROSC), ventricular fibrillation/tachycardia (VF/VT), or asystole (ASY). The aim of this study was to explore and quantify the evolution from primary/secondary PEA to ROSC in adults during in-hospital cardiac arrest (IHCA). METHODS: We analyzed 700 IHCA episodes at one Norwegian hospital and three U.S. hospitals at different time periods between 2002 and 2021. During resuscitation ECG, chest compressions, and ventilations were recorded by defibrillators. Each event was manually annotated using a graphical application. We quantified the transition intensities, i.e., the propensity to change from PEA to another clinical state using time-to-event statistical methods. RESULTS: Most patients experienced PEA at least once before achieving ROSC or being declared dead. Time average transition intensities to ROSC from primary PEA (n = 230) and secondary PEA after ASY (n = 72) were 0.1 per min, peaking at 4 and 7 minutes, respectively; thus, a patient in these types of PEA showed a 10% chance of achieving ROSC in one minute. Much higher transition intensities to ROSC, average of 0.15 per min, were observed for secondary PEA after VF/VT (n = 83) or after ROSC (n = 134). DISCUSSION: PEA is a crossroad in which the subsequent course is determined. The four distinct presentations of PEA behave differently on important characteristics. A transition to PEA during resuscitation should encourage the resuscitation team to continue resuscitative efforts.

Paclitaxel stent coating inhibits neointimal hyperplasia at 4 weeks in a porcine model of coronary restenosis.

BACKGROUND: Despite limiting elastic recoil and late vascular remodeling after angioplasty, coronary stents remain vulnerable to restenosis, caused primarily by neointimal hyperplasia. Paclitaxel, a microtubule-stabilizing drug, has been shown to inhibit vascular smooth muscle cell migration and proliferation contributing to neointimal hyperplasia. We tested whether paclitaxel-coated coronary stents are effective at preventing neointimal proliferation in a porcine model of restenosis. METHODS AND RESULTS: Palmaz-Schatz stents were dip-coated with paclitaxel (0, 0.2, 15, or 187 microgram/stent) by immersion in ethanolic paclitaxel and evaporation of the solvent. Stents were deployed with mild oversizing in the left anterior descending coronary artery (LAD) of 41 minipigs. The treatment effect was assessed 4 weeks after stent implantation. The angiographic late loss index (mean luminal diameter) decreased with increasing paclitaxel dose (P<0.0028 by ANOVA), declining by 84.3% (from 0.352 to 0.055, P<0.05) at the highest level tested (187 microgram/stent versus control). Accompanying this change, the neointimal area decreased (by 39.5%, high-dose versus control; P<0.05) with increasing dose (P<0.040 by ANOVA), whereas the luminal area increased (by 90.4%, high-dose versus control; P<0.05) with escalating dose (P<0.0004 by ANOVA). Inflammatory cells were seen infrequently, and there were no cases of aneurysm or thrombosis. CONCLUSIONS: Paclitaxel-coated coronary stents produced a significant dose-dependent inhibition of neointimal hyperplasia and luminal encroachment in the pig LAD 28 days after implantation; later effects require further study. These results demonstrate the potential therapeutic benefit of paclitaxel-coated coronary stents in the prevention and treatment of human coronary restenosis.

Prediction of countershock success in patients using the autoregressive spectral estimation.

OBJECTIVES: Ventricular fibrillation (VF) is a life-threatening cardiac arrhythmia and within of minutes of its occurrence, optimal timing of countershock therapy is highly warranted to improve the chance of survival. This study was designed to investigate whether the autoregressive (AR) estimation technique was capable to reliably predict countershock success in VF cardiac arrest patients. METHODS: ECG data of 1077 countershocks applied to 197 cardiac arrest patients with out-of-hospital and in-hospital cardiac arrest between March 2002 and July 2004 were retrospectively analyzed. The ECG from the 2.5 s interval of the precountershock VF ECG was used for computing the AR based features Spectral Pole Power (SPP) and Spectral Pole Power with Dominant Frequency weighing (SPPDF) and Centroid Frequency (CF) and Amplitude Spectrum Area (AMSA) based on Fast Fourier Transformation (FFT). RESULTS: With ROC AUC values up to 84.1% and diagnostic odds ratio up to 19.12 AR based features SPP and SPPDF have better prediction power than the FFT based features CF (80.5%; 6.56) and AMSA (82.1%; 8.79). CONCLUSIONS: AR estimation based features are promising alternatives to FFT based features for countershock outcome when analyzing human data.

Does prematurity alter the course of respiratory syncytial virus infection?

We compared previously healthy prematurely born infants with full-term infants hospitalized with respiratory syncytial virus (RSV) infection to evaluate the role of prematurity on the clinical course of the illness. During a 5-yr period (1984 to 1989), 484 previously healthy patients were admitted to the hospital with RSV infection. No differences were found in the presenting symptoms of respiratory distress, cough, fever or shock, although the premature group was more likely to present with apnea (p less than .001). Chest roentgenograms revealed that premature infants had a higher incidence of atelectasis/infiltrate and hyperinflation (p less than .05). Premature infants had longer hospital stays as well as a higher Physiologic Stability Index and Therapeutic Intervention Score (p less than .001). They were also more likely to receive supplemental oxygen, ICU admission, mechanical ventilation, and nothing by mouth status (p less than .001). We conclude that premature birth increases the risk of more severe and prolonged RSV disease.

A large family of putative transmembrane receptors homologous to the product of the Drosophila tissue polarity gene frizzled.

In Drosophila melanogaster, the frizzled gene plays an essential role in the development of tissue polarity as assessed by the orientation of cuticular structures. Through a combination of random cDNA sequencing, degenerate polymerase chain reaction amplification, and low stringency hybridization we have identified six novel frizzled homologues from mammals, at least 11 from zebrafish, several from chicken and sea urchin, and one from Caenorhabditis elegans. The complete deduced amino acid sequences of the mammalian and nematode homologues share with the Drosophila frizzled protein a conserved amino-terminal cysteine-rich domain and seven putative transmembrane segments. Each of the mammalian homologues is expressed in a distinctive set of tissues in the adult, and at least three are expressed during embryogenesis. As hypothesized for the Drosophila frizzled protein, the frizzled homologues are likely to act as transmembrane receptors for as yet unidentified ligands. These observations predict the existence of a family of signal transduction pathways that are homologous to the pathway that determines tissue polarity in Drosophila.