Resveratrol enhances airway surface liquid depth in sinonasal epithelium by increasing cystic fibrosis transmembrane conductance regulator open probability.

BACKGROUND: Chronic rhinosinusitis engenders enormous morbidity in the general population, and is often refractory to medical intervention. Compounds that augment mucociliary clearance in airway epithelia represent a novel treatment strategy for diseases of mucus stasis. A dominant fluid and electrolyte secretory pathway in the nasal airways is governed by the cystic fibrosis transmembrane conductance regulator (CFTR). The objectives of the present study were to test resveratrol, a strong potentiator of CFTR channel open probability, in preparation for a clinical trial of mucociliary activators in human sinus disease. METHODS: Primary sinonasal epithelial cells, immortalized bronchoepithelial cells (wild type and F508del CFTR), and HEK293 cells expressing exogenous human CFTR were investigated by Ussing chamber as well as patch clamp technique under non-phosphorylating conditions. Effects on airway surface liquid depth were measured using confocal laser scanning microscopy. Impact on CFTR gene expression was measured by quantitative reverse transcriptase polymerase chain reaction. RESULTS: Resveratrol is a robust CFTR channel potentiator in numerous mammalian species. The compound also activated temperature corrected F508del CFTR and enhanced CFTR-dependent chloride secretion in human sinus epithelium ex vivo to an extent comparable to the recently approved CFTR potentiator, ivacaftor. Using inside out patches from apical membranes of murine cells, resveratrol stimulated an ~8 picosiemens chloride channel consistent with CFTR. This observation was confirmed in HEK293 cells expressing exogenous CFTR. Treatment of sinonasal epithelium resulted in a significant increase in airway surface liquid depth (in µm: 8.08+/-1.68 vs. 6.11+/-0.47,control,p<0.05). There was no increase CFTR mRNA. CONCLUSION: Resveratrol is a potent chloride secretagogue from the mucosal surface of sinonasal epithelium, and hydrates airway surface liquid by increasing CFTR channel open probability. The foundation for a clinical trial utilizing resveratrol as a therapeutic intervention to increase mucociliary transport and airway surface liquid hydration in sinus disease is strongly supported by these findings.

Unusual presentation of extracardiac fetal rhabdomyoma of the larynx in a pediatric patient with tuberous sclerosis.

Tuberous sclerosis (TSC) is an autosomal-dominant genetic disease characterized by a spectrum of pathologic manifestations involving skin, brain, kidney, and heart. These manifestations include neuroectodermal, mesodermal, and skin lesions as well as a variety of associated tumors and hamartomas. We report an 11-year-old male with previously diagnosed TSC who presented with a laryngeal mass shown on histology to be fetal cellular rhabdomyoma. Cardiac rhabdomyomas are common in TSC patients, but to our knowledge, the association between TSC and extracardiac rhabdomyomas has not been previously reported.

Cystic fibrosis transmembrane conductance regulator modulation by the tobacco smoke toxin acrolein.

OBJECTIVES/HYPOTHESIS: Evidence indicates that decreased mucociliary clearance (MCC) is a major contributing feature to chronic rhinosinusitis. Tobacco-smoke exposure is thought to inhibit transepithelial Cl(-) secretion, a major determinant of airway surface liquid hydration and MCC. The objective of the current study was to evaluate the effects of acrolein exposure (a prominent tobacco smoke toxin) on vectorial Cl(-) transport through the major apical anion channel cystic fibrosis transmembrane conductance regulator (CFTR) in sinonasal epithelium. STUDY DESIGN: In vitro investigation. METHODS: Primary murine nasal septal epithelia (MNSE; wild-type and transgenic CFTR(-/-)) cultures were exposed to acrolein in Ussing chambers and the effects on Cl(-) secretion investigated using pharmacologic manipulation. Cellular cyclic adenosine monophosphate (cAMP) signaling and cytotoxicity were also investigated. RESULTS: Acrolein stimulated Cl(-) secretion (ΔI(SC) - change in short-circuit current in µA/cm(2)) at concentrations similar to smoker's airways (100 µM, 15.8 ± 2.2 vs. 2.4 ± 0.8 [control]; P < .0001), suppressed forskolin-stimulated C- transport at 300 µM (13.3 ± 1.2 vs. 19.9 ± 1.0; P < .01), and completely abolished all transport at 500 µM (-1.1 ± 1.6). Stimulated Cl(-) secretion was solely reliant upon the presence of CFTR (confirmed in transgenic CFTR(-/-) MNSE), but independent of cAMP signaling. Inhibition at higher concentrations was not secondary to cellular cytotoxicity. CONCLUSIONS: The present study demonstrates that acrolein has complex but pronounced interaction with the major apical Cl(-) transport mechanism that uses CFTR. Further investigations are required to determine acrolein's impact as a tobacco smoke constituent on mucociliary transport.

Cerebrospinal fluid volume replacement following large endoscopic anterior cranial base resection.

BACKGROUND: Large endoscopic skull-base resections often result in extensive postoperative pneumocephalus secondary to copious evacuation of cerebrospinal fluid (CSF) during the procedures. Replacing CSF lost during craniotomy with saline is a common technique in neurosurgery, but is difficult after extensive transnasal resection of the anterior cranial base because direct transnasal CSF augmentation will escape until the skull base reconstruction is sealed. The present study evaluated the effectiveness of intraoperative CSF volume replacement via lumbar drains on improving postoperative outcomes. METHODS: Ten large endoscopic anterior skull-base resections (>2.5 cm) were performed from 2008 to 2011. Sellar, parasellar, and transplanum resections were excluded. Etiologies included esthesioneuroblastoma (2), squamous cell carcinoma (2), intracranial dermoid (2), adenocarcinoma (1), adenoid cystic carcinoma (1), melanoma (1), and meningioma (1). Six patients were administered preservative-free normal saline via lumbar drain during skull-base reconstruction. Data collected included volume of postoperative pneumocephalus, intravenous pain medicine requirements 24 hours after surgery, and length of hospital stay. RESULTS: Volume of pneumocephalus (4.78 cm vs 12.8 cm(3) , p = 0.04) and length of hospital stay (2.17 days vs 8.5 days, p = 0.03) were significantly decreased in the normal saline volume replacement group. Average intravenous pain medication requirements were reduced in the first 24 hours postoperatively (8 mg morphine vs 14 mg morphine, p = 0.25), but did not reach statistical significance. CONCLUSION: Evacuation of intracranial air by transthecal administration of saline during reconstruction of large anterior cranial base defects was an effective technique to decrease postoperative pneumocephalus and length of hospital stay. Further evaluation is warranted.

Transepithelial ion transport is suppressed in hypoxic sinonasal epithelium.

OBJECTIVES/HYPOTHESIS: Sinonasal respiratory epithelial mucociliary clearance is dependent on the transepithelial transport of ions such as Cl(-) . The objectives of the present study were to investigate the role of oxygen restriction in 1) Cl(-) transport across primary sinonasal epithelial monolayers, 2) expression of the apical Cl(-) channels cystic fibrosis transmembrane conductance regulator (CFTR) and transmembrane protein 16A (TMEM16A), and 3) the pathogenesis of chronic rhinosinusitis. STUDY DESIGN: In vitro investigation. METHODS: Murine nasal septal epithelial (MNSE), wild type, and human sinonasal epithelial (HSNE) cultures were incubated under hypoxic conditions (1% O(2) , 5% CO(2) ). Cultures were mounted in Ussing chambers for ion transport measurements. CFTR and TMEM16A expression were measured using quantitative reverse-transcription polymerase chain reaction (RT-PCR). RESULTS: The change in short-circuit current (ΔI(SC) in microamperes per square centimeter) attributable to CFTR (forskolin-stimulated) was significantly decreased due to a 12-hour hypoxia exposure in both MNSE (13.55 ± 0.46 vs. 19.23 ± 0.18) and HSNE (19.55 ± 0.56 vs. 25.49 ± 1.48 [control]; P < .05). TMEM16A (uridine triphosphate-stimulated transport) was inhibited by 48 hours of hypoxic exposure in MNSE (15.92 ± 2.87 vs. 51.44 ± 3.71 [control]; P < .05) and by 12 hours of hypoxic exposure in HSNE (16.75 ± 0.68 vs. 24.15 ± 1.35 [control]). Quantitative RT-PCR (reported as relative mRNA levels ± standard deviation) demonstrated significant reductions in both CFTR and TMEM16A mRNA expression in MNSE and HSNE owing to airway epithelial hypoxia. CONCLUSIONS: Sinonasal epithelial CFTR and TMEM16A-mediated Cl(-) transport and mRNA expression were robustly decreased in an oxygen-restricted environment. These findings indicate that persistent hypoxia may lead to acquired defects in sinonasal Cl(-) transport in a fashion likely to confer mucociliary dysfunction in chronic rhinosinusitis.

Juvenile nasopharyngeal angiofibroma.

Juvenile nasopharyngeal angiofibromas (JNAs) are rare, benign, highly vascular, locally aggressive tumors that primarily affect male adolescents. Historical treatment of these neoplasms has been primarily surgical. In the past decade, endoscopic resection of JNAs has become a viable and promising surgical treatment option. Endoscopic resection has many advantages over traditional open techniques, including better cosmesis, decreased blood loss, shortened hospital stays, and equivalent or improved recurrence rates. Emerging endoscopic technology continues to push the boundaries of resection of skull base tumors and will no doubt become the surgical treatment of choice for most JNAs in the near future.

Validation of a laryngeal dissection module for phonomicrosurgical training.

OBJECTIVES: To validate the use of a new phonomicrosurgical trainer called the laryngeal dissection module. STUDY DESIGN: The module used synthetic, multilayered vocal folds inside a model larynx mounted on a platform, a microscope, and microsurgical instruments. The study was designed to test the module's ability to differentiate novices from expert surgeons and to test the module's ability to improve novice performance with training. METHODS: Expert (n = 5) and novice (n = 21) phonomicrosurgeons were instructed to remove a superficial ovoid lesion from a synthetic, right vocal fold. The task was assessed for total errors, total operating time, and injury to the superficial peripheral tissue, the lesion, and the deep tissue. Novice and expert performance was compared using an independent samples t test and a Fisher exact test. Subsequently, novices completed three practice trials and a posttraining trial, which was assessed for improvement compared with pretraining performance using a Wilcoxon signed rank test. RESULTS: Experts completed the task with fewer total errors than novices (P < .001) and made fewer injuries to the oval lesion (P = .01). Novices improved performance with training, making fewer total errors in the posttraining trial (P = .003), reducing injury to the superficial peripheral tissue (P = .02), and taking less time to complete the task (P = .04). CONCLUSIONS: The laryngeal dissection module was validated as a surgical trainer. It was able to differentiate expert versus novice performance, and it improved novice performance through training.

Resource use associated with topiramate in migraine prophylaxis.

PURPOSE: The effect of topiramate prophylaxis on medication use and medical resource use for migraine patients was studied. METHODS: Medical and pharmacy claims from a commercially insured population were analyzed from July 1, 1999, to March 31, 2004. The study sample included patients with at least one physician encounter or facility claim with a diagnosis of migraine at any point during the study's time frame. Patients either were naive to drugs labeled for migraine prophylaxis or had switched to topiramate from another drug labeled for migraine prophylaxis. The date of topiramate initiation was between January 1, 2000, and September 30, 2003; topiramate initiation was the index date. Demographic and clinical characteristics were evaluated. Migraine-related medication use and resource use were compared between the pre- and postindex periods. RESULTS: Of the 1749 patients analyzed, 90.2% were female. Neurologists wrote 54% of the index prescriptions. The mean +/- S.D. topiramate dosage was 98 +/- 65 mg/day. Statistically significant decreases occurred in the proportion of patients using drugs not labeled for migraine prophylaxis, nonopioid analgesics, nonsteroidal antiinflammatory drugs, and headache and migraine relief medications (p < 0.05). There was a 44.9% reduction in emergency room services, 53.2% reduction in migraine- related diagnostic procedures, and 57.1% reduction in migraine-related hospitalization days. Encounter claims for physicians' office visits did not change significantly. CONCLUSION: Migraine patients within commercially insured health plans incurred substantial resource use. Within six months following initiation of topiramate preventive therapy, reductions in acute migraine medication and medical resource use were observed among this population of migraine sufferers.

Topiramate in migraine prophylaxis: long-term impact on resource utilization and cost.

OBJECTIVE: To evaluate the medical resource utilization and overall cost of care among patients treated with topiramate (TPM) for migraine prevention in a commercially insured population. Background.-Preventive migraine therapy with TPM significantly reduces the frequency of migraine attacks. Limited data exist on the real-world health care consumption associated with TPM therapy for migraine prevention. METHODS: Data were obtained from a large geographically diverse integrated medical and pharmacy claims database representative of the commercially insured population. The date of the first TPM claim between July 2000 and December 2003 was considered the index date. Patients needed at least 1 triptan prescription (Rx) claim during the 6-month preindex period, and > or =2 TPM Rx claims in the 12 months following index TPM Rx to be included in the analysis. Headache-related inpatient and outpatient resource use were compared: preindex vs postindex period 1 (months 1-6) and preindex vs postindex period 2 (months 7-12). Subgroup analyses were conducted based on the triptan consumption during the 6-month preindex period: Cohort L (low triptan users) with < or =36 triptan doses, and Cohort H (high triptan users) with >36 triptan doses. RESULTS: The sample included 2645 plan members (1778 patients in Cohort L, and 867 patients in Cohort H). TPM utilization was associated with significantly less triptan utilization in the first (34.8 quantity dispensed; 7.5% decrease) and second (30.2; 19.6% decrease) follow-up periods compared to the preindex period (37.6; both P < .0001). In postindex period 1, there was a 46% decrease in emergency department (ED) visits, 39% decrease in diagnostic procedures (eg, CT scans and MRIs), and a 33% decrease in hospital admission; physician office visits were unchanged. In postindex period 2, there was a 46% decrease in ED visits, 72% decrease in diagnostic procedures, 61% decrease in hospital admissions, and a 35% decrease in physician office visits. Decreases in resource use were observed in both cohorts L and H. Mean +/- SD total headache-related cost was $2118 +/- $3406 per patient in the preperiod, versus $2450 +/- $3318 in follow-up period 1 and $2009 +/- $3136 in follow-up period 2. CONCLUSION: In this sample of patients from a diverse set of health plans receiving TPM, significant decreases in resource use were observed within 6 months of TPM initiation, and this trend continued in follow-up period 2. Although there was an initial increase in total headache-related cost upon introduction of TPM (follow-up period 1), the cost in follow-up period 2 was lower than in the preindex period, suggesting that benefits of long-term treatment with TPM can be achieved without increasing total cost.

Modifying a breast cancer risk factor survey for African American women.

PURPOSE/OBJECTIVES: To evaluate a breast cancer risk factor survey for use with African American women. DESIGN: Two focus groups consisting of women randomly selected from the patient population of Henry Ford Health System in Detroit, MI. SETTING: A large, vertically integrated, private, nonprofit health system. SAMPLE: Focus Group I consisted of 11 African American women aged 18-50, with a mean age of 41 years. Focus Group II consisted of nine African American women aged 51 and older, with a mean age of 60.9 years. METHODS: A qualitative approach was used to gather and interpret the focus group data. MAIN RESEARCH VARIABLES: Perceptions of a breast cancer risk factor survey and perceptions of breast cancer risk factors. FINDINGS: The focus group participants suggested ways to improve the survey. Women in the younger age group appeared to lack awareness regarding breast cancer risk factors. Women in the older age group reported not knowing their family health histories. CONCLUSIONS: Based on comments made by the focus group participants, the survey was modified substantially. Breast cancer risk factors were perceived differently by women in the two age groups. IMPLICATIONS FOR NURSING: Results of a survey of a large, ethnically diverse sample of women could inform the development of culturally and age-appropriate nursing interventions designed to address breast cancer risk perceptions and enhance the likelihood of adherence to recommended mammography screening guidelines.

Improving quality of care for acute myocardial infarction: The Guidelines Applied in Practice (GAP) Initiative.

CONTEXT: Quality of care of patients with acute myocardial infarction (AMI) has received intense attention. However, it is unknown if a structured initiative for improving care of patients with AMI can be effectively implemented at a wide variety of hospitals. OBJECTIVE: To measure the effects of a quality improvement project on adherence to evidence-based therapies for patients with AMI. DESIGN AND SETTING: The Guidelines Applied in Practice (GAP) quality improvement project, which consisted of baseline measurement, implementation of improvement strategies, and remeasurement, in 10 acute-care hospitals in southeast Michigan. PATIENTS: A random sample of Medicare and non-Medicare patients at baseline (July 1998--June 1999; n = 735) and following intervention (September 1--December 15, 2000; n = 914) admitted at the 10 study centers for treatment of confirmed AMI. A random sample of Medicare patients at baseline (January--December 1998; n = 513) and at remeasurement (March--August 2001; n = 388) admitted to 11 hospitals that volunteered, but were not selected, served as a control group. INTERVENTION: The GAP project consisted of a kickoff presentation; creation of customized, guideline-oriented tools designed to facilitate adherence to key quality indicators; identification and assignment of local physician and nurse opinion leaders; grand rounds site visits; and premeasurement and postmeasurement of quality indicators. MAIN OUTCOME MEASURES: Differences in adherence to quality indicators (use of aspirin, beta-blockers, and angiotensin-converting enzyme [ACE] inhibitors at discharge; time to reperfusion; smoking cessation and diet counseling; and cholesterol assessment and treatment) in ideal patients, compared between baseline and postintervention samples and among Medicare patients in GAP hospitals and the control group. RESULTS: Increases in adherence to key treatments were seen in the administration of aspirin (81% vs 87%; P =.02) and beta-blockers (65% vs 74%; P =.04) on admission and use of aspirin (84% vs 92%; P =.002) and smoking cessation counseling (53% vs 65%; P =.02) at discharge. For most of the other indicators, nonsignificant but favorable trends toward improvement in adherence to treatment goals were observed. Compared with the control group, Medicare patients in GAP hospitals showed a significant increase in the use of aspirin at discharge (5% vs 10%; P<.001). Use of aspirin on admission, ACE inhibitors at discharge, and documentation of smoking cessation also showed a trend for greater improvement among GAP hospitals compared with control hospitals, although none of these were statistically significant. Evidence of tool use noted during chart review was associated with a very high level of adherence to most quality indicators. CONCLUSIONS: Implementation of guideline-based tools for AMI may facilitate quality improvement among a variety of institutions, patients, and caregivers. This initial project provides a foundation for future initiatives aimed at quality improvement.

Taking the national guideline for care of acute myocardial infarction to the bedside: developing the guideline applied in practice (GAP) initiative in Southeast Michigan.

BACKGROUND: The Guideline Applied in Practice (GAP) program was developed in 2000 to improve the quality of care by improving adherence to clinical practice guidelines. For the first GAP project, the American College of Cardiology (ACC) partnered with the Southeast Michigan Quality Forum Cardiovascular Subgroup and the Michigan Peer Review Organization (MPRO) to develop interventions that might facilitate the use of the ACC/AHA Acute Myocardial Infarction (AMI) guideline in the practice setting. Ten Michigan hospitals participated in implementing the project, which began in March 2000. DESIGNING THE PROJECT: The project developed a multifaceted intervention aimed at key players in the care delivery triangle: the physician, nurse, and patient. Intervention components included a project kick-off presentation and dinner, creation and implementation of a customized tool kit, identification and assignment of local nurse and physician opinion leaders, grand rounds site visits, and measurement before and after the intervention. IMPLEMENTING THE PROJECT: The GAP project experience suggests that hospitals are enthusiastic about partnering with ACC to improve quality of care; partners can work together to develop a program for guideline implementation; rapid-cycle implementation is possible with the GAP model; guidelines and quality indicators for AMI are well accepted; and hospitals can adapt the national guideline for care into usable tools focused on physicians, nurses, and patients. DISCUSSION: Important structure and process changes--both of which are required for successful QI efforts--have been demonstrated in this project. Ultimately, the failure or success of this initiative will depend on an indication that the demonstrated improvement in the quality indicators is sustained over time.