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Inner ear gene therapy using adeno-associated viral vectors (AAV) promises to alleviate hearing and balance disorders. We previously established the benefits of Anc80L65 in targeting inner and outer hair cells in newborn mice. To accelerate translation to humans, we now report the feasibility and efficiency of the surgical approach and vector delivery in a nonhuman primate model. Five rhesus macaques were injected with AAV1 or Anc80L65 expressing eGFP using a transmastoid posterior tympanotomy approach to access the round window membrane after making a small fenestra in the oval window. The procedure was well tolerated. All but one animal showed cochlear eGFP expression 7-14 days following injection. Anc80L65 in 2 animals transduced up to 90% of apical inner hair cells; AAV1 was markedly less efficient at equal dose. Transduction for both vectors declined from apex to base. These data motivate future translational studies to evaluate gene therapy for human hearing disorders.
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Dependovirus , Vectores Genéticos , Animales , Cóclea/fisiología , Dependovirus/genética , Técnicas de Transferencia de Gen , Terapia Genética/métodos , Vectores Genéticos/genética , Macaca mulatta/genética , RatonesRESUMEN
OBJECTIVE: To characterize the prevalence, imaging characteristics, and cochlear implant candidacy of pediatric patients with single-sided deafness (SSD). METHODS: An audiometric database of patients evaluated at a large tertiary academic medical center was retrospectively queried to identify pediatric patients (<18 years old) with SSD, defined as severe to profound sensorineural hearing loss in one ear and normal hearing in the other. Medical records of identified patients were reviewed to characterize the prevalence, etiology, and cochlear implant candidacy of pediatric patients with SSD. RESULTS: We reviewed audiometric data obtained from 1993 to 2018 for 52,878 children at our institution. 191 (0.36%) had the diagnosis of SSD. Cochlear nerve deficiency (either hypoplasia or aplasia) diagnosed on MRI and/or CT was the most common etiology of SSD and was present in 22 of 88 (25%) pediatric SSD patients with available imaging data. 70 of 106 (66%) pediatric SSD patients with available imaging had anatomy amenable to cochlear implantation. CONCLUSIONS: Pediatric SSD is a rare condition and the most common etiology based on radiology is cochlear nerve deficiency. High resolution imaging of the temporal bone is essential to determine cochlear nerve morphology prior to consideration of cochlear implantation.
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Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/epidemiología , Pérdida Auditiva Unilateral/diagnóstico , Pérdida Auditiva Unilateral/epidemiología , Niño , Preescolar , Implantación Coclear , Implantes Cocleares , Femenino , Pérdida Auditiva Sensorineural/terapia , Pérdida Auditiva Unilateral/terapia , Pruebas Auditivas , Humanos , Imagen por Resonancia Magnética , Masculino , Prevalencia , Estudios Retrospectivos , Tomografía Computarizada por Rayos XRESUMEN
OBJECTIVE: To assess the efficacy and toxicity of proton radiotherapy in vestibular schwannoma. STUDY DESIGN: Retrospective chart review and volumetric MRI-analyses. SETTING: Tertiary referral center. PATIENTS: Vestibular schwannoma patients treated with protons between 2003 and 2018. INTERVENTION: Proton radiotherapy. MAIN OUTCOME MEASURES: Tumor control was defined as not requiring salvage treatment. Progressive hearing loss was defined as a decrease in maximum speech discrimination score below the 95% critical difference in reference to the pretreatment score. Hearing assessment includes contralateral hearing and duration of follow-up. Dizziness and/or unsteadiness and facial and trigeminal nerve function were scored. Patients who had surgery prior to proton radiotherapy were separately assessed. RESULTS: Of 221 included patients, 136 received single fraction and 85 fractionated proton radiotherapy. Actuarial 5-year local control rate was 96% (95% CI 90-98%). The median radiological follow-up was 4.5âyears. Progressive postirradiation speech discrimination score loss occurred in 42% of patients with audiometric follow-up within a year. Facial paresis was found in 5% (usually mild), severe dizziness in 5%, and trigeminal neuralgia in 5% of patients receiving protons as primary treatment. CONCLUSIONS: Proton radiotherapy achieves high tumor control with modest side effects aside from hearing loss in vestibular schwannoma patients. Limited and heterogeneous outcome reporting hamper comparisons to the literature. Potential sequelae of radiation therapy impacting vestibular function, cognitive function, and quality of life warrant further evaluation. Subgroups that benefit most from proton radiotherapy should be identified to optimize allocation and counterbalance its costs.
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Neuroma Acústico , Terapia de Protones , Radiocirugia , Estudios de Cohortes , Estudios de Seguimiento , Humanos , Neuroma Acústico/complicaciones , Terapia de Protones/efectos adversos , Calidad de Vida , Radiocirugia/efectos adversos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVE: To describe a novel use of a radial forearm free flap (RFFF) for soft tissue coverage over a cochlear implant (CI) in a post-irradiated field. PATIENTS: Single patient case report of a woman with a history of radiation therapy for brainstem astrocytoma who suffered from repeated CI extrusion despite tympanomastoid obliteration and locoregional pedicled flap soft tissue coverage. INTERVENTION(S): Sequential bilateral, single-staged revision cochlear implantation with RFFF soft tissue coverage. MAIN OUTCOME MEASURE(S): Postoperative wound healing complications including infection or device extrusion. RESULTS: There have been no further issues with wound healing, infection, or device extrusion with a follow up period of 3 years on one side and 8 months on the second side. Both CIs are functioning well with the flaps being sufficiently thin to allow for the use of typical external processor magnets. CONCLUSIONS: A RFFF can be used to provide robust soft tissue coverage over a CI in a post-irradiated field. The RFFF and CI may safely be performed in a single operation.
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Implantación Coclear , Implantes Cocleares , Colgajos Tisulares Libres , Procedimientos de Cirugía Plástica , Femenino , Antebrazo/cirugía , HumanosRESUMEN
BACKGROUND: Although slow growing, head and neck paragangliomas (HNPG) can cause significant morbidity. We evaluated the efficacy of proton therapy in the management of HNPG. METHODS: Retrospective review of an institutional proton therapy experience of treating patients between 1997 and 2016; 37 patients and 40 tumors were included. RESULTS: Proton therapy was delivered to a median of 50.4 Gy(RBE) (range: 45-68). Having a genetic/family predisposition for HNPG was associated with multifocal tumors (P = .02) and younger diagnosis age (P = .02). Twenty-six (70%) patients had symptom improvement posttreatment, and 65% of treated tumors showed ≥20% volumetric shrinkage. The 5-year recurrence-free and overall survival rates were both 97%. Grade 2 to grade 3 toxicities (54%) included subjective hearing impairment (19%), middle ear inflammation (14%), and dry mouth (8%). There were no grade 4-5 toxicities. CONCLUSIONS: Patients with HNPGs can be effectively and safely treated with proton therapy with excellent tumor control, successful volumetric tumor reduction, and symptomatic improvement.
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Neoplasias de Cabeza y Cuello , Paraganglioma Extraadrenal , Terapia de Protones , Neoplasias de Cabeza y Cuello/radioterapia , Humanos , Recurrencia Local de Neoplasia , Terapia de Protones/efectos adversos , Estudios RetrospectivosRESUMEN
OBJECTIVE: To describe the presentations and treatment results for patients with concurrent otosclerosis and superior semicircular canal dehiscence (SCD). STUDY DESIGN: Retrospective case series and literature review. SETTING: Tertiary academic medical center. PATIENTS: Patients with concurrent diagnoses of otosclerosis (radiographically and/or surgically confirmed) and SCD (radiographically confirmed) in the same ear. INTERVENTION(S): Review of medical records. MAIN OUTCOME MEASURE(S): Clinical presentations, outcomes following stapedotomy. RESULTS: Eight patients with 10 affected ears were identified. All patients presented with slowly progressive conductive hearing loss, normal otoscopy, absent acoustic reflexes, and without other symptoms of SCD syndrome. Seven patients were treated with stapedotomy and 1 with hearing aids. Of those treated with stapedotomy, a persistent conductive hearing loss was the most common hearing result. One patient had near-complete closure of their air bone gap. None had a profound sensorineural hearing loss. Four patients had unmasking of SCD symptoms. CONCLUSIONS: The clinical and audiometric presentations of patients with concurrent otosclerosis and SCD are often indistinguishable from those of patients with only otosclerosis. Computed tomography of the temporal bone is the only way to identify concurrent SCD. Stapedotomy in these patients typically results in a persistent conductive hearing loss, though 14 to 33% of patients experience near-complete closure of their air bone gap. SCD symptoms are unmasked in 57 to 63% of patients who undergo stapedotomy. Further work is needed to delineate the utility of routine preoperative computed tomography scan in otosclerosis patients, and to identify prognostic factors for patients with concurrent otosclerosis and SCD who wish to undergo stapedotomy.
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Otosclerosis , Dehiscencia del Canal Semicircular , Cirugía del Estribo , Pérdida Auditiva Conductiva/etiología , Pérdida Auditiva Conductiva/cirugía , Humanos , Otosclerosis/complicaciones , Otosclerosis/diagnóstico por imagen , Otosclerosis/cirugía , Estudios Retrospectivos , Canales Semicirculares/diagnóstico por imagen , Canales Semicirculares/cirugíaRESUMEN
A study of clinical records and temporal bone histopathology from a woman with bilateral otosclerosis who was treated with lateral semicircular canal fenestration procedures as well as stapedectomy.
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OBJECTIVE: To develop and validate an automated smartphone app that determines bone-conduction pure-tone thresholds. METHODS: A novel app, called EarBone, was developed as an automated test to determine best-cochlea pure-tone bone-conduction thresholds using a smartphone driving a professional-grade bone oscillator. Adult, English-speaking patients who were undergoing audiometric assessment by audiologists at an academic health system as part of their prescribed care were invited to use the EarBone app. Best-ear bone-conduction thresholds determined by the app and the gold standard audiologist were compared. RESULTS: Forty subjects with varied hearing thresholds were tested. Sixty-one percent of app-determined thresholds were within 5 dB of audiologist-determined thresholds, and 79% were within 10 dB. Nearly all subjects required assistance with placing the bone oscillator on their mastoid. CONCLUSION: Best-cochlea bone-conduction thresholds determined by the EarBone automated smartphone audiometry app approximate those determined by an audiologist. This serves as a proof of concept for automated smartphone-based bone-conduction threshold testing. Further improvements, such as the addition of contralateral ear masking, are needed to make the app clinically useful.
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Audiometría/instrumentación , Audiometría/métodos , Umbral Auditivo , Conducción Ósea , Pérdida Auditiva Conductiva/diagnóstico , Pérdida Auditiva Sensorineural/diagnóstico , Teléfono Inteligente , Validación de Programas de Computación , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prueba de Estudio Conceptual , Adulto JovenRESUMEN
OBJECTIVE:: To describe an observed case of spontaneous regression of cholesteatoma in a patient on chronic anti-tumor necrosis factor-alpha (TNF-a) therapy and inspire further research into the role of TNF-a in cholesteatoma. METHODS:: Clinical assessment of disease in a single-patient case report. RESULTS:: A 49-year-old woman suffered a severe case of Stevens-Johnson syndrome when she was 12 years old, leaving her with bilateral corneal opacification and tympanic membrane perforations with extensive cholesteatoma. For her corneal opacification, a corneal prosthesis was placed, which was complicated by a foreign body reaction necessitating long-term therapy with infliximab, a monoclonal antibody against TNF-a that is therapeutic in some chronic inflammatory diseases. She was otherwise healthy and took no other medications. While on infliximab, the patient had spontaneous and complete resolution of her cholesteatoma without any surgical intervention. CONCLUSIONS:: This surprising case suggests that there may be a prominent role of TNF-a in cholesteatoma pathophysiology and that TNF-a may be an effective target for nonsurgical therapy.
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Colesteatoma , Reacción a Cuerpo Extraño/tratamiento farmacológico , Infliximab/administración & dosificación , Implantación de Prótesis/efectos adversos , Hueso Temporal/diagnóstico por imagen , Anticuerpos Monoclonales , Colesteatoma/complicaciones , Colesteatoma/diagnóstico , Colesteatoma/fisiopatología , Colesteatoma/terapia , Opacidad de la Córnea/etiología , Reposicionamiento de Medicamentos , Femenino , Reacción a Cuerpo Extraño/complicaciones , Humanos , Persona de Mediana Edad , Procedimientos Quirúrgicos Oftalmológicos/efectos adversos , Procedimientos Quirúrgicos Oftalmológicos/instrumentación , Procedimientos Quirúrgicos Oftalmológicos/métodos , Implantación de Prótesis/instrumentación , Implantación de Prótesis/métodos , Remisión Espontánea , Síndrome de Stevens-Johnson/complicaciones , Tomografía Computarizada por Rayos X/métodos , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
OBJECTIVE: Evaluate the relationship between objective audiometric and vestibular tests and patient symptoms in superior canal dehiscence (SCD) syndrome. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary care center. PATIENTS: Ninety-eight patients with SCD, preoperative threshold audiograms, cervical vestibular evoked myogenic potential (cVEMP) thresholds, and computed tomography (CT) imaging were included. Clinical reports were reviewed for self-reported SCD symptoms. Twenty-five patients completed the Hearing Handicap Inventory (HHI), Dizziness Handicap Inventory (DHI), Autophony Index (AI), and the 36-item Short Form Survey (SF-36). MAIN OUTCOME MEASURES: Correlations between preoperative low-frequency air-bone gap (ABG), cVEMP thresholds, and symptoms (including HHI, DHI, AI, and SF-36). Symptoms included hearing loss, aural fullness, autophony, hyperacusis, tinnitus, vertigo, imbalance and sound-, pressure and exercise provoked dizziness. Secondary outcome measure: Correlations between changes of objective and subjective measures before and after surgery. RESULTS: Patients who reported hearing loss had larger ABGs at 250âHz than patients without subjective hearing loss (pâ=â0.001). ABGs and cVEMP thresholds did not correlate with any other symptom. No significant correlation was found between ABG or cVEMP threshold and the HHI, DHI, AI or Health Utility Value (derived from the SF-36 quality of life score). Following SCD surgery, ABG decreased (pâ<â0.001), cVEMP thresholds increased (pâ<â0.001) and overall symptoms, handicap scores and quality-of-life improved; however, there was no significant relationship between these measures. CONCLUSION: While threshold audiometry and cVEMP are important tools to diagnose SCD and monitor surgical outcomes, these measures showed no significant correlation with vestibular and most auditory symptoms or their severity.
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Audiometría , Enfermedades del Laberinto/complicaciones , Enfermedades del Laberinto/diagnóstico , Potenciales Vestibulares Miogénicos Evocados , Adulto , Anciano , Audiometría/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Canales Semicirculares/patología , Potenciales Vestibulares Miogénicos Evocados/fisiologíaRESUMEN
Grill wire brush bristle foreign bodies most commonly embed in the oropharynx. Often these bristles can be removed in the clinic; however, on occasion, the patient requires general anesthesia for retrieval because of the gag reflex and difficulty with access and visualization. We report here on 2 cases of patients who underwent successful transoral robotic surgical retrieval of wire bristles from the base of tongue after unsuccessful direct laryngoscopy. Otolaryngologists should be aware of the use of robotic assistance for oropharyngeal foreign body retrieval.
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Cuerpos Extraños/cirugía , Artículos Domésticos , Procedimientos Quirúrgicos Robotizados , Lengua , Adulto , Anciano , Medios de Contraste , Diagnóstico Diferencial , Femenino , Cuerpos Extraños/diagnóstico , Humanos , Laringoscopía , Masculino , Tomografía Computarizada por Rayos XRESUMEN
OBJECTIVES/HYPOTHESIS: Develop and validate an automated smartphone word recognition test. STUDY DESIGN: Cross-sectional case-control diagnostic test comparison. METHODS: An automated word recognition test was developed as an app for a smartphone with earphones. English-speaking adults with recent audiograms and various levels of hearing loss were recruited from an audiology clinic and were administered the smartphone word recognition test. Word recognition scores determined by the smartphone app and the gold standard speech audiometry test performed by an audiologist were compared. RESULTS: Test scores for 37 ears were analyzed. Word recognition scores determined by the smartphone app and audiologist testing were in agreement, with 86% of the data points within a clinically acceptable margin of error and a linear correlation value between test scores of 0.89. CONCLUSIONS: The WordRec automated smartphone app accurately determines word recognition scores. LEVEL OF EVIDENCE: 3b. Laryngoscope, 128:707-712, 2018.
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Audiometría de Tonos Puros/métodos , Umbral Auditivo/fisiología , Pérdida Auditiva/diagnóstico , Teléfono Inteligente , Programas Informáticos , Percepción del Habla/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Estudios Transversales , Femenino , Pérdida Auditiva/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Prueba del Umbral de Recepción del Habla/métodos , Adulto JovenRESUMEN
We conducted a retrospective case review to determine if the presence of an Accreditation Council for Graduate Medical Education (ACGME) fellowship-trained pediatric anesthesiologist improves efficiency during pediatric tonsillectomies and adenotonsillectomies in hospitals that do not have dedicated pediatric operating rooms and, if so, to determine which specific anesthesia practices might account for such a difference. We reviewed the charts of all patients aged 12 years and younger who had undergone a tonsillectomy or adenotonsillectomy from Jan. 1, 2008, through Aug. 1, 2013, at San Francisco General Hospital. A total of 75 cases met our eligibility criteria. We compiled information on patient demographics, surgical time, anesthesia time, and anesthesia practices. Our primary study outcome was the amount of anesthesia-controlled time (ACT), which is the sum of time spent in induction and emergence. Cases were grouped according to whether the operation was staffed by an ACGME fellowship-trained pediatric anesthesiologist or a general anesthesiologist. Data were analyzed for 1 pediatric anesthesiologist and 23 general anesthesiologists. We found that ACT was significantly shorter during the cases staffed by the ACGME fellowship-trained pediatric anesthesiologist, although there were no major differences in anesthesia practices between the types of anesthesiologist. We suggest that staffing pediatric tonsillectomy operations with a fellowship-trained pediatric anesthesiologist may be an effective strategy for increasing operating room efficiency.
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Adenoidectomía , Anestesiólogos , Competencia Clínica/normas , Quirófanos/organización & administración , Tonsilectomía , Acreditación/normas , Adenoidectomía/métodos , Adenoidectomía/normas , Anestesia/métodos , Anestesia/normas , Anestesiólogos/educación , Anestesiólogos/normas , Niño , Becas , Femenino , Humanos , Masculino , Mejoramiento de la Calidad , Tonsilectomía/métodos , Tonsilectomía/normas , Resultado del Tratamiento , Estados UnidosRESUMEN
BACKGROUND: Deletion of Toll-like receptor 9 (Tlr9) signaling, which is important for sterile inflammatory processes, results in impaired resolution of venous thrombosis (VT) in mice. The purpose of this study was to determine if deletion of Tlr9 affected sterile necrosis, apoptosis, and neutrophil extracellular trap (NET) production in VT. METHODS: Stasis and nonstasis murine models of VT were used in wild-type (WT) and Tlr9-/- mice, with assessment of thrombus size and determination of NETs, necrosis, and apoptosis markers. Anti-polymorphonuclear neutrophil (PMN) and antiplatelet antibody strategies were used to determine the cellular roles and their roles in WT and Tlr9-/- mice. RESULTS: At 2 days, stasis thrombi in Tlr9-/- mice were 62% larger (n = 6-10), with 1.4-fold increased uric acid levels, 1.7-fold more apoptotic cells, 2-fold increased citrullinated histones, 2-fold increased peptidylarginine deiminase 4 (PAD4), and 1.5-fold increased elastase and a 2.4-fold reduction in tissue factor pathway inhibitor compared with WT mice (all n = 4-7; P < .05). In contrast, the sizes of nonstasis thrombi were not significantly different in Tlr9-/- mice (n = 4-6), and they did not have elevated necrosis or NET markers. Stasis thrombus size was not reduced at the 2-day time point in WT or Tlr9-/- mice that received treatment with deoxyribonuclease I or in PAD4-/- mice, which are incapable of forming NETs. In Tlr9-/- mice undergoing PMN depletion (n = 8-10), stasis thrombus size was reduced 18% and was associated with 29-fold decreased citrullinated histones, 1.3-fold decreased elastase, and 1.5-fold increased tissue factor pathway inhibitor (all n = 6; P < .05). Last, platelet depletion (>90% reduction) did not significantly reduce stasis thrombus size in Tlr9-/- mice. CONCLUSIONS: These data suggest that the thrombogenic model affects Tlr9 thrombogenic mechanisms and that functional Tlr9 signaling in PMNs, but not in platelets or NETs, is an important mechanism in early stasis experimental venous thrombogenesis.
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Coagulación Sanguínea , Neutrófilos/metabolismo , Receptor Toll-Like 9/metabolismo , Trombosis de la Vena/metabolismo , Animales , Apoptosis , Biomarcadores/sangre , Coagulación Sanguínea/efectos de los fármacos , Desoxirribonucleasa I/farmacología , Modelos Animales de Enfermedad , Trampas Extracelulares/metabolismo , Genotipo , Hidrolasas/deficiencia , Hidrolasas/genética , Masculino , Ratones Endogámicos BALB C , Ratones Noqueados , Necrosis , Neutrófilos/efectos de los fármacos , Neutrófilos/patología , Fenotipo , Arginina Deiminasa Proteína-Tipo 4 , Transducción de Señal , Factores de Tiempo , Receptor Toll-Like 9/deficiencia , Receptor Toll-Like 9/genética , Trombosis de la Vena/sangre , Trombosis de la Vena/genética , Trombosis de la Vena/patologíaRESUMEN
Deep-vein thrombosis (DVT) resolves via a sterile inflammatory response. Defining the inflammatory response of DVT may allow for new therapies that do not involve anticoagulation. Previously, we have shown that Toll-like receptor 9 (Tlr9) gene deleted mice had impaired venous thrombosis (VT) resolution. Here, we further characterise the role of Tlr9 signalling and sterile inflammation in chronic VT and vein wall responses. First, we found a human precedent exists with Tlr9+ cells present in chronic post thrombotic intraluminal tissue. Second, in a stasis VT mouse model, endogenous danger signal mediators of uric acid, HMGB-1, and neutrophil extracellular traps marker of citrullinated histone-3 (and extracellular DNA) were greater in Tlr9-/- thrombi as compared with wild-type (WT), corresponding with larger VT at 8 and 21 days. Fewer M1 type (CCR2+) monocyte/macrophages (MØ) were present in Tlr9-/- thrombi than WT controls at 8 days, suggesting an impaired inflammatory cell influx. Using bone marrow-derived monocyte (BMMØ) cell culture, we found decreased fibrinolytic gene expression with exposure to several endogenous danger signals. Next, adoptive transfer of cultured Tlr9+/+ BMMØ to Tlr9-/- mice normalised VT resolution at 8 days. Lastly, although the VT size was larger at 21 days in Tlr9-/- mice and correlated with decreased endothelial antigen markers, no difference in fibrosis was found. These data suggest that Tlr9 signalling in MØ is critical for later VT resolution, is associated with necrosis clearance, but does not affect later vein wall fibrosis. These findings provide insight into the Tlr9 MØ mechanisms of sterile inflammation in this disease process.
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Células de la Médula Ósea/fisiología , Monocitos/fisiología , Receptor Toll-Like 9/metabolismo , Venas/patología , Trombosis de la Vena/inmunología , Traslado Adoptivo , Animales , Progresión de la Enfermedad , Fibrinólisis/genética , Fibrosis , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Modelos Animales , Transducción de Señal/genética , Receptor Toll-Like 9/genética , Trombosis de la Vena/fisiopatologíaRESUMEN
OBJECTIVE: To relate poststapedectomy change in tinnitus loudness to change in tinnitus severity. STUDY DESIGN: Prospective, within-subjects. SETTING: A single otology and neurotology subspecialty referral practice. SUBJECTS AND METHODS: Forty-nine subjects undergoing stapedectomy completed the study between January 2012 and October 2013. Tinnitus instruments, audiometric data, and demographic information were collected prior to and 1 and 6 months after surgery. Tinnitus loudness was assessed using an 11-point (0 = none; 5 = conversation level; 10 = jet engine) visual analog scale, and severity was measured using the validated Tinnitus Functional Index. The relationship between change in tinnitus loudness and change in tinnitus severity was evaluated using linear regression and receiver operating characteristic (ROC) analyses. RESULTS: A linear regression model of change in tinnitus loudness averaged for both ears on a visual analog scale (ΔVASavg) versus change in Tinnitus Functional Index score (ΔTFI) showed a strong correlation (ΔTFI = 9.35 ×ΔVASavg; R = 0.64; P < .001). An ROC analysis identified ΔVASavg between 1.5 and 2.0 as the optimal threshold for predicting a clinically significant change in tinnitus severity (ΔTFI ≥ 13), with sensitivity and specificity of approximately 0.62 and a positive predictive value (PPV) of 0.64. CONCLUSION: For poststapedectomy patients, a VAS loudness change by 1.5 to 2.0 points averaged for both ears in bilateral tinnitus or ~3 points in unilateral tinnitus has a PPV ~0.64 for a clinically significant change in tinnitus severity.
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Percepción Sonora/fisiología , Cirugía del Estribo , Acúfeno/fisiopatología , Femenino , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Otosclerosis/cirugía , Estudios Prospectivos , Curva ROC , Escala Visual AnalógicaRESUMEN
BACKGROUND: Tumor regression after induction chemotherapy (ICT) identifies laryngeal cancers that are responsive to chemoradiation. Patient immune parameters have recently been associated with response to chemotherapy and may identify responding patients. A retrospective analysis was performed to determine if pretreatment, circulating T lymphocyte levels predicted ICT response in patients with advanced laryngeal cancer. METHODS: Pretreatment, circulating T lymphocyte subpopulations were correlated with response to therapy and survival. Results were compared with similar data from an identical phase II trial involving patients with oropharyngeal cancer. RESULTS: An increased percentage of CD4+ cells predicted response to ICT and suggested improved survival in patients with laryngeal, but not oropharyngeal, cancer. In the combined group of patients, increased CD4 levels predicted response to ICT. CONCLUSION: These findings demonstrate the potential importance of the immune system in chemotherapy response and clinical outcome. Differences in findings between patients with advanced laryngeal and oropharyngeal cancer may reflect different cellular immunity function in the patients with human papillomavirus (HPV)-16+ oropharyngeal cancer.
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Linfocitos T CD4-Positivos/metabolismo , Quimioterapia de Inducción/métodos , Neoplasias Laríngeas/tratamiento farmacológico , Neoplasias Orofaríngeas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Linfocitos T CD4-Positivos/inmunología , Estudios de Cohortes , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Laríngeas/mortalidad , Neoplasias Laríngeas/patología , Neoplasias Laríngeas/cirugía , Laringectomía/métodos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Neoplasias Orofaríngeas/mortalidad , Neoplasias Orofaríngeas/patología , Neoplasias Orofaríngeas/cirugía , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Medición de Riesgo , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
OBJECTIVE: Deep vein thrombosis (DVT) resolution instigates an inflammatory response, resulting in vessel wall damage and scarring. Urokinase-plasminogen activator (uPA) and its inhibitor, plasminogen activator inhibitor-1 (PAI-1), are integral components of the fibrinolytic system, essential for venous thrombosis (VT) resolution. This study determined the vein wall response when exposed to increased and decreased plasmin activity. METHODS: A mouse inferior vena cava (IVC) ligation model in uPA -/- or PAI-1 -/- and their genetic wild types (B6/SvEv and C57/BL6, respectively) was used to create stasis thrombi, with tissue harvest at either 8 or 21 days. Tissue analysis included gene expression of vascular smooth muscle cells (alpha smooth muscle actin [αSMA], SM22) and endothelial marker (CD31), by real-time polymerase chain reaction, enzyme-linked immunosorbent assay, matrix metalloproteinase (MMP)-2 and -9 activity by zymography, and vein wall collagen by picro-Sirius red histologic analysis. A P < .05 was considered significant. RESULTS: Thrombi were significantly larger in both 8-day and 21-day uPA -/- as compared with wild type (WT) and were significantly smaller in both 8-day and 21-day PAI-1 -/- as compared with WT. Correspondingly, 8-day plasmin levels were reduced in half in uPA -/- and increased three-fold in PAI-1 -/- when compared with respective WT thrombi (P < .05; n = 5-6). The endothelial marker CD31 was elevated two-fold in PAI-1 -/- mice at 8 days, but reduced 2.5-fold at 21 days in uPA -/- as compared with WT (P = .02; n = 5-6), suggesting less endothelial preservation. Vein wall vascular smooth muscle cell (VSMC) gene expression showed that 8-day and 21-day PAI-1 -/- mice had 2.3- and 3.8-fold more SM22 and 1.8- and 2.3-fold more αSMA expression than respective WT (P < .05; n = 5-7), as well as 1.8-fold increased αSMA (+) cells (P ≤ .05; n = 3-5). No significant difference in MMP-2 or -9 activity was found in the PAI-1 -/- mice compared with WT, while 5.4-fold more MMP-9 was present in 21-day WT than 21-day uPA -/- (P = .03; n = 5). Lastly, collagen was â¼two-fold greater at 8 days in PAI-1 -/- IVC as compared with WT (P = .03; n = 6) with no differences observed in uPA -/- mice. CONCLUSIONS: In stasis DVT, plasmin activity is critical for thrombus resolution. Divergent vein wall responses occur with gain or loss of plasmin activity, and despite smaller VT, greater vein wall fibrosis was associated with lack of PAI-1.