Active Transport of Peptides Across the Intact Human Tympanic Membrane.

We previously identified peptides that are actively transported across the intact tympanic membrane (TM) of rats with infected middle ears. To assess the possibility that this transport would also occur across the human TM, we first developed and validated an assay to evaluate transport in vitro using fragments of the TM. Using this assay, we demonstrated the ability of phage bearing a TM-transiting peptide to cross freshly dissected TM fragments from infected rats or from uninfected rats, guinea pigs and rabbits. We then evaluated transport across fragments of the human TM that were discarded during otologic surgery. Human trans-TM transport was similar to that seen in the animal species. Finally, we found that free peptide, unconnected to phage, was transported across the TM at a rate comparable to that seen for peptide-bearing phage. These studies provide evidence supporting the concept of peptide-mediated drug delivery across the intact TM and into the middle ears of patients.

Isolated sphenoid sinus opacifications: a systematic review and meta-analysis.

BACKGROUND: Isolated sphenoid sinus opacifications (ISSOs) represent a relatively uncommon disease with the potential for serious complications. To better understand this disease, we performed a systematic review to further characterize the underlying pathologies, associated symptoms, and treatment outcomes of patients with ISSOs. METHODS: A systematic review of ISSO case series was performed utilizing the Medline, Embase, Web of Science, and Cochrane databases in accordance with guidelines established by PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Data of interest included disease pathology, associated symptoms, and treatment outcomes. RESULTS: Of the initial 1051 hits from the 4 databases, 17 articles, with a combined 1133 ISSO patients, were ultimately included in the review. On a weighted analysis, the underlying pathologies were classified as chronic rhinosinusitis without nasal polyps (CRSsNP) (28.3%), mucoceles (20.3%), fungal sinusitis (12.5%), malignant neoplasms (7.7%), intracranial lesions (7.0%), benign neoplasms (5.7%), chronic rhinosinusitis with nasal polyps (CRSwNP) (3.4%), and other lesions (4.7%). Cranial neuropathies were present in 16.3% (95% confidence interval [CI], 10.1-22.5%) of ISSO patients. A favorable surgical complication rate of 1.5% (95% CI, -0.1% to 3.2%) was found in patients undergoing surgery for an ISSO. CONCLUSION: ISSOs are caused by diverse pathologies. Given the considerable rates of neoplastic disease and cranial neuropathies, patients affected by an ISSO should be monitored closely and treated aggressively. Prompt surgical intervention, with either diagnostic or therapeutic intent, is often indicated.

Chronic sialadenitis with sialolithiasis associated with parapharyngeal fistula and tonsillolith.

Sialolithiasis is a common salivary pathology, suggested to affect over 1% of the population by postmortem studies. An uncommon complication of sialadenitis and sialolithiasis is the formation of fistulous tracts to other cervicofacial compartments. Submandibular gland sialocutaneous and sialo-oral fistulae have been sparsely described, but a sialo-pharyngeal fistula manifesting as a tonsillolith has yet to be described. We present an unusual case of a 35-year-old male presenting with recalcitrant neck pain and a presumed tonsillolith in the background of chronic submandibular sialadenitis, subsequently demonstrating a salivary fistula through the parapharyngeal space. We offer a thorough review of the literature to highlight the possibility of migratory sialolithiasis and its complications.

Impact of Humanitarian Experiences on Otolaryngology Trainees: A Follow-up Study of Travel Grant Recipients.

In this study, we seek (1) to determine the impact of humanitarian experiences on otolaryngology trainee recipients of the American Academy of Otolaryngology-Head and Neck Surgery Foundation humanitarian travel grant (2001-2015); (2) to better understand trainee and trip characteristics, as well as motivations and attitudes toward future volunteerism; and (3) and to identify potential barriers to participation. An anonymous 30-question survey was distributed to 207 individuals, and 52 (25.1%) responded. Respondents viewed the trip as very worthwhile (score = 98 of 100), expressed improved cultural understanding (75.0%), and continued participation in humanitarian activities (75.0%). Competency-based evaluation results suggest a positive impact on systems-based practice and professionalism. Respondents commented on the trip's positive value and shared concerns regarding expense. Despite potential barriers, Foundation-supported humanitarian trips during training are perceived as worthwhile; they may enhance cultural understanding and interest in future humanitarian efforts; and they may positively affect competency-based metrics. Based on the potential benefits, continued support and formalization of these experiences should be considered.

A Review of Hard Palate Fracture Repair Techniques.

PURPOSE: Hard palate trauma is a relatively infrequent occurrence compared with other craniofacial injuries. Several techniques of hard palate fracture repair have been described. To date, there is no consensus on the optimal management of this type of fracture. The purpose of this study was to compile and analyze studies describing hard palate fracture repair techniques with outcomes data. MATERIALS AND METHODS: A systematic review of the Medline, Scopus, and Web of Science databases was performed for articles describing hard palate fracture repair techniques. RESULTS: Eight articles were ultimately included in the review. Of the collective 310 fractures reported, postoperative malocclusion occurred in 21 of 235 cases (8.9%) and other complications occurred in 13 of 299 cases (4.3%). The most important variability in technique was the method of palatal vault stabilization. Three studies described wiring techniques, 3 described internal fixation techniques, and 2 described external fixation techniques. Studies describing internal fixation techniques reported higher rates of wound complications. Proponents of rigid internal fixation believe that this technique provides better fracture reduction. External fixation techniques appear to impart low rates of wound complications, but their overall effectiveness remains in question. CONCLUSIONS: Hard palate fractures are associated with high rates of malocclusion and wound complications. The most established methods of palatal vault stabilization are closed reduction with wiring and internal plate fixation. Depending on the fracture type, patient comorbidities, and associated injuries, either technique might be preferable in a given circumstance.

Successful Treatment of Multifocal Histiocytic Sarcoma Occurring after Renal Transplantation with Cladribine, High-Dose Cytarabine, G-CSF, and Mitoxantrone (CLAG-M) Followed by Allogeneic Hematopoietic Stem Cell Transplantation.

Histiocytic sarcoma (HS) is a rare, aggressive malignancy. Lesions previously called HS were typically non-Hodgkin lymphomas, not HS. As such, chemotherapy directed at lymphoid neoplasms was frequently successful, but it is unclear if these regimens are ideal for HS. We present a 33-year-old African gentleman who underwent sequential renal transplants for glomerulonephritis. He subsequently developed HS of the upper airway and multiple cutaneous sites. The patient received cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) followed by salvage ifosfamide, carboplatin, and etoposide (ICE) but had continuous progression of cutaneous involvement. Cladribine, high-dose cytarabine, G-CSF, and mitoxantrone (CLAG-M) yielded a partial response with near resolution of disease. Ultimately, the patient achieved a complete remission after myeloablative allogeneic hematopoietic stem cell transplant. HS occurring after solid organ transplant raises the possibility of HS as a potential posttransplant malignancy. The use of CLAG-M has not been reported in HS. In this case, histiocyte-directed chemotherapy with CLAG-M was superior to lymphoma-directed regimens.

Increased ILC2s in the eosinophilic nasal polyp endotype are associated with corticosteroid responsiveness.

Group 2 innate lymphoid cells (ILC2s) have recently been identified in human nasal polyps, but whether numbers of ILC2s differ by polyp endotype or are influenced by corticosteroid use is unknown. Here, we show that eosinophilic nasal polyps contained double the number of ILC2s vs. non-eosinophilic polyps. Polyp ILC2s were also reduced by 50% in patients treated with systemic corticosteroids. Further, using a fungal allergen challenge mouse model, we detected greatly reduced Th2 cytokine-producing and Ki-67+ proliferating lung ILC2s in mice receiving dexamethasone. Finally, ILC2 Annexin V staining revealed extensive apoptosis after corticosteroid treatment in vivo and in vitro. Thus, ILC2s are elevated in the eosinophilic nasal polyp endotype and systemic corticosteroid treatment correlated with reduced polyp ILC2s. Finally, allergen-challenged mice showed reduced ILC2s and increased ILC2 apoptosis after corticosteroid treatment suggesting that ILC2 may be responsive to corticosteroids in eosinophilic respiratory disease.

The new Nucleus 5 model cochlear implant: a new surgical technique and early clinical results.

OBJECTIVE: The Nucleus 5 or CI500 series cochlear implants are the new generation of Nucleus(®) cochlear implants. The receiver-stimulator package has a low profile without a pedestal projecting from the medial surface. This study aimed to demonstrate that the new design can facilitate a minimally invasive surgical approach, without the need for tie-down sutures and without a seat drilled for the receiver-stimulator package. METHODS: The surgical technique involved placing the device directly on the surface of the bone in a secure sub-periosteal pocket with a channel drilled for the lead. A well or ramped seat was not drilled and tie-down sutures were not used. Measurements were taken from the transmitting coil to the tragus and the coil to the lobule immediately after implantation, and serially thereafter to document implant position. RESULTS: To date, over 200 implants have been performed with the Nucleus 5 device. In all cases, healing was uneventful without major complications. Of 137 patients with at least 6-week follow-up data, 8% showed a measurement change of greater than 1 cm whereas only 4.4% demonstrated any clinically evident movement. None had any complications relating to migration and none required repositioning of the device. DISCUSSION: The new design can safely be inserted without drilling a well for the receiver-stimulator package. Some early post-operative movement of the package was observed which caused no clinical impact. This modified surgical technique reduces the risk of intracranial complications and reduces operating time.

Transmastoid repair of superior semicircular canal dehiscence.

Objective/Hypothesis Superior semicircular canal (Sup SC) dehiscence syndrome is a rare condition, causing a variety of auditory and vestibular symptoms. The traditional surgical management is a middle cranial fossa, extradural approach to resurface the Sup SC. Recently, a transmastoid approach for plugging of the Sup SC has been developed. We present further data supporting the use of the transmastoid approach in preference to the middle fossa approach. Design This is a retrospective multi-institutional case series. Method We included 10 patients in this case series from two tertiary otology institutions. Sup SC dehiscence was confirmed by correlation of clinical symptoms with positive audiometric, vestibular evoked myogenic potential, and computed tomography findings. A transmastoid approach was used for plugging of the Sup SC. Either a single fenestration was created at the site of dehiscence or separate fenestrations sited ampullopetal and ampullofugal to the dehiscence. Results All patients who underwent this procedure had good symptom control and hearing preservation postoperatively. Conclusion In patients with adequate temporal bone pneumatization, the transmastoid approach provides a safe and effective alternative to the middle cranial fossa approach. This series has demonstrated excellent symptom control and preservation of hearing with the transmastoid approach.

The role of vascular endothelial growth factors and fibroblast growth factors in angiogenesis during otitis media.

The middle ear response to otitis media includes transformation and hyperplasia of the mucosal epithelium and subepithelial connective tissue. Significant neovascularization is also noted, which occurs both to support the hypertrophied mucosa and to mediate the increased trafficking of leukocytes. We investigated the role of two known potent angiogenic growth factor families, the fibroblast growth factors (FGFs) and vascular endothelial growth factors (VEGFs), in middle ear mucosal angiogenesis. DNA microarrays were used to evaluate the expression of FGFs and VEGFs, as well as their receptors and unique signaling proteins, in the middle ears of mice undergoing a complete course of acute bacterial otitis media. In addition, a member of each family was introduced to the middle ear submucosal compartment of the normal middle ears of guinea pigs, by a continuous-release osmotic minipump system over 1 week. During the course of bacterial otitis media, a significant regulation of a number of genes important for angiogenesis was identified. Histologic evaluation of middle ear mucosa following micropump infusion of both FGF1 and VEGF-A showed significant angiogenesis at the site of infusion in comparison to control saline infusion. These results support a role for FGFs and VEGFs in the neovascularization of the middle ear mucosa during otitis media, and offer a potential avenue for therapeutic intervention.

TNFA deletion alters apoptosis as well as caspase 3 and 4 expression during otitis media.

BACKGROUND: Tumor necrosis factor (TNFA) is the canonical member of the TNF superfamily, which plays a major role in both inflammation and apoptosis. To evaluate the role of TNFs in otitis media (OM), the most common disease of childhood, we evaluated middle ear (ME) expression of genes encoding the TNF and TNF receptor superfamilies during bacterial OM in the mouse, characterized OM in TNFA-deficient mice, and assessed apoptosis during OM in normal versus TNF-deficient MEs. RESULTS: TNFs and TNF receptors were broadly regulated during OM, with TNFA showing the highest level of up-regulation. TNF deficient mice exhibited mucosal hyperplasia even in the absence of infection and exuberant growth of the mucosa during OM, including the formation of mucosal polyps. Mucosal recovery during OM was also delayed, in parallel with a delay in mucosal apoptosis and reduced caspase gene expression. CONCLUSIONS: The TNF and TNF receptor superfamilies mediate both inflammation and apoptosis during OM. TNF appears to be critical for the maintenance of mucosal architecture in both the normal and infected ME, since excessive accumulation of mucosal tissue is seen in TNFA-/- MEs both before and after bacterial inoculation of the ME. TNFA is also required for appropriate regulation of caspase genes.

Gene therapy in the inner ear using adenovirus vectors.

Therapies for the protection and regeneration of auditory hair cells are of great interest given the significant monetary and lifestyle impact of hearing loss. The past decade has seen tremendous advances in the use of adenoviral vectors to achieve these aims. Preliminary data demonstrated the functional capacity of this technique as adenoviral-induced expression of neurotrophic and growth factors protected hair cells and spiral ganglion neurons from ototoxic insults. Subsequent efforts confirmed the feasibility of adenoviral transfection of cells in the auditory neuroepithelium via cochleostomy into the scala media. Most recently, efforts have focused on regeneration of depleted hair cells. Mammalian hearing loss is generally considered a permanent insult as the auditory epithelium lacks a basal layer capable of producing new hair cells. Recently, the transcription factor Atoh1 has been found to play a critical role in hair cell differentiation. Adenoviral-mediated overexpression of Atoh1 in culture and in vivo have shown the ability to regenerate auditory and vestibular hair cells by causing transdifferentiation of neighboring epithelial-supporting cells. Functional recovery of both the auditory and vestibular systems has been documented following adenoviral induced Atoh1 overexpression.

Management of synkinesis.

Facial synkinesis is one of the most distressing consequences of facial paralysis. Synkinesis refers to the abnormal involuntary facial movement that occurs with voluntary movement of a different facial muscle group. The pathophysiologic basis of facial synkinesis is likely multifactorial although the predominant mechanism appears to be aberrant regeneration of facial nerve fibers to the facial muscle groups after facial nerve injury. Patients experience hypertonic contractures and synkinetic movements such as eye closure with volitional movement of the mouth or midfacial movement during volitional or reflexive eye closure. Synkinesis can cause functional limitation with activities such as eating, drinking, smiling, and may even lead to social isolation. Evaluation of synkinesis is primarily subjective with facial grading scales such as the Sunnybrook scale. Objective measures of synkinesis using computerized video analysis show promise although no objective techniques are currently widely used. The most common therapeutic modalities for the treatment of facial synkinesis include (1) botulinum toxin type A (BTX-A) injections for selective chemodenervation of affected muscle groups and (2) facial neuromuscular retraining. Biofeedback using mirrors or electromyography has been used both for the treatment and prevention of facial synkinesis. Other treatment options include surgical therapies, such as selective neurolysis or myectomy, although these have been rendered nearly obsolete with the advent of BTX-A.

Use of a sprayed fibrin hemostatic sealant after laser therapy for hereditary hemorrhagic telangiectasia epistaxis.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a relatively common autosomal dominant condition. Epistaxis is a frequent manifestation, often occurring daily and requiring iron and blood transfusions. Surgery often is bloody and difficult. The aim of this study was to evaluate the effectiveness of a sprayed fibrin, hemostatic sealant in preventing postoperative epistaxis after laser treatment of nasal mucosa in HHT. Fibrin sealant was compared with nasal packing for likelihood of postoperative epistaxis and financial impact including material costs and hospitalization fees. METHODS: Retrospective review was performed of 64 individual laser treatments for epistaxis in HHT patients at the University of California, San Diego, Medical Center between 2002 and 2005. Nasal packing was used in 30 procedures and fibrin sealant was used in 34 procedures. RESULTS: Six of 30 (20%) procedures using postoperative nasal packing required admission with an average hospital expense of $5914. One of 34 patients (3%) in the fibrin sealant group required hospitalization (p = 0.04). CONCLUSION: Aerosolized fibrin sealant prevents postoperative epistaxis after nasal laser treatment in HHT patients. Compared with traditional nasal packing we found improved patient comfort and recovery with substantial cost savings.

Constitutive Wee1 activity in adult brain neurons with M phase-type alterations in Alzheimer neurodegeneration.

The cdc2/cyclin B1 kinase is absent from neurons that are terminally differentiated. However, unscheduled activation of Cdc2/cyclin B and accumulation of mitotic phosphoepitopes have been described in degenerating neurons of Alzheimer's disease (AD), and their appearance precedes hallmark lesion formation. In cycling cells the timing of cdc2 activation and onset of mitosis are determined by the Wee1 tyrosine kinase. We therefore investigated the Wee1 kinase in human brain. Surprisingly, we have found that the enzyme is constitutively active in neurons of normal brain. Consistent with its behavior in M phase, Wee1 in AD has decreased activity, becomes MPM-2 immunoreactive, and is redistributed from its normally nuclear domain to the cytoplasm of affected neurons. These data suggest that Wee1 functions in normal postmitotic neurons, but is altered in AD so as to promote activation of Cdc2/cyclin B1. Thus, Wee1 is yet another mitotic regulator that participates in the AD neurodegenerative process.