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1.
Int J Pediatr Otorhinolaryngol ; 131: 109868, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31931391

RESUMO

OBJECTIVES: Congenital encephaloceles provide unique diagnostic and reconstructive challenges for the pediatric rhinologist. The objectives of the current study were to evaluate contemporary treatment strategies for congenital encephaloceles focusing on presentation, surgical technique, and outcomes. METHODS: Multi-institutional retrospective chart review of congenital encephaloceles (2003-2019). Data regarding demographics, presenting symptoms, associated abnormalities, surgical technique, size, location, and complications were collected. RESULTS: Fourteen patients with 15 congenital encephaloceles were treated using endoscopic techniques (avg 6.0 years, range 2 months-22 years) with mean follow up of 23 months. The majority presented with nasal obstruction (n = 13); only one child had cerebrospinal fluid (CSF) rhinorrhea. Associated anomalies included nasal deformities, congenital hypopituitarism, and Morning Glory syndrome. Average encephalocele size was 2.44 cm (range 0.5-3.6 cm) with mean skull base defect size of 8.6 x 7.7 mm. Locations included the foramen cecum (n = 9), central sphenoid (n = 3), midline anterior cranial fossa (n = 1), orbital plate of frontal bone (n = 1), and ethmoid roof (n = 1). Because of favorable expansion from encephaloceles, it was unnecessary to postpone surgeries to allow nasal cavity growth. Three individuals had prior operations, including surgeries for "nasal polyp" or "adenoid cyst". Two patients had post-operative complications (meningitis and CSF leak) effectively treated with no further sequelae. CONCLUSIONS: In the current study, congenital encephaloceles in children as young as 2 months were successfully repaired using endoscopic techniques. Endoscopic approaches remain a safe and effective intervention for management of these lesions.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31922358

RESUMO

BACKGROUND: The Lactococcus strain of bacteria has been introduced as a probiotic nasal rinse for alleged salubrious effects on the sinonasal bacterial microbiome. However, data regarding interactions with pathogenic bacteria within the sinuses are lacking. The purpose of this study is to assess the interaction between L. lactis and patient-derived Pseudomonas aeruginosa, an opportunistic pathogen in recalcitrant chronic rhinosinusitis (CRS). METHODS: Commercially available probiotic suspension containing L. lactis W136 was grown in an anaerobic chamber and colonies were isolated. Colonies were co-cultured with patient-derived P. aeruginosa strains in the presence of porcine gastric mucin (mimicking human mucus) for 72 hours. P. aeruginosa cultures without L. lactis served as controls. Colony forming units (CFUs) were compared. RESULTS: Six P. aeruginosa isolates collected from 5 CRS patients (3 isolates from cystic fibrosis [CF], 1 mucoid strain) and laboratory strain PAO1 were co-cultured with L. lactis. There was no statistical difference in CFUs of 5 P. aeruginosa isolates grown with L. lactis compared to CFUs without presence of L. lactis. CFU counts were much higher when the mucoid strain was co-cultured with L. lactis (CFU+L.lactis = 1.9 × 108 ± 1.44 × 107, CFU-L.lactis = 1.3 × 108 ± 8.9 × 106, p = 0.01, n = 7). L. lactis suppressed the growth of 1 P. aeruginosa strain (CFU+L.lactis = 2.15 × 108 ± 2.9 × 107, CFU-L.lactis = 3.95 × 108 ± 4.8 × 106, p = 0.03, n = 7). CONCLUSION: L. lactis suppressed the growth of 1 patient P. aeruginosa isolate and induced growth of another (a mucoid strain) in in vitro co-culture setting in the presence of mucin. Further experiments are required to assess the underlying interactions between L. lactis and P. aeruginosa.

3.
Int Forum Allergy Rhinol ; 10(1): 121-127, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31692289

RESUMO

BACKGROUND: Chronic rhinosinusitis (CRS) is a chronic inflammatory disease characterized by persistent inflammation and bacterial infection. Ciprofloxacin and azithromycin are commonly prescribed antibiotics for CRS, but the ability to provide targeted release in the sinuses could mitigate side effects and improve drug concentrations at the infected site. This study was aimed to evaluate the efficacy of the novel ciprofloxacin-azithromycin sinus stent (CASS) in vitro. METHODS: The CASS was created by coating ciprofloxacin (hydrophilic, inner layer) and azithromycin (hydrophobic, outer layer) onto a biodegradable poly-l-lactic acid (PLLA) stent. In-vitro evaluation included: (1) assessment of drug-coating stability within the stent using scanning electron microscopy (SEM); (2) determination of ciprofloxacin and azithromycin release kinetics; and (3) assessment of anti-biofilm activities against Pseudomonas aeruginosa. RESULTS: The ciprofloxacin nanoparticle suspension in the inner layer was confirmed by zeta potential. Both ciprofloxacin (60 µg) and azithromycin (3 mg) were uniformly coated on the surface of the PLLA stents. The CASS showed ciprofloxacin/azithromycin sustained release patterns, with 80.55 ± 11.61% of ciprofloxacin and 93.85 ± 6.9% of azithromycin released by 28 days. The CASS also significantly reduced P aeruginosa biofilm mass compared with bare stents and controls (relative optical density units at 590-nm optical density: CASS, 0.037 ± 0.006; bare stent, 0.911 ± 0.015; control, 1.000 ± 0.000; p < 0.001; n = 3). CONCLUSION: The CASS maintains a uniform coating and sustained delivery of ciprofloxacin and azithromycin, providing anti-biofilm activities against P aeruginosa. Further studies evaluating the efficacy of CASS in a preclinical model are planned.

4.
Laryngoscope ; 130(2): 556-560, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31038747

RESUMO

OBJECTIVE: Examine the patient characteristics of those undergoing upper airway stimulation (UAS) for the treatment of continuous positive airway pressure (CPAP)-refractive obstructive sleep apnea (OSA) at a tertiary care medical center to determine objective clinical predictors of success. METHODS: Retrospective chart review of the first 25 consecutive patients between August 2015 and December 2016 treated with UAS at a tertiary care academic center. Demographic data, medical and sleep history, pre- and postoperative polysomnography data, and sleep endoscopy findings were collected. Statistical analysis was performed using two-sided t test with bivariate and linear regression analysis. RESULTS: In our cohort of 25 patients, mean age was 67.5 ± 7.6 years, and mean body mass index (BMI) was 28.2 ± 3.8 kg/m2 with 42% female. One patient was excluded from analysis for unmasking of complete central apnea with therapy. AHI decreased by a mean of 33.8 events/hour following treatment (95% confidence interval: 25.8 to 41.7, P < 0.001). Preintervention AHI was associated with therapy response, with each point of preintervention AHI leading to an average decrease of 1.03 points (P < 0.001). Eighty-three percent of patients achieved a treatment AHI < 5, whereas 92% achieved an AHI < 10. Mean device use was 49.5 ± 10.4 hours per week. Ninety-two percent of patients were discharged the day of surgery. No major adverse events occurred. CONCLUSION: UAS continues to gain popularity for the treatment of CPAP-refractive OSA; therefore, identification of predictors of success is crucial. Our study, although small, suggests that more severe preintervention AHI does not preclude significant therapy response and may expand the inclusion criteria for UAS, meriting further investigation. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:556-560, 2020.

5.
Curr Opin Otolaryngol Head Neck Surg ; 28(1): 52-60, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31834027

RESUMO

PURPOSE OF REVIEW: Traditionally, frontal sinus trauma has been treated using open incisions to access the anterior and/or posterior table. Mounting evidence indicates frontal sinus trauma can be managed using an endoscopic endonasal approach (EEA) with less morbidity. Such an approach permits preservation of a functional sinus and less reliance on computed tomography for postoperative follow up. The goal of this article is to highlight a shift in paradigm away from open approaches using external incisions towards an EEA to repair cerebrospinal fluid (CSF) leaks and fractures of the frontal sinus. RECENT FINDINGS: In a prospective case series of 46 patients undergoing EEA to frontal sinus fractures, 41 patients had active CSF leaks arising from the posterior table of the frontal sinus. A successful endoscopic repair was achieved in 97.6% with only one patient requiring revision Draf IIB surgery. Anterior table fractures were also successfully reduced with excellent cosmesis. SUMMARY: Endoscopic repair of frontal sinus fractures and CSF leaks is effective and well tolerated. In select patients, it is the preferred treatment as it maintains normal sinus structure and function, minimizing both early and late complications.

6.
Ann Otol Rhinol Laryngol ; 129(1): 12-17, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31394908

RESUMO

OBJECTIVE: To define a new anatomic relationship in pediatric sinus surgery, assessing the maxillary roof as a constant safe landmark to avoid skull base injury in the pediatric population. STUDY DESIGN: Retrospective analysis. SETTING: Tertiary care children hospital. SUBJECTS AND METHODS: A retrospective analysis was performed of all computed tomography scans of the sinuses and facial bones at the emergency department of a tertiary children's hospital over the course of a year. Radiographic measurements included the lowest cribriform plate and planum sphenoidale (PS) heights, or posterior skull base when not yet pneumatized, as well as the highest maxillary roof height. The nasal floor was used for reference. Statistics were performed via Shapiro-Wilks test with a P-value of .05 indicating statistical significance. RESULTS: Three hundred and seven unique scans were reviewed (38.9% female; n = 122; P = .58). Age stratification was based on previously described sinus growth patterns. In all patients, the maximum maxillary height was inferior to the lowest measured cribriform lamella and PS (P < .001; CI, 98.5%-99%). Inter- and intrarater reliability and accuracy were verified through blinded review and re-review (ρ = .99 and .98 respectively, P ≤ .001). The validity of sole coronal measurements due to incomplete sagittal reformatting was also confirmed (ρ = 1.00, P ≤ .001). CONCLUSION: Despite variation in sinus growth and development in children, the current study demonstrated the validity of the maxillary sinus roof as a constant safe landmark in the pediatric population, offering a novel anatomic relationship for teaching safety in performing pediatric sinus surgery. LEVEL OF EVIDENCE: 4.


Assuntos
Pontos de Referência Anatômicos , Endoscopia/métodos , Seio Maxilar/diagnóstico por imagem , Procedimentos Cirúrgicos Otorrinolaringológicos/métodos , Base do Crânio/diagnóstico por imagem , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Seio Maxilar/cirurgia , Reprodutibilidade dos Testes , Estudos Retrospectivos , Base do Crânio/cirurgia , Tomografia Computadorizada por Raios X , Adulto Jovem
7.
Artigo em Inglês | MEDLINE | ID: mdl-31872532

RESUMO

BACKGROUND: Pseudomonas aeruginosa is common in chronic rhinosinusitus (CRS) and frequently resistant to antibiotic treatment. We recently described the ciprofloxacin and ivacaftor-releasing biodegradable sinus stent (CISS)-a drug-delivery system that administers ciprofloxacin and the mucociliary activator (ivacaftor) at high local concentrations with prolonged mucosal contact time and sustained delivery. The objective of this study is to evaluate the efficacy of the CISS in a rabbit model of P aeruginosa (PAO1 strain) sinusitis. METHODS: Ciprofloxacin/ivacaftor (double layer) was coated on biodegradable poly-D/L-lactic acid (PLLA). A total of 10 sinus stents (5 bare PLLA stent controls, 5 CISSs) were placed unilaterally in rabbit maxillary sinuses via dorsal sinusotomy after inducing infection for 1 week with PAO1. Animals were assessed 3 weeks after stent insertion with sinus culture, nasal endoscopy, computed tomography scan, histopathology, and in-vivo sinus potential difference (SPD) assay. RESULTS: Rabbits treated with CISS had significant reductions in computed tomography (∆ Kerschner scale: control, 0.55 ± 0.92; CISS, -5.92 ± 1.69; p = 0.024) and endoscopy (control, 4.0 ± 0.0; CISS, 1.875 ± 0.74; p = 0.003) scores. A 2-log reduction of PAO1 was observed (control, -2.14 ± 0.77; CISS, 1.84 ± 1.52; p = 0.047). SPD revealed significantly increased Cl- transport in the CISS group compared with the control group (Cl- -free + forskolin ΔPD: control, -4.23 ± 1.04 mV; CISS, -18.36 ± 6.31 mV; p = 0.026). Finally, marked improvements were noted in the histology of the mucosa and submucosa in treated animals. CONCLUSION: The CISS had robust clinical efficacy in treating P aeruginosa rabbit sinusitis. The innovative design of double-layered drug coating on the surface of the biodegradable stent may provide therapeutic advantages over current treatment strategies for P aeruginosa sinusitis.

8.
Int Forum Allergy Rhinol ; 9(12): 1430-1435, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31430425

RESUMO

BACKGROUND: Mucociliary clearance is a main defense mechanism of the airway and is impaired in ciliary dyskinesia. The objective of this study was to evaluate the prevalence of chronic rhinosinusitis (CRS) and its characteristics in bronchiectasis patients suspected of harboring ciliary dyskinesia. METHODS: Bronchiectasis patients referred to a rhinology clinic for nasal brush biopsy (NBB) were included in this study. NBB was performed using a curettage technique whereby ciliated epithelial cells were obtained from the surface of the inferior nasal turbinate. Results of transmission electron microscopy findings, primary ciliary dyskinesia (PCD) gene (35 genes) analyses (Invitae), and sinus computed tomography (CT) scans were reviewed. RESULTS: Twenty-three patients (age, 54 ± 2.9 years) were referred for NBB between 2015 and 2018. Thirteen patients (56.5%) met the criteria for diagnosis of CRS. Nineteen patients had ciliary ultrastructural defects. The most common finding was compound cilia (n = 11, 47.8%). Five patients (21.7%) had central microtubule defects (CMD) with higher forced expiratory volume in 1 second (FEV1 ) at the time of referral than those without CMD (CMD+ , 91 ± 3.7%; CMD- , 73.5 ± 5.7%; p = 0.023). Of 15 subjects with a PCD gene panel, 67% (9 of 15) carried at least 1 gene associated with PCD. Only 1 patient reached diagnosis of PCD. Approximately 50% of non-PCD carriers had a smoking history (p < 0.05). Lund-Mackay scores did not significantly differ between PCD and non-PCD carriers (p = 0.72). CONCLUSION: Nearly half of bronchiectasis patients referred for NBB had concurrent CRS. The presence of ciliary abnormalities was not amplified in bronchiectasis patients with CRS compared to those without CRS. Extrinsic factors may be related to ciliary structural abnormalities in non-PCD gene carriers.

9.
Sci Transl Med ; 11(504)2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391319

RESUMO

Cystic fibrosis (CF) is a genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Although impairment of mucociliary clearance contributes to severe morbidity and mortality in people with CF, a clear understanding of the pathophysiology is lacking. This is, in part, due to the absence of clinical imaging techniques capable of capturing CFTR-dependent functional metrics at the cellular level. Here, we report the clinical translation of a 1-µm resolution micro-optical coherence tomography (µOCT) technology to quantitatively characterize the functional microanatomy of human upper airways. Using a minimally invasive intranasal imaging approach, we performed a clinical study on age- and sex-matched CF and control groups. We observed delayed mucociliary transport rate at the cellular level, depletion of periciliary liquid layer, and prevalent loss of ciliation in subjects with CF. Distinctive morphological differences in mucus and various forms of epithelial injury were also revealed by µOCT imaging and had prominent effects on the mucociliary transport apparatus. Elevated mucus reflectance intensity in CF, a proxy for viscosity in situ, had a dominant effect. These results demonstrate the utility of µOCT to determine epithelial function and monitor disease status of CF airways on a per-patient basis, with applicability for other diseases of mucus clearance.

10.
Int Forum Allergy Rhinol ; 9(9): 1041-1045, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31173672

RESUMO

BACKGROUND: Sinonasal and skull-base tumors that previously required open resection can often be completely resected via an endonasal approach. The nasoseptal flap (NSF) is the workhorse vascularized tissue flap for the endoscopic reconstruction of large skull-base defects from tumor resections. The objective of the current article is to describe a novel modification of the NSF for simultaneous reconstruction of skull-base and medial orbital wall defects. METHODS: An extension of the standard NSF to include mucosa of the lateral nasal wall was developed for closure of simultaneous skull-base and medial orbital wall defects. Outcomes including successful cerebrospinal fluid (CSF) leak closure, orbital edema, and postoperative cosmesis are reported. Eyelid edema was characterized according to the Surgeon Periorbital Rating of Edema and Ecchymosis (SPREE) scale. RESULTS: Three patients underwent reconstruction using the modified NSF (average age 75 years). The average defect size of the skull base was 3.6 ± 0.1 cm by 2.3 ± 0.2 cm. The average defect size of the medial orbit was 2.7 ± 0.1 cm by 2.6 ± 0.1 cm. All defects were successfully covered intraoperatively using the lateral nasal wall extension of the NSF. Two patients developed mild eyelid edema, whereas 1 individual had no noticeable swelling (SPREE classification 2, 2, and 1). All patients were successfully sealed at last clinical follow up (average 28 weeks). CONCLUSION: The modification of the NSF described here provides excellent coverage for reconstruction of large anterior skull-base defects and simultaneous medial orbital wall defects.

11.
Int Forum Allergy Rhinol ; 9(5): 486-492, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30702211

RESUMO

BACKGROUND: We recently developed a novel ciprofloxacin-coated sinus stent capable of releasing antibiotics over a sustained period of time. Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that has synergistic bactericidal activity with ciprofloxacin and also enhances sinus mucociliary clearance. The objective of this study was to optimize and evaluate the efficacy of a ciprofloxacin- and ivacaftor-releasing biodegradable sinus stent (CISS) in vitro. METHODS: A CISS was created by coating ciprofloxacin/ivacaftor-embedded nanoparticles with an acrylate and ammonium methacrylate copolymer onto a biodegradable poly-L-lactic acid stent. In-vitro evaluation of the CISS included: (1) assessment of drug stability in nanoparticles by zeta potential, and drug-coating stability within the CISS using scanning electron microscopy (SEM); (2) determination of ciprofloxacin- and ivacaftor-release kinetics; and (3) assessment of anti-Pseudomonas aeruginosa biofilm formation by calculating relative optical density units (RODUs) compared with control stents at 590-nm optical density. RESULTS: The presence of drugs and a uniform coating on the stent were confirmed by zeta potential and SEM. Sustained drug release was observed through 21 days without an initial burst release. Anti-biofilm formation was observed after placing the CISS for 3 days onto a preformed 1-day P aeruginosa biofilm. The CISS significantly reduced biofilm mass compared with bare stents and controls (RODUs at 590-nm optical density; CISS, 0.31 ± 0.01; bare stent, 0.78 ± 0.12; control, 1.0 ± 0.00; p = 0.001; n = 3). CONCLUSION: The CISS maintains a uniform coating and sustained delivery of drugs providing a marked reduction in P aeruginosa biofilm formation. Further studies evaluating the efficacy of CISS in a preclinical model are planned.

12.
Int Forum Allergy Rhinol ; 9(6): 629-637, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30657641

RESUMO

BACKGROUND: Enhancing chloride (Cl- ) secretion in sinus epithelia represents a novel therapeutic approach to chronic rhinosinusitis (CRS). Herbal dry extract BNO 1011 enhances mucociliary clearance (MCC) via upregulation of Cl- secretion in sinonasal cultures in vitro and murine epithelium in vivo. The objective of this study is to evaluate whether the BNO 1011 improves MCC and clinical parameters in a rabbit model of CRS. METHODS: After the development of CRS in 30 New Zealand white rabbits, animals were randomly assigned to receive oral placebo (n = 10), BNO 1011 (low dose [LD], 25 mg/kg/daily) (n = 10), or BNO1011 (high dose [HD], 125 mg/kg/daily) (n = 10) for 4 weeks. Outcomes included sinus opacification (Kerschner's rabbit sinus CT grade), maxillary epithelial Cl- secretion (sinus potential difference [PD] assay), airway surface liquid (ASL) depth using micro-optical coherence tomography (µOCT), and submucosal gland density (SMD) on histopathology. Outcome parameters were analyzed by 2 blinded investigators. RESULTS: BNO 1011 significantly cleared sinus opacification (HD = 1.21 ± 0.63, LD = 1.26 ± 0.37,) compared to placebo (4.02 ± 0.92) (p = 0.009). BNO 1011 resulted in markedly greater mean sinus PD polarization (HD = -12.23 ± 1.4 mV, LD = -12.0 ± 3.0 mV) when compared to rabbits treated with placebo (-4.1 ± 1.1 mV) (p = 0.03). ASL depth was significantly improved when treated with HD (4.08 ± 0.06 µm) and LD (4.05 ± 0.06 µm) compared to placebo (3.5 ± 0.05 µm) (post hoc analysis, p < 0.0001). Histologically, epithelial thickness (HD = 10.0 ± 0.7 µm; LD = 13.7 ± 0.9 µm; placebo = 21.1 ± 2.3 µm; p < 0.005), subepithelial thickness (HD = 63.1 ± 6.6 µm; LD = 103.2 ± 6.7 µm; placebo = 113.3 ± 6.0 µm; p < 0.001), and SMD (HD = 22.2 ± 2.9%; LD = 31.8 ± 1.1%; placebo = 43.8 ± 1.7%; p < 0.0001) were noticeably better with the HD. CONCLUSION: Herbal dry extract BNO 1011 improves radiographic, histologic, and MCC parameters in a rabbit model of CRS.

13.
Laryngoscope ; 129(11): E389-E394, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30644565

RESUMO

OBJECTIVES/HYPOTHESIS: The objectives of this study were to examine patient outcomes using a 36-month age cutoff as a strict admission criterion following tonsillectomy, and review the safety and determine the plausibility of same-day discharge of children under 3 years old following tonsillectomy. STUDY DESIGN: Retrospective chart review. METHODS: A chart review of patients aged 24 to 42 months undergoing tonsillectomy over a 3-year period was conducted. Patients were stratified into <36 months and ≥ 36 months cohorts. Data collected included demographics, medical/sleep history, inpatient records, 30-day emergency department visits, and readmission data. Bivariate comparisons were made using χ2 and Wilcoxon tests for categorical and continuous variables. RESULTS: Between July 2014 and July 2017, 427 patients aged 24 to 42 months underwent tonsillectomy at our institution. Thirty-day emergency department visit, readmission, and greater-than-expected length of stay rates were 3.0% versus 3.7% (P = .75), 1.0 versus 1.8% (P = .61), and 4.7% versus 4.5% (P = 1.00) between the younger and older cohorts, respectively, with no difference in complication rates identified based on age. CONCLUSIONS: No significant difference in adverse outcomes was appreciated based on a cutoff of 36 months of age at a tertiary center over 3 years. There should continue to be ongoing studies addressing strict age-related admission criteria. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:E389-E394, 2019.


Assuntos
Fatores Etários , Serviço Hospitalar de Emergência/estatística & dados numéricos , Admissão do Paciente/estatística & dados numéricos , Complicações Pós-Operatórias/epidemiologia , Tonsilectomia/estatística & dados numéricos , Pré-Escolar , Feminino , Humanos , Masculino , Alta do Paciente/estatística & dados numéricos , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Tonsilectomia/efeitos adversos
15.
Int Forum Allergy Rhinol ; 9(3): 292-297, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30472785

RESUMO

BACKGROUND: Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that improves pulmonary function in cystic fibrosis (CF) patients with at least 1 copy of the G551D CFTR mutation. The purpose of this study is to evaluate the impact of ivacaftor on chronic rhinosinusitis (CRS) symptoms in this population. METHODS: The G551D Observational (GOAL) study was a multicenter prospective cohort study enrolling CF patients ≥6 years with at least 1 G551D mutation. Subjects were provided 20-item Sino-Nasal Outcome Test (SNOT-20) questionnaires prior to ivacaftor therapy and at 1, 3, and 6 months afterward. The impact on rhinologic (R), psychological (P), sleep (S), and ear/facial (E) quality of life (QOL) domains was evaluated separately. RESULTS: Of 153 subjects, 129 (84%) completed all questionnaires. Typical baseline symptom burden was low (75% with scores <1) and degree of improvement (ie, reduced scores) was greater with higher baseline scores. SNOT-20 decreased, reflecting improvement, at all follow-up intervals (1 month: [mean change ± standard deviation] -0.25 ± 0.53, p < 0.01; 3 months; -0.29 ± 0.58, p < 0.01; 6 months: -0.21 ± 0.58, p = 0.02), but less than the prespecified minimal clinically important difference (0.8). Significant improvement was observed at 1, 3, and 6 months in the R domain (1 month: -0.24, p < 0.01; 3 months: -0.34, p < 0.01; 6 months: -0.25, p < 0.01) and P domain (1 month: -0.25, p < 0.01; 3 months: -0.32, p < 0.01; 6 months: -0.26, p < 0.01), and 1 and 3 months in the S domain (1 months: -0.35, p < 0.01; 3 months: -0.32, p < 0.01; 6 months: -0.18, p = 0.07). There was no improvement in the E domain at any time point. CONCLUSION: Ivacaftor improves QOL in the R, P, and S domains in G551D CF patients, although QOL instruments validated for CRS may not translate well to CF CRS patients because symptom burden was surprisingly low.


Assuntos
Aminofenóis/uso terapêutico , Regulador de Condutância Transmembrana em Fibrose Cística/antagonistas & inibidores , Fibrose Cística/tratamento farmacológico , Quinolonas/uso terapêutico , Rinite/tratamento farmacológico , Sinusite/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminofenóis/farmacologia , Criança , Doença Crônica , Estudos de Coortes , Fibrose Cística/genética , Fibrose Cística/psicologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Feminino , Humanos , Masculino , Saúde Mental , Pessoa de Meia-Idade , Mutação/genética , Estudos Prospectivos , Qualidade de Vida , Quinolonas/farmacologia , Rinite/genética , Rinite/psicologia , Sinusite/genética , Sinusite/psicologia , Sono , Inquéritos e Questionários , Adulto Jovem
16.
Int Forum Allergy Rhinol ; 9(1): 100-105, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30152192

RESUMO

BACKGROUND: Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene result in defective Cl- transport and cause chronic bacterial infections in the upper and lower airways of cystic fibrosis (CF) patients. Ivacaftor is a CFTR potentiator that improves Cl- transport in CF patients with at least 1 copy of the G551D mutation. Resveratrol is also a potent CFTR potentiator that increases determinants of mucociliary transport. The objective of this study is to determine whether resveratrol and ivacaftor improve Cl- secretion in G551D CFTR over either agent alone. METHODS: Fisher rat thyroid cells (FRT) transfected with G551D CFTR and human sinonasal epithelial cells (HSNE) containing the CFTR G551D mutation were subjected to pharmacologic manipulation of transepithelial ion transport in Ussing chambers. Activity was further evaluated using whole-cell patch clamp methods in G551D FRT cells. RESULTS: In G551D FRT cells, resveratrol (100 µM) and ivacaftor (10 µM) significantly increased Cl- transport (change in short-circuit current, δISC = µA/cm2 ) compared with single-agent and dimethylsulfoxide vehicle controls (resveratrol + ivacaftor 4.97 ± 0.57 vs ivacaftor 0.74 ± 0.12 vs resveratrol 2.96 ± 0.52 vs control 0.74 ± 0.12; p < 0.001). Maximal Cl- secretion (20 µM forskolin) was also significantly enhanced (p < 0.0001). Activity was confirmed in G551D HSNE (resveratrol + ivacaftor 4.48 ± 0.39 vs ivacaftor 1.05 ± 0.11 vs. resveratrol 0.84 ± 0.3 vs control, 0.0 ± 0.02; p < 0.001), and whole-cell patch clamp analysis in G551D FRT cells (resveratrol + ivacaftor -2535 ± 179.3 pA vs ivacaftor -1408.9 ± 101.3 pA vs resveratrol; -766.2 ± 71.2 pA; p < 0.0001). CONCLUSION: Additive improvement in G551D CFTR-mediated Cl- secretion suggests that resveratrol could enhance ivacaftor therapy in these patients and improve CF-related rhinosinusitis.


Assuntos
Aminofenóis/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/tratamento farmacológico , Mutação/genética , Mucosa Nasal/fisiologia , Doenças dos Seios Paranasais/tratamento farmacológico , Quinolonas/farmacologia , Resveratrol/farmacologia , Glândula Tireoide/fisiologia , Animais , Células Cultivadas , Cloretos/metabolismo , Fibrose Cística/genética , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Transporte de Íons/efeitos dos fármacos , Depuração Mucociliar/efeitos dos fármacos , Mucosa Nasal/patologia , Doenças dos Seios Paranasais/genética , Ratos , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/patologia
17.
Am J Rhinol Allergy ; 33(2): 129-136, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30585080

RESUMO

BACKGROUND: Methods to improve the clinical efficacy of currently available antibiotics against multidrug resistant bacteria in cystic fibrosis (CF) chronic rhinosinusitis (CRS) are greatly needed. Ivacaftor, a cystic fibrosis transmembrane conductance regulator potentiator, was recently identified as having potentially beneficial off-target effects as a weak inhibitor of bacterial DNA gyrase and topoisomerase IV. The objective of the current study is to evaluate whether ivacaftor enhances the antimicrobial activity of ciprofloxacin against Pseudomonas aeruginosa. METHODS: The planktonic growth of the PAO-1 strain of P. aeruginosa was studied in the presence of ciprofloxacin and/or ivacaftor. Effects were measured according to optical density of cultured PAO-1 at 600 nm. For a static PAO-1 biofilm assay, the PAO-1 strain was inoculated and cultured for 72 h in the presence of the drugs. Formed PAO-1 biofilms were quantified by crystal violet staining and imaged with confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM). RESULTS: PAO-1 growth was significantly reduced in the presence of ivacaftor (8 or 16 µg/mL) and ciprofloxacin (0.02 or 0.05 µg/mL) compared to ciprofloxacin alone ( P < .001). Similarly, ivacaftor (8 or 16 µg/mL) showed a significant reduction of PAO-1 biofilms when treated with 0.05 µg/mL of ciprofloxacin. Significant synergism was noted between ciprofloxacin and 16 µg/mL of ivacaftor ( P < .0001) in reducing planktonic growth and biofilm formation. Quantitative measurements with crystal violet staining were correlated to CLSM and SEM images. CONCLUSION: Ivacaftor enhanced ciprofloxacin's antimicrobial activity against P. aeruginosa. Further studies evaluating the efficacy of ivacaftor/ciprofloxacin combination for P. aeruginosa for CF CRS are warranted.


Assuntos
Aminofenóis/farmacologia , Antibacterianos/farmacologia , Ciprofloxacino/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Quinolonas/farmacologia , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Sinergismo Farmacológico , Pseudomonas aeruginosa/crescimento & desenvolvimento
18.
Artigo em Inglês | MEDLINE | ID: mdl-30506051

RESUMO

Sinonasal respiratory epithelium is a highly regulated barrier that employs mucociliary clearance (MCC) as the airways first line of defense. The biological properties of the airway surface liquid (ASL), combined with coordinated ciliary beating, are critical components of the mucociliary apparatus. The ASL volume and viscosity is modulated, in part, by the cystic fibrosis transmembrane conductance regulator (CFTR). The CFTR is an anion transporter of chloride (Cl-) and bicarbonate (HCO3 -) that is located on the apical surface of respiratory epithelium and exocrine glandular epithelium. Improved understanding of how dysfunction or deficiency of CFTR influences the disease process in both genetically defined cystic fibrosis (CF) and acquired conditions has provided further insight into potential avenues of treatment. This review discusses the latest data regarding acquired CFTR deficiency and use of CFTR specific treatment strategies for CRS and other chronic airway diseases.

20.
Int Forum Allergy Rhinol ; 8(10): 1162-1168, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29856526

RESUMO

BACKGROUND: To better understand upper airway tissue regeneration, the exposed cartilage and bone at donor sites of tissue flaps may serve as in vivo "Petri dishes" for active wound healing. The pedicled nasoseptal flap (NSF) for skull-base reconstruction creates an exposed donor site within the nasal airway. The objective of this study is to evaluate whether grafting the donor site with a sinonasal repair cover graft is effective in promoting wound healing. METHODS: In this multicenter, prospective trial, subjects were randomized to intervention (graft) or control (no graft) intraoperatively after NSF elevation. Individuals were evaluated at 2, 6, and 12 weeks postintervention with endoscopic recordings. Videos were graded (Likert scale) by 3 otolaryngologists blinded to intervention on remucosalization, crusting, and edema. Scores were analyzed for interrater reliability and cohorts compared. Biopsy and immunohistochemistry at the leading edge of wound healing was performed in select cases. RESULTS: Twenty-one patients were randomized to intervention and 26 to control. Subjects receiving the graft had significantly greater overall remucosalization (p = 0.01) than controls over 12 weeks. Although crusting was less in the small intestine submucosa (SIS) group, this was not statistically significant (p = 0.08). There was no overall effect on nasal edema (p = 0.2). Immunohistochemistry demonstrated abundant upper airway basal cell progenitors in 2 intervention samples, suggesting that covering grafts may facilitate tissue proliferation via progenitor cell expansion. CONCLUSION: This prospective, randomized, controlled trial indicates that a porcine SIS graft placed on exposed cartilage and bone within the upper airway confers improved remucosalization compared to current practice standards.


Assuntos
Mucosa Intestinal/transplante , Septo Nasal/cirurgia , Rinoplastia/métodos , Base do Crânio/cirurgia , Células-Tronco/citologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Septo Nasal/patologia , Estudos Prospectivos , Base do Crânio/patologia , Células-Tronco/metabolismo , Retalhos Cirúrgicos/patologia , Suínos , Resultado do Tratamento , Cicatrização
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