Adenoviral gene transfer corrects the ion transport defect in the sinus epithelia of a porcine CF model.

Cystic fibrosis (CF) pigs spontaneously develop sinus and lung disease resembling human CF. The CF pig presents a unique opportunity to use gene transfer to test hypotheses to further understand the pathogenesis of CF sinus disease. In this study, we investigated the ion transport defect in the CF sinus and found that CF porcine sinus epithelia lack cyclic AMP (cAMP)-stimulated anion transport. We asked whether we could restore CF transmembrane conductance regulator gene (CFTR) current in the porcine CF sinus epithelia by gene transfer. We quantified CFTR transduction using an adenovirus expressing CFTR and green fluorescent protein (GFP). We found that as little as 7% of transduced cells restored 6% of CFTR current with 17-28% of transduced cells increasing CFTR current to 50% of non-CF levels. We also found that we could overcorrect cAMP-mediated current in non-CF epithelia. Our findings indicate that CF porcine sinus epithelia lack anion transport, and a relatively small number of cells expressing CFTR are required to rescue the ion transport phenotype. These studies support the use of the CF pig as a preclinical model for future gene therapy trials in CF sinusitis.

The effect of geniglossal advancement on airway flow using a computational flow dynamics model.

OBJECTIVES/HYPOTHESIS: Obstructive sleep apnea (OSA) is a sleep disorder caused by partial or complete collapse of the pharyngeal airway. Genioglossal advancement (GGA) is a well-tolerated surgical procedure intended to address hypopharyngeal collapse, yet there are few studies that monitor changes in airflow dynamics at this site. Computation fluid dynamics (CFD) utilizes airflow simulation to predict changes in airflow after anatomic manipulation. STUDY DESIGN: We investigated the change in volume and airflow dynamics of the pharyngeal airway after GGA in a cadaveric model. METHODS: We performed serial GGA from 1 mm (control) to 3, 7, and 9 mm on a lightly preserved cadaver. After each intervention, we performed high-resolution computed tomography scans, reconstructed the pharyngeal airway, and quantified airspace volume and CFD analysis with both laminar and large eddy simulation models. RESULTS: Airway volume increased with linear GGA. In both CFD simulation models, velocity increased and pressure decreased after 9-mm advancement secondary to increased airway diameter and less abrupt changes in airway geometry. CONCLUSIONS: These results suggest that GGA may be effective in increasing airway volume and flow to address hypopharyngeal obstruction in OSA.

Sinus hypoplasia precedes sinus infection in a porcine model of cystic fibrosis.

OBJECTIVES/HYPOTHESIS: Chronic sinusitis is nearly universal in humans with cystic fibrosis (CF) and is accompanied by sinus hypoplasia (small sinuses). However, whether impaired sinus development is a primary feature of loss of the cystic fibrosis transmembrane conductance regulator (CFTR) or a secondary consequence of chronic infection remains unknown. Our objective was to study the early pathogenesis of sinus disease in CF. STUDY DESIGN: Animal/basic science research. METHODS: Sinus development was studied in a porcine CF model. RESULTS: Porcine sinus epithelia expressed CFTR and exhibited transepithelial anion transport. Disruption of the CFTR gene eliminated both. Sinuses of newborn CF pigs were not infected and showed no evidence of inflammation, yet were hypoplastic at birth. Older CF pigs spontaneously developed sinus disease similar to that seen in humans with CF. CONCLUSIONS: These results define a role for CFTR in sinus development and suggest the potential of the CF pig as a genetic model of CF-sinus disease in which to test therapeutic strategies to minimize sinus-related CF morbidity.

Successful reconstruction of scalp and skull defects: lessons learned from a large series.

OBJECTIVE: To provide a framework for the management of scalp and skull defects. DESIGN: Retrospective chart review. SETTING: Two tertiary care hospitals. PATIENTS/INTERVENTION: Fifty-six consecutive patients who underwent reconstruction of scalp and/or skull defects with free flaps, rotational skin/fascia flaps, skin grafts, and implants. Defects closed primarily and those of the lateral temporal bone and skull base were excluded. RESULTS: Sixty-two reconstructions were performed. Treatment of skin cancers and intracranial tumors necessitated 31 (50%) and 22 (35%) of the reconstructions, respectively. Defects included partial-thickness soft tissue (9, 15%), full-thickness soft tissue (28, 45%), full-thickness soft tissue and skull (17, 27%), and full-thickness soft tissue, skull, and dura (8, 13%). Radiation or prereconstruction wound breakdown or infection was involved in 33 (53%) and 25 (40%) of cases, respectively. The most common method of reconstruction was free tissue transfer (27, 44%) followed by local skin (15, 24%) or fascia (9, 15%) flaps. There was a 15% (9/62) complication rate; 89% (8/9) of these occurred in radiated tissues and 44% (4/9) occurred in smokers. Seven of the nine patients with complications (78%) were managed with local wound care and/or removal of an implant, whereas 2 (22%) required a second reconstructive procedure. All patients ultimately achieved a safe outcome with no infection and no bone or dural exposure. CONCLUSIONS: In addition to defect location and extent, availability of surrounding tissue and wound healing characteristics direct reconstruction. Patients who receive radiation therapy are at increased risk of complications. Use of vascularized tissue is critical for successful management, making local flaps and free tissue transfer the mainstay of reconstruction.

Continued alcohol use in patients with head and neck cancer.

BACKGROUND: The effect of posttreatment alcohol consumption on health-related quality of life (QOL) and factors predicting overall QOL and continued alcohol consumption were examined in patients with head and neck cancer. METHODS: Self-reported alcohol use and abuse 1 year after diagnosis was analyzed. RESULTS: Although current drinkers (44.5% of 283 patients) had better overall QOL and fewer depressive symptoms, current social drinkers had the best scores, whereas current problem drinkers had the worst. Female sex, fewer depressive symptoms, less pain, and better eating function predicted better QOL. Oral function was the only predictor of 12-month alcohol use. CONCLUSION: Depression, pain, and eating function predicted overall QOL. Alcohol consumption was not associated with QOL, but was associated with better oral function, which in turn predicted better QOL. Alcohol consumption itself does not improve QOL in this population, and these patients should be counseled regarding detrimental effects of continued drinking after treatment.