Sinus microbiome diversity depletion and Corynebacterium tuberculostearicum enrichment mediates rhinosinusitis.

Persistent mucosal inflammation and microbial infection are characteristics of chronic rhinosinusitis (CRS). Mucosal microbiota dysbiosis is found in other chronic inflammatory diseases; however, the relationship between sinus microbiota composition and CRS is unknown. Using comparative microbiome profiling of a cohort of CRS patients and healthy subjects, we demonstrate that the sinus microbiota of CRS patients exhibits significantly reduced bacterial diversity compared with that of healthy controls. In our cohort of CRS patients, multiple, phylogenetically distinct lactic acid bacteria were depleted concomitant with an increase in the relative abundance of a single species, Corynebacterium tuberculostearicum. We recapitulated the conditions observed in our human cohort in a murine model and confirmed the pathogenic potential of C. tuberculostearicum and the critical necessity for a replete mucosal microbiota to protect against this species. Moreover, Lactobacillus sakei, which was identified from our comparative microbiome analyses as a potentially protective species, defended against C. tuberculostearicum sinus infection, even in the context of a depleted sinus bacterial community. These studies demonstrate that sinus mucosal health is highly dependent on the composition of the resident microbiota as well as identify both a new sino-pathogen and a strong bacterial candidate for therapeutic intervention.

Nucleic acid extraction efficiency and bacterial recovery from maxillary sinus mucosal samples obtained by brushing or biopsy.

BACKGROUND: Chronic rhinosinusitis (CRS) is a common disease with a complex pathophysiology involving a microbial component. Culture-independent molecular analysis represents a promising new approach to clarify the microbiology of CRS, but standardized, optimized sampling methods still have not been defined. This study was designed to compare nucleic acid extraction rates and recovery of bacteria for two methods of sampling the maxillary sinus, mucosal biopsy, and brushing. METHODS: Samples were obtained from 20 patients undergoing maxillary sinus surgery. Total extracted nucleic acid concentration and bacterial burden were compared between sample types. RESULTS: Total nucleic acid concentration varied across patients. No statistically significant difference in mean total DNA concentration from mucosal biopsy specimens or brushings was observed. However, compared with biopsy specimens, brush samples possessed a significant (p < 0.035) increase in bacterial copy number. CONCLUSION: Endoscopically directed mucosal brushings of the maxillary sinus provide equivalent concentrations of total DNA to mucosal biopsy specimens but possess greater concentrations of bacterial DNA, likely because of the greater surface area sampled by this method. Given the additional advantage of lower risk associated with obtaining brush samples, we suggest they represent the preferred sampling method for future genomic sinus studies.

Adult subglottic stenosis: management with laser incisions and mitomycin-C.

OBJECTIVES/HYPOTHESIS: To assess the efficacy of endoscopic laser radial incisions with mitomycin-C application (ELRM) in managing adult subglottic stenosis (SGS). STUDY DESIGN: Retrospective case series review. METHODS: Fifteen consecutive cases of adult SGS treated with ELRM at a single tertiary referral center over three years were reviewed. Subjects with SGS secondary to Wegener's granulomatosis (WG) and idiopathic SGS were included. Patients with cartilaginous SGS were excluded. The primary outcome measure was postoperative reduction in symptoms. Secondary outcome measures included total number of procedures required to relieve symptoms, interval between procedures, and improvement in pulmonary function tests when available. In addition to surgery, 14 of 15 patients were treated medically for reflux. RESULTS: Ten women and five men with average age 48 years were identified. Ten patients had idiopathic SGS and five had WG. The predominant presenting symptom was dyspnea on exertion in all patients. All subjects reported at least a temporary postoperative reduction in symptoms. Six patients (40%) required only one ELRM and nine patients (60%) required repeat ELRM at an average interval of 9 months. The average interval for the six patients with idiopathic etiology requiring a second procedure was 9 months. One subject with WG required four procedures. His interval improved from 2.5 to 7 months between procedures. Evidence of extrathoracic airway obstruction resolved in three of four patients with pre and postoperative pulmonary function tests. CONCLUSIONS: ELRM is an effective method of managing SGS associated with idiopathic causes. In patients with WG, ELRM reduced airway associated symptoms and avoided need for tracheotomy.

AAV-mediated delivery of the caspase inhibitor XIAP protects against cisplatin ototoxicity.

HYPOTHESIS: Delivery of the gene encoding X-linked inhibitor of apoptosis (XIAP) using an adeno-associated viral (AAV) vector can protect against cisplatin-mediated ototoxicity. BACKGROUND: Cisplatin is a widely used chemotherapeutic agent with significant ototoxic side effects. One possible mechanism of toxicity is apoptotic death of many cochlear cell types. Acute treatment with inhibitors of caspases- enzymes critical for apoptosis- has been shown to prevent hearing loss in vivo, but is too short-acting for therapeutic use. Gene therapy provides a specific and chronic means of delivering potential therapeutic gents. Introducing an anti-apoptotic gene into the cochlea could provide long-term prophylaxis against the ototoxic effects of cisplatin. METHOD: Two groups of rats were treated with unilateral injection into the round window of AAV harboring a gene encoding either XIAP or green fluorescent protein (GFP). After at least two months of gene expression, auditory-brainstem-response (ABR) threshold shifts and outer-hair-cell (OHC) number were measured in these two groups of animals after 72-hour treatment with cisplatin. RESULTS: Consistent with previous reports, uninjected and AAV.GFP-injected ears displayed profound ABR threshold elevations and OHC loss after cisplatin treatment. Ears that had been injected with AAV encoding XIAP, however, were significantly protected from these effects: cisplatin-induced ABR-threshold shift and hair-cell loss were attenuated by as much as 78% and 45%, respectively, when compared with contralateral (untreated) ears. CONCLUSION: XIAP delivery to the cochlea can protect against the audiometric changes and hair-cell loss associated with cisplatin ototoxicity. The efficacy, specificity, and duration of the protective effects make this a potentially attractive therapeutic paradigm.