Dysfunction of pulmonary surfactant mediated by phospholipid oxidation is cholesterol-dependent.

Pulmonary surfactant forms a cohesive film at the alveolar air-lung interface, lowering surface tension, and thus reducing the work of breathing and preventing atelectasis. Surfactant function becomes impaired during inflammation due to degradation of the surfactant lipids and proteins by free radicals. In this study, we examine the role of reactive nitrogen (RNS) and oxygen (ROS) species on surfactant function with and without physiological cholesterol levels (5-10%). Surface activity was assessed in vitro in a captive bubble surfactometer (CBS). Surfactant chemistry, monolayer fluidity and thermodynamic behavior were also recorded before and after oxidation. We report that physiologic amounts of cholesterol combined with oxidation results in severe impairment of surfactant function. We also show that surfactant polyunsaturated phospholipids are the most susceptible to oxidative alteration. Membrane thermodynamic experiments showed significant surfactant film stiffening after free radical exposure in the presence of cholesterol. These results point to a previously unappreciated role for cholesterol in amplifying defects in surface activity caused by oxidation of pulmonary surfactant, a finding that may have implications for treating several lung diseases.

Immediate Bedding and Patient Satisfaction in a Pediatric Emergency Department.

BACKGROUND: Immediate bedding has been shown to increase efficiency in general emergency departments (EDs), but little has been published regarding its use in pediatric emergency medicine. OBJECTIVE: Our aims were to improve door-to-provider (DTP) times and patient satisfaction and to better define the relationships between throughput times and patient satisfaction in a pediatric ED. METHODS: On November 1, 2011, we changed to a new immediate bedding triage process in our academic, urban pediatric Level I trauma center. Both outcome and balancing measures were compared for the 6 months before and after this change in process. To evaluate the relationship between throughput times and patient satisfaction, we also analyzed data collected during a 32-month period. RESULTS: The median DTP decreased from 44 min in the pre period to 25 min in the post period (Cohen's r value = 0.29; p < 0.001). The percent DTP < 30 min also significantly improved (pre: 31.8%, post: 58.2%, odds ratio = 2.99; 95% confidence interval 2.87-3.12; p < 0.001). For the benchmark satisfaction question of "likelihood to recommend," there was also an improvement in the mean responses (pre: 89.0, post: 92.7, Cohen's r value = 0.10; p = 0.03). There were no significant differences in the balancing measures of nurse practitioner productivity and compliance with two nurse-initiated protocols. There was a weak inverse correlation between throughput times and satisfaction scores (Spearman's rank correlation -0.18; p < 0.001). CONCLUSIONS: Although immediate bedding improved the front-end efficiency in our ED, it cannot yet be considered as a "best practice" in pediatric emergency medicine.

Methyl-beta-cyclodextrin restores the structure and function of pulmonary surfactant films impaired by cholesterol.

Pulmonary surfactant, a defined mixture of lipids and proteins, imparts very low surface tension to the lung-air interface by forming an incompressible film. In acute respiratory distress syndrome and other respiratory conditions, this function is impaired by a number of factors, among which is an increase of cholesterol in surfactant. The current study shows in vitro that cholesterol can be extracted from surfactant and function subsequently restored to dysfunctional surfactant films in a dose-dependent manner by methyl-beta-cyclodextrin (MbetaCD). Bovine lipid extract surfactant was supplemented with cholesterol to serve as a model of dysfunctional surfactant. Likewise, when cholesterol in a complex with MbetaCD ("water-soluble cholesterol") was added in aqueous solution, surfactant films were rendered dysfunctional. Atomic force microscopy showed recovery of function by MbetaCD is accompanied by the re-establishment of the native film structure of a lipid monolayer with scattered areas of lipid bilayer stacks, whereas dysfunctional films lacked bilayers. The current study expands upon a recent perspective of surfactant inactivation in disease and suggests a potential treatment.

Outcomes of major trauma among patients with chronic kidney disease and receiving dialysis in Nova Scotia: a retrospective analysis.

BACKGROUND: The risk of death and complications after major trauma in patients with chronic kidney disease (CKD) is higher than in the general population, but whether this association holds true among Canadian trauma patients is unknown. OBJECTIVES: To characterize patients with CKD/receiving dialysis within a regional major trauma cohort and compare their outcomes with patients without CKD. METHODS: All major traumas requiring hospitalization between 2006 and 2017 were identified from a provincial trauma registry in Nova Scotia, Canada. Trauma patients with stage ≥3 CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2) or receiving dialysis were identified by cross-referencing two regional databases for nephrology clinics and dialysis treatments. The primary outcome was in-hospital mortality; secondary outcomes included hospital/intensive care unit (ICU) length of stay (LOS) and ventilator-days. Cox regression was used to adjust for the effects of patient characteristics on in-hospital mortality. RESULTS: In total, 6237 trauma patients were identified, of whom 4997 lived within the regional nephrology catchment area. CKD/dialysis trauma patients (n=101; 28 on dialysis) were older than patients without CKD (n=4896), with higher rates of hypertension, diabetes, and cardiovascular disease, and had increased risk of in-hospital mortality (31% vs 11%, p<0.001). No differences were observed in injury severity, ICU LOS, or ventilator-days. After adjustment for age, sex, and injury severity, the HR for in-hospital mortality was 1.90 (95% CI 1.33 to 2.70) for CKD/dialysis compared with patients without CKD. CONCLUSION: Independent of injury severity, patients without CKD/dialysis have significantly increased risk of in-hospital mortality after major trauma.

Verification of in situ thresholds and integrated real-ear measurements.

BACKGROUND: Accurate prescriptive gain results in a more accurate fit, lower return rate in hearing aids, and increased patient satisfaction. In situ threshold measurements can be used to determine required gain. The Widex Corporation uses an in situ threshold measurement strategy, called the Sensogram. Real-ear measurements determine if prescriptive gain targets have been achieved. Starkey Laboratories introduced an integrated real-ear measurement system in their hearing aids. PURPOSE: To determine whether the responses obtained using the Widex Sensogram were equivalent to those obtained using current clinical threshold measurement methods. To determine the accuracy of the Starkey IREMS™ (Integrated Real Ear Measurement System) in measuring RECD (real-ear to coupler difference) values compared to a dedicated real-ear measurement system. RESEARCH DESIGN: A verification design was employed by comparing participant data measured from standard, benchmark equipment and procedures against new techniques offered by hearing-aid manufacturers. STUDY SAMPLE: A total of 20 participants participated in this study. Ten participants with sensorineural hearing loss were recruited from the Ohio University Hearing, Speech, and Language Clinic participated in the first experiment. Ten participants with normal hearing were recruited from the student population at Ohio University participated in both experiments. The normal-hearing group had thresholds of 15 dB HL or better at the octave frequencies of 250-8000 Hz. The hearing-impaired group had thresholds of varying degrees and configurations with thresholds equal to or poorer than 25 dB HL three-frequency pure-tone average. DATA COLLECTION AND ANALYSIS: The order of measurement method for both experiments was counterbalanced. In Experiment 1, thresholds obtained via the Widex Sensogram were compared to thresholds obtained for each participant using a clinical audiometer and ER-3A insert ear phones. In Experiment 2, RECD values obtained via the Starkey IREMS were compared to RECD values obtained via the Audioscan Verifit™. A repeated-measures analysis of variance (ANOVA) was used for statistical analysis, and a Fisher's LSD (least significant difference) was used as a post hoc analysis tool. RESULTS: A significant difference between Sensogram thresholds and conventional audiometric thresholds was found with the Sensogram method resulting in better threshold values at 0.5, 1.0, and 2.0 kHz for both groups. In Experiment 2, a significant difference between RECD values obtained by the Starkey IREMS and the Audioscan Verifit system was found with significant differences in RECD values found at 0.25, 0.5, 0.75, 1.5, 2.0, and 6.0 kHz. CONCLUSIONS: The Sensogram data differ significantly from traditional audiometry at several frequencies important for speech intelligibility. Real-ear measures are still required for verification of prescribed gain, however, calling into question any claims of shortened fitting time. The Starkey IREMS does perform real-ear measurements that vary significantly from benchmark equipment. These technologies represent a positive direction in prescribing accurate gain during hearing-aid fittings, but a stand-alone system is still the preferred method for real-ear measurements in hearing-aid fittings.

Use of denosumab to treat refractory hypercalcemia in a peritoneal dialysis patient with immobilization and tertiary hyperparathyroidism.

Hypercalcemia due to excess parathyroid hormone (PTH) production is a common condition among patients with end-stage renal disease (ESRD), often referred to as tertiary hyperparathyroidism. There are limited effective medical treatment options currently available for such patients. Denosumab is a monoclonal antibody that inhibits osteoclast activation, thereby reducing calcium release from bones. Denosumab has been used to treat medically-refractory hypercalcemia in non-ESRD patients with hyperparathyroidism. Denosumab has also been used to treat non-PTH-mediated hypercalcemia in patients with advanced chronic kidney disease and ESRD. In this case report, we describe the use of denosumab to successfully treat a case of medically refractory hypercalcemia due to immobilization in a patient on peritoneal dialysis with severe underlying tertiary hyperparathyroidism. In spite of persistently elevated PTH, hypercalcemia quickly resolved after a single dose of denosumab. The patient subsequently developed temporary hypocalcemia requiring medical intervention. Our case report, which is the first described use of denosumab for treatment of hypercalcemia in the setting of tertiary hyperparathyroidism in a peritoneal dialysis patient, adds to the body of literature suggesting denosumab is a useful therapeutic agent in patients with ESRD. Issues with post-treatment electrolyte management and other therapeutic considerations are also discussed.

Surfactant Dysfunction in ARDS and Bronchiolitis is Repaired with Cyclodextrins.

Objectives: Acute respiratory distress syndrome (ARDS) is caused by many factors including inhalation of toxicants, acute barotrauma, acid aspiration, and burns. Surfactant function is impaired in ARDS and acute airway injury resulting in high surface tension with alveolar and small airway collapse, edema, hypoxemia, and death. In this study, we explore the mechanisms whereby surfactant becomes dysfunctional in ARDS and bronchiolitis and its repair with a cyclodextrin drug that sequesters cholesterol. Methods: We used in vitro model systems, a mouse model of ARDS, and samples from patients with acute bronchiolitis. Surface tension was measured by captive bubble surfactometry. Results: Patient samples showed severe surfactant inhibition even in the absence of elevated cholesterol levels. Surfactant was also impaired in ARDS mice where the cholesterol to phospholipid ratio (W/W%) was increased. Methyl-ß-cyclodextrin (MßCD) restored surfactant function to normal in both human and animal samples. Model studies showed that the inhibition of surfactant was due to both elevated cholesterol and an interaction between cholesterol and oxidized phospholipids. MßCD was also shown to have anti-inflammatory effects. Conclusions: Inhaled cyclodextrins have potential for the treatment of ARDS. They could be delivered in a portable device carried in combat and used following exposure to toxic gases and fumes or shock secondary to hemorrhage and burns.

Pulmonary surfactant dysfunction in pediatric cystic fibrosis: Mechanisms and reversal with a lipid-sequestering drug.

BACKGROUND: Airway surfactant is impaired in cystic fibrosis (CF) and associated with declines in pulmonary function. We hypothesized that surfactant dysfunction in CF is due to an excess of cholesterol with an interaction with oxidation. METHODS: Surfactant was extracted from bronchial lavage fluid from children with CF and surface tension, and lipid content, inflammatory cells and microbial flora were determined. Dysfunctional surfactant samples were re-tested with a lipid-sequestering agent, methyl-ß-cyclodextrin (MßCD). RESULTS: CF surfactant samples were unable to sustain a normal low surface tension. MßCD restored surfactant function in a majority of samples.Mechanistic studies showed that the dysfunction was due to a combination of elevated cholesterol and an interaction with oxidized phospholipids and their pro-inflammatory hydrolysis products. CONCLUSION: We confirm that CF patients have impaired airway surfactant function which could be restored with MßCD. These findings have implications for improving lung function and mitigating inflammation in patients with CF.

Re-evaluating the role of ELT-3 in a GATA transcription factor circuit proposed to guide aging in C. elegans.

Budovskaya et al. (Cell. 134, 291-303, 2008) have proposed that the ELT-3 GATA factor regulates somatic aging genes, including those expressed in the intestine, and participates in a transcription factor circuit that "guides Caenorhabditis elegans aging". We have re-investigated two key features of this proposal: (i) expression of elt-3 in the C. elegans adult intestine where the majority of somatic aging genes are expressed, and; (ii) the ability of elt-3 loss-of-function to revert the extended lifespan of daf-2(e1370) mutants. We find that: (i) in agreement with our previously published results, ELT-3 expression is largely hypodermal and is not expressed at significant levels in the adult C. elegans intestine, and; (ii) the elt-3(vp1) zinc-finger deletion mutant does not significantly influence the extended lifespan of daf-2(e1370) mutants. We thus suggest that the role of ELT-3 in C. elegans aging should be re-evaluated.