RESUMEN
BACKGROUND: Head and neck squamous cell carcinomas (HNSCC) are frequently diagnosed in advanced stages, which limits therapeutic options and results in persistently poor patient outcomes. The aim of this study was to use liquid-based swab cytology (LBC) in combination with dual immunocytochemical detection of migration and proliferation markers Sec62 and Ki67 in order to allow non-invasive early detection of HNSCC as well as to analyse the diagnostic validity of this method for predicting the malignancy of suspicious oral lesions. METHODS: 104 HNSCC patients and 28 control patients, including healthy patients (n = 17), papilloma (n = 1) and leukoplakia patients (n = 10), were included in this study. For all patients, an LBC swab followed by simultaneous immunocytochemical detection of Sec62 and Ki67 was performed. Immunocytochemical as well as cytopathological results were correlated with histological diagnoses and clinical findings. RESULTS: All HNSCC patients (100%) showed dual Sec62/Ki67 positivity, and all control patients except for the papilloma patient were negative for Sec62/Ki67 (96.4%), resulting in a 100% sensitivity and 96.4% specificity of Sec62/Ki67 dual stain for non-invasive detection of HNSCC. The positive predictive value was 99% and the negative predictive value was 100%. Sec62 expression levels showed a positive correlation with tumour de-differentiation (p = 0.0489). CONCLUSION: Simultaneous immunocytochemical detection of Sec62/Ki67 using LBC represents a promising non-invasive and easy-to-apply tool for the early detection of HNSCC in routine clinical practice. This novel technique can help to avoid incisional biopsies and reduce the frequency with which general anaesthesia is used in diagnostic procedures in patients with suspicious oral lesions.
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Neoplasias de Cabeza y Cuello , Papiloma , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico , Antígeno Ki-67/metabolismo , Inmunohistoquímica , Neoplasias de Cabeza y Cuello/diagnósticoRESUMEN
BACKGROUND: Peripheral facial palsy (PFP) is a common neurologic symptom which can be triggered by pathogens, autoimmunity, trauma, tumors, cholesteatoma or further local conditions disturbing the peripheral section of the nerve. In general, its cause is often difficult to identify, remaining unknown in over two thirds of cases. As we have previously shown that the quantity and quality of pathogen-specific T cells change during active infections, we hypothesized that such changes may also help to identify the causative pathogen in PFPs of unknown origin. METHODS: In this observational study, pathogen-specific T cells were quantified in blood samples of 55 patients with PFP and 23 healthy controls after stimulation with antigens from varicella-zoster virus (VZV), herpes-simplex viruses (HSV) or borrelia. T cells were further characterized by expression of the inhibitory surface molecule CTLA-4, as well as markers for differentiation (CD27) and proliferation (Ki67). Pathogen-specific antibody responses were analyzed using ELISA. Results were compared with conventional diagnostics. RESULTS: Patients with PFP were more often HSV-seropositive than controls (p = 0.0003), whereas VZV- and borrelia-specific antibodies did not differ between groups. Although the quantity and general phenotypical characteristics of antigen-specific T cells did not differ either, expression of CTLA-4 and Ki67 was highly increased in VZV-specific T cells of 9 PFP patients, of which 5 showed typical signs of cutaneous zoster. In the remaining 4 patients, a causal relationship with VZV was possible but remained unclear by clinical standard diagnostics. A similar CTLA-4- and Ki67-expression profile of borrelia-specific T cells was also found in a patient with acute neuroborreliosis. DISCUSSION: In conclusion, the high prevalence of HSV-seropositivity among PFP-patients may indicate an underestimation of HSV-involvement in PFP, even though HSV-specific T cell characteristics seem insufficient to identify HSV as a causative agent. In contrast, striking alterations in VZV- and borrelia-specific T cell phenotype and function may allow identification of VZV- and borrelia-triggered PFPs. If confirmed in larger studies, antigen-specific immune-phenotyping may have the potential to improve specificity of the clinical diagnosis.
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Parálisis Facial , Herpes Zóster , Humanos , Antígeno CTLA-4 , Inmunidad Humoral , Antígeno Ki-67 , Herpesvirus Humano 3 , SimplexvirusRESUMEN
BACKGROUND: Infections of the respiratory tract are the main indication for outpatient antibiotic therapy in children and adolescents. In recent years the antibiotic prescription rate (APR) in the pediatric population has decreased significantly. OBJECTIVES: The aim of the retrospective mastoiditis audit in the PaedineSaar network is to investigate the incidence of inpatient acute mastoiditis (AM) in Saarland (2014-2019) regarding to the decreasing APRs in children, as well as to gather data of the clinical course of AM. METHODS: All inpatient AM cases 2014-2019 were analyzed retrospectively from 6 hospitals for pediatrics and/or otorhinolaryngology in Saarland and Trier. Children and adolescents aged 0-17 years and residing in Saarland were included in the study. RESULTS: 2014-2019 53 inpatient treated AM cases have been recorded. During the study period there was no significant increase of AM incidence (mean incidence 2014-2019: 6.1/100,000). 34% (18/53) of the patients received prehospital antibiotic treatment (main indication: acute otitis media (AOM) 15/18, 83%). At least one complication occurred in 30% of the patients (16/53). There was a slight trend to more complications in children without oral antibiotic treatment before admission (14/35 (40%) vs. 2/18 (11%) p=0.056). CONCLUSIONS: The incidence of AM leading to inpatient treatment in children in Saarland did not increase 2014-2019 despite a significant and sustained decline in the outpatient APRs. The results of this audit should be used for the development of a more standardized approach concerning the diagnostics and treatment of children with AM.
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Mastoiditis , Adolescente , Niño , Humanos , Lactante , Enfermedad Aguda , Antibacterianos/efectos adversos , Mastoiditis/diagnóstico , Mastoiditis/tratamiento farmacológico , Mastoiditis/epidemiología , Pacientes Ambulatorios , Estudios Retrospectivos , Recién Nacido , PreescolarRESUMEN
TRPC channels are critical players in cochlear hair cells and sensory neurons, as demonstrated in animal experiments. However, evidence for TRPC expression in the human cochlea is still lacking. This reflects the logistic and practical difficulties in obtaining human cochleae. The purpose of this study was to detect TRPC6, TRPC5 and TRPC3 in the human cochlea. Temporal bone pairs were excised from ten body donors, and the inner ear was first assessed based on computed tomography scans. Decalcification was then performed using 20% EDTA solutions. Immunohistochemistry with knockout-tested antibodies followed. The organ of Corti, the stria vascularis, the spiral lamina, spiral ganglion neurons and cochlear nerves were specifically stained. This unique report of TRPC channels in the human cochlea supports the hypothesis of the potentially critical role of TRPC channels in human cochlear health and disease which has been suggested in previous rodent experiments.
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Cóclea , Oído Interno , Animales , Humanos , Inmunohistoquímica , Cóclea/metabolismo , Oído Interno/metabolismo , Estría Vascular/metabolismo , AudiciónRESUMEN
BACKGROUND: This cross-sectional study aimed to assess the frequency and type of firework-associated acoustic trauma occurring in Germany on New Year's Eve 2021, despite the ban on firework sales due to the COVID-19 pandemic. MATERIALS AND METHODS: The survey period lasted 7 days, from 28 December 2021 to 03 January 2022. A questionnaire inquired date, type and treatment of trauma, sex, and age of the patient, and whether the trauma occurred when lighting or watching fireworks. Hearing impairment was classified according to the World Health Organization (WHO grades 0 to 4), and concomitant tinnitus, vertigo, or other injuries were recorded. The questionnaire was sent to the otorhinolaryngology departments of 171 hospitals in Germany. RESULTS: Of 37 otorhinolaryngology departments, 16 reported no and 21 reported 50 patients with firework-associated acoustic trauma. Mean age was 29⯱ 16 years and 41 of 50 patients were males. Of these 50 patients, 22 presented without and 28 with hearing loss, 32 reported tinnitus and 3 vertigo; 20 patients were injured when lighting fireworks and 30 when watching. Hearing impairment was classified as 14â¯× WHO grade 0, 5â¯× WHO grade 1, 4â¯× WHO grade 2, 2â¯× WHO grade 3, and 3â¯× WHO grade 4. Inpatient treatment was received by 8 patients and 11 suffered from concomitant burn injuries. CONCLUSION: Despite the sales ban, some firework-associated acoustic traumas occurred at New Year 2021/2022 in Germany. Some instances led to hospitalization, but an even higher number of unreported cases can be assumed. This study can serve as a baseline for further annual surveys to raise the awareness of the danger of seemingly harmless fireworks for the individual.
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Traumatismos por Explosión , COVID-19 , Pérdida Auditiva Provocada por Ruido , Relámpago , Acúfeno , Masculino , Humanos , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Femenino , Traumatismos por Explosión/diagnóstico , Traumatismos por Explosión/epidemiología , Traumatismos por Explosión/terapia , Pérdida Auditiva Provocada por Ruido/diagnóstico , Pérdida Auditiva Provocada por Ruido/epidemiología , Estudios Transversales , Pandemias , Acúfeno/diagnóstico , Acúfeno/epidemiologíaRESUMEN
We report on the metachronic appearance of an inverted papilloma in the ipsilateral middle ear after resection of an endonasal inverted papilloma and its malignant transformation. After multiple surgical interventions and adjuvant radiation and chemotherapy, there was recurrence with intracerebral growth, which ultimately led to the patient's death 3 years after the initial presentation.
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Trompa Auditiva , Neoplasias Nasales , Papiloma Invertido , Humanos , Trompa Auditiva/cirugía , Papiloma Invertido/cirugía , Nariz/patología , Oído Medio/cirugía , Oído Medio/patología , Neoplasias Nasales/diagnóstico , Neoplasias Nasales/cirugía , Recurrencia Local de NeoplasiaRESUMEN
BACKGROUND: This cross-sectional study aimed to assess the frequency and type of firework-associated acoustic trauma occurring in Germany on New Year's Eve 2021, despite the ban on firework sales due to the COVID-19 pandemic. MATERIALS AND METHODS: The survey period lasted 7 days, from 28 December 2021 to 03 January 2022. A questionnaire inquired date, type and treatment of trauma, sex, and age of the patient, and whether the trauma occurred when lighting or watching fireworks. Hearing impairment was classified according to the World Health Organization (WHO grades 0 to 4), and concomitant tinnitus, vertigo, or other injuries were recorded. The questionnaire was sent to the otorhinolaryngology departments of 171 hospitals in Germany. RESULTS: Of 37 otorhinolaryngology departments, 16 reported no and 21 reported 50 patients with firework-associated acoustic trauma. Mean age was 29⯱ 16 years and 41 of 50 patients were males. Of these 50 patients, 22 presented without and 28 with hearing loss, 32 reported tinnitus and 3 vertigo; 20 patients were injured when lighting fireworks and 30 when watching. Hearing impairment was classified as 14â¯× WHO grade 0, 5â¯× WHO grade 1, 4â¯× WHO grade 2, 2â¯× WHO grade 3, and 3â¯× WHO grade 4. Inpatient treatment was received by 8 patients and 11 suffered from concomitant burn injuries. CONCLUSION: Despite the sales ban, some firework-associated acoustic traumas occurred at New Year 2021/2022 in Germany. Some instances led to hospitalization, but an even higher number of unreported cases can be assumed. This study can serve as a baseline for further annual surveys to raise the awareness of the danger of seemingly harmless fireworks for the individual.
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Traumatismos por Explosión , COVID-19 , Pérdida Auditiva Provocada por Ruido , Relámpago , Acúfeno , Masculino , Humanos , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Femenino , Traumatismos por Explosión/diagnóstico , Traumatismos por Explosión/epidemiología , Traumatismos por Explosión/terapia , Pérdida Auditiva Provocada por Ruido/diagnóstico , Pérdida Auditiva Provocada por Ruido/epidemiología , Estudios Transversales , Pandemias , Acúfeno/diagnóstico , Acúfeno/epidemiologíaRESUMEN
BACKGROUND: The aim of this article is to report on the integration of endoscopic ear surgery (EES) into daily clinical practice. MATERIAL AND METHODS: In a monocentric prospective study, the endoscopy unit was set up during even weeks over a period of 10 months and the procedure was primarily started endoscopically via a transmeatal approach. In odd weeks, the endoscopy was omitted. A total of 60 procedures in 59 patients were evaluated. Points of comparison were intraoperative vision, incision-suture time, postoperative hearing outcome, and postoperative otoscopic findings. RESULTS: With the exception of the facial nerve (pâ¯= 0.15 Mann-Whitney Utest), the EES showed significantly improved visualization of all areas in the middle ear. The incision-suture times were similar in both methods. If bimanual placement of an ossicular prosthesis was necessary, the incision-suture time increased disproportionately (MES: 57.18⯱ 9.7â¯min, EES: 76.83⯱ 24.99â¯min; pâ¯= 0.019, *). There were no statistically significant changes related to hearing outcomes when comparing EES with the microscopic technique. There were no postoperative complications in the EES surgery group. CONCLUSION: Integration of EES proved to be successful and advantageous in a real patient collective at this location.
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Colesteatoma del Oído Medio , Otolaringología , Procedimientos Quirúrgicos Otológicos , Humanos , Estudios Prospectivos , Centros de Atención Terciaria , Resultado del Tratamiento , Procedimientos Quirúrgicos Otológicos/métodos , Endoscopía/métodos , Oído Medio , Estudios RetrospectivosRESUMEN
PURPOSE: Liquid-based cytology (LBC) is routinely used in gynecology but is rarely applied in head and neck oncology though many suspicious lesions are easily accessible. While several studies have evaluated the potential use of LBC for early detection and molecular characterization of head and neck squamous cell carcinomas (HNSCCs), no study investigated its potential role in surgical management and therapy planning so far. METHODS: Twenty-five patients with cT1-2 squamous cell carcinomas of the oral cavity and oropharynx were prospectively enrolled in this study and were randomized to two treatment arms: in the control arm, a diagnostic panendoscopy with incisional biopsy was followed by a second operation with transoral tumor resection ± neck dissection and tracheostomy. In the intervention arm, patients underwent LBC diagnostics and in case of a positive result received one single operation with panendoscopy and incisional biopsy for confirmation of LBC result by rapid section histology followed by transoral tumor resection ± neck dissection and tracheostomy in the same session. RESULTS: Time between clinical diagnosis and definitive surgical treatment was significantly shorter in the intervention group compared with the control group (p < 0.0001). Additionally, time of hospitalization (p < 0.0001) and cumulative operation time (p = 0.062) were shorter in the intervention group. No significant differences in overall, progression-free, and disease-specific survival were observed. CONCLUSION: Cytology-based cancer surgery is a promising therapeutic strategy that can potentially be considered for a well-defined group of early-stage HNSCC patients and help to avoid repetitive general anesthesia, shorten the diagnosis-to-treatment interval and spare operation as well as hospitalization time.
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Carcinoma de Células Escamosas , Cycas , Neoplasias de Cabeza y Cuello , Carcinoma de Células Escamosas/patología , Neoplasias de Cabeza y Cuello/diagnóstico , Neoplasias de Cabeza y Cuello/cirugía , Humanos , Disección del Cuello , Estudios Prospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello/cirugíaRESUMEN
The etiology of juvenile angiofibroma (JA) has been a controversial topic for more than 160 years. Numerous theories have been proposed to explain this rare benign neoplasm arising predominately in adolescent males, focusing mainly on either the vascular or fibrous component. To assess our hypothesis of JA's being a malformation arising from neural crest cells/remnants of the first branchial arch plexus, we performed immunohistochemical analyses of neural crest stem cells (NCSC) and epithelial-mesenchymal transition (EMT) candidates. Immunoexpression of the NCSC marker CD271p75 was observed in all investigated JA's (n = 22), mainly around the pathological vessels. Close to CD271p75-positive cells, high MMP3-staining was also observed. Additionally, from one JA with sufficient material, RT-qPCR identified differences in the expression pattern of PDGFRß, MMP2 and MMP3 in MACS®-separated CD271p75positive vs. CD271p75 negative cell fractions. Our results, together with the consideration of the literature, provide evidence that JA's represent a malformation within the first branchial arch artery/plexus remnants deriving from NCSC. This theory would explain the typical site of tumor origin as well as the characteristic tumor blood supply, whereas the process of EMT provides an explanation for the vascular and fibrous tumor component.
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Angiofibroma/patología , Cresta Neural/patología , Células-Madre Neurales/patología , Adolescente , Adulto , Angiofibroma/metabolismo , Niño , Humanos , Masculino , Persona de Mediana Edad , Proteínas del Tejido Nervioso/metabolismo , Cresta Neural/metabolismo , Células-Madre Neurales/metabolismo , Adulto JovenRESUMEN
Pott's puffy tumor (PPT) is an infection of the frontal sinus with subperiosteal and intracranial abscess formation and one of the rare entities in pediatrics. We present a series of four cases of PPT that occurred in two children (6 and 9 years) and in two young adults (17 and 19 years). All patients were treated by an interdisciplinary team of pediatric, neurosurgical, ENT, radiological, and neuroradiological specialists. Antibiotic treatment was combined with single endoscopic surgery in one case and combined endoscopic sinus surgery with an open transcranial approach to drain intracranial abscess formation in three cases. It is important to be aware that PPT occurs in children with the finding of intracranial abscess formation. Therefore, a close interdisciplinary cooperation for successful treatment is needed in this rare disease.
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Seno Frontal , Sinusitis Frontal , Tumor Hinchado de Pott , Niño , Drenaje , Endoscopía , Humanos , Tumor Hinchado de Pott/diagnóstico por imagen , Tumor Hinchado de Pott/cirugía , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
Pott's puffy tumor (PPT) is an infection of the frontal sinus with subperiosteal and intracranial abscess formation and one of the rare entities in pediatrics. We present a series of four cases of PPT that occurred in two children (6 and 9 years) and in two young adults (17 and 19 years). All patients were treated by an interdisciplinary team of pediatric, neurosurgical, ENT, radiological, and neuroradiological specialists. Antibiotic treatment was combined with single endoscopic surgery in one case and combined endoscopic sinus surgery with an open transcranial approach to drain intracranial abscess formation in three cases. It is important to be aware that PPT occurs in children with the finding of intracranial abscess formation. Therefore, a close interdisciplinary cooperation for successful treatment is needed in this rare disease.
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Sinusitis Frontal , Tumor Hinchado de Pott , Absceso , Niño , Drenaje , Endoscopía , Sinusitis Frontal/diagnóstico , Sinusitis Frontal/terapia , Humanos , Tumor Hinchado de Pott/cirugía , Tumor Hinchado de Pott/terapia , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
Owing to the lack of specific symptoms, diagnosis of head and neck squamous cell carcinoma (HNSCC) may be delayed. We evaluated volatile organic compounds in tumor samples from patients suffering from HNSCC and tested the hypothesis that there is a characteristic altered composition in the headspace of HNSCC compared with control samples from the same patient with normal squamous epithelium. These results provide the basis for future noninvasive breath analysis in HNSCC. Headspace air of suspected tumor and contralateral control samples in 20 patients were analyzed using ion-mobility spectrometry. Squamous cell carcinoma was diagnosed in 16 patients. In total, we observed 93 different signals in headspace measurements. Squamous cell carcinomas revealed significantly higher levels of volatile cyclohexanol (0.54 ppbv , 25th to 75th percentiles 0.35-0.86) compared with healthy squamous epithelium (0.24 ppbv , 25th to 75th percentiles 0.12-0.3; p < 0.001). In conclusion, head and neck squamous cell carcinoma emitted significantly higher levels of volatile cyclohexanol in headspace compared with normal squamous epithelium. These findings form the basis for future breath analysis for diagnosis, therapy control and the follow-up of HNSSC to improve therapy and aftercare.
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Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico , Compuestos Orgánicos Volátiles/química , Anciano , Anciano de 80 o más Años , Pruebas Respiratorias , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Carcinoma de Células Escamosas de Cabeza y Cuello/química , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Compuestos Orgánicos Volátiles/metabolismoRESUMEN
PURPOSE: Gagging may be a challenge in daily otorhinolaryngology (ORL) routine. This cross-sectional study aimed to examine conditions of gagging as limitation to ORL examination and the efficacy of acupressure as tool to reduce exaggerated gagging. METHODS: The study was conducted on a total of 360 study subjects. There was a survey part and a routine ORL examination with observation of gagging behaviour. Through binomial univariate logistic regression, predictors of clinically relevant exaggerated gagging were identified. Wilcoxon signed rank test was used to evaluate efficacy of acupressure point CV-24 to reduce gagging while examination. RESULTS: First gagging's relevance was indicated by over 40% of study subjects showing clinically relevant exaggerated gagging. Furthermore, we found that more psychogenic than somatogenic features proved to be predictors of exaggerated gagging. Third acupressure point CV-24 showed statistical significant reduction of gagging intensity and improved examination feasibility. CONCLUSION: Awareness of exaggerated gagging's predictors are the first step to deal with gagging in daily practice. Acupressure might be an effective tool to overcome gagging in the affected patients. LEVEL OF EVIDENCE: We suggest at least Level IV according to Oxford (UK) CEBM Levels of Evidence.
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Acupresión , Atragantamiento/prevención & control , Otolaringología , Adulto , Estudios Transversales , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Perineuronal nets (PNNs) are specialized aggregations of extracellular matrix (ECM) molecules surrounding specific neurons in the central nervous system (CNS). PNNs are supposed to control synaptic transmission and are frequently associated with neurons firing at high rates, including principal neurons of auditory brainstem nuclei. The origin of high-frequency activity of auditory brainstem neurons is the indefatigable sound-driven transmitter release of inner hair cells (IHCs) in the cochlea. RESULTS: Here, we show that synaptic poles of IHCs are ensheathed by basket-like ECM complexes formed by the same molecules that constitute PNNs of neurons in the CNS, including brevican, aggreccan, neurocan, hyaluronan, and proteoglycan link proteins 1 and 4 and tenascin-R. Genetic deletion of brevican, one of the main components, resulted in a massive degradation of ECM baskets at IHCs, a significant impairment in spatial coupling of pre- and postsynaptic elements and mild impairment of hearing. CONCLUSIONS: These ECM baskets potentially contribute to control of synaptic transmission at IHCs and might be functionally related to PNNs of neurons in the CNS.
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Brevicano/genética , Oído Interno/fisiología , Matriz Extracelular/metabolismo , Transmisión Sináptica/fisiología , Animales , Brevicano/metabolismo , Femenino , Masculino , Ratones , Ratones NoqueadosRESUMEN
INTRODUCTION: Defects in the head region may be caused by tumour treatments, injuries, as well as congenital malformations. The restoration of these defects that can be performed through reconstructive plastic surgery and/or prosthetic surgery occupies a high priority in the physical and psychological rehabilitation of the patient. The present study reports on long-term experience in supply of facial prosthesis. MATERIALS AND METHODS: The medical records of 99 patients, who had been supplied with custom-made facial prostheses between 2001 and 2011, were evaluated retrospectively. RESULTS: There were 59 male (60%) and 40 (40%) female patients. The reason for prosthetic supplement was a tumour disease in 50 patients, congenital malformation in 39 patients, and trauma in 10 patients. Fifty-three patients were treated with ear prosthesis, twenty-seven patients were treated with eye prosthesis, and nineteen patients with nasal prosthesis. 82.8% of prosthetic supplies were designed as magnetic support prostheses. The most common complication was skin redness around the implants. 10% of patients suffered the loss of the osseointegrated implants. CONCLUSION: The osseointegrated titanium implants with magnet support provide a reliable attachment for prosthesis and constitute a promising alternative to surgical reconstruction of complex facial defects.
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Cara/cirugía , Neoplasias de Cabeza y Cuello/cirugía , Procedimientos de Cirugía Plástica , Prótesis e Implantes , Implantación de Prótesis/métodos , Adulto , Oído/anomalías , Ojo , Cara/anomalías , Femenino , Humanos , Estimación de Kaplan-Meier , Imanes , Masculino , Persona de Mediana Edad , Nariz/cirugía , Oseointegración , Satisfacción del Paciente , Prótesis e Implantes/efectos adversos , Diseño de Prótesis , Implantación de Prótesis/instrumentación , Estudios Retrospectivos , TitanioRESUMEN
The auxiliary subunit α2δ2 modulates the abundance and function of voltage-gated calcium channels. Here we show that α2δ2 mRNA is expressed in neonatal and mature hair cells. A functional α2δ2-null mouse, the ducky mouse (du), showed elevated auditory brainstem response click and frequency-dependent hearing thresholds. Otoacoustic emissions were not impaired pointing to normal outer hair cell function. Peak Ca2+ and Ba2+ currents of mature du/du inner hair cells (IHCs) were reduced by 30-40%, respectively, and gating properties, such as the voltage of half-maximum activation and voltage sensitivity, were altered, indicating that Cav1.3 channels normally coassemble with α2δ2 at IHC presynapses. The reduction of depolarization-evoked exocytosis in du/du IHCs reflected their reduced Ca2+ currents. Ca2+- and voltage-dependent K+ (BK) currents and the expression of the pore-forming BKα protein were normal. Cav1.3 and Cavß2 protein expression was unchanged in du/du IHCs, forming clusters at presynaptic ribbons. However, the close apposition of presynaptic Cav1.3 clusters with postsynaptic glutamate receptor GluA4 and PSD-95 clusters was significantly impaired in du/du mice. This implies that, in addition to controlling the expression and gating properties of Cav1.3 channels, the largely extracellularly localized α2δ2 subunit moreover plays a so far unknown role in mediating trans-synaptic alignment of presynaptic Ca2+ channels and postsynaptic AMPA receptors. SIGNIFICANCE STATEMENT: Inner hair cells possess calcium channels that are essential for transmitting sound information into synaptic transmitter release. Voltage-gated calcium channels can coassemble with auxiliary subunit α2δ isoforms 1-4. We found that hair cells of the mouse express the auxiliary subunit α2δ2, which is needed for normal hearing thresholds. Using a mouse model with a mutant, nonfunctional α2δ2 protein, we showed that the α2δ2 protein is necessary for normal calcium currents and exocytosis in inner hair cells. Unexpectedly, the α2δ2 protein is moreover required for the optimal spatial alignment of presynaptic calcium channels and postsynaptic glutamate receptor proteins across the synaptic cleft. This suggests that α2δ2 plays a novel role in organizing the synapse.
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Canales de Calcio Tipo L/metabolismo , Canales de Calcio/metabolismo , Células Ciliadas Auditivas Internas/fisiología , Audición/fisiología , Sinapsis/fisiología , Transmisión Sináptica/fisiología , Animales , Calcio/metabolismo , Canales de Calcio/genética , Señalización del Calcio/fisiología , Femenino , Activación del Canal Iónico/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Loss of function of the gene SCN9A, encoding the voltage-gated sodium channel Na(v)1.7, causes a congenital inability to experience pain in humans. Here we show that Na(v)1.7 is not only necessary for pain sensation but is also an essential requirement for odour perception in both mice and humans. We examined human patients with loss-of-function mutations in SCN9A and show that they are unable to sense odours. To establish the essential role of Na(v)1.7 in odour perception, we generated conditional null mice in which Na(v)1.7 was removed from all olfactory sensory neurons. In the absence of Na(v)1.7, these neurons still produce odour-evoked action potentials but fail to initiate synaptic signalling from their axon terminals at the first synapse in the olfactory system. The mutant mice no longer display vital, odour-guided behaviours such as innate odour recognition and avoidance, short-term odour learning, and maternal pup retrieval. Our study creates a mouse model of congenital general anosmia and provides new strategies to explore the genetic basis of the human sense of smell.
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Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutación/genética , Trastornos del Olfato/genética , Trastornos del Olfato/fisiopatología , Canales de Sodio/genética , Potenciales de Acción , Animales , Conducta Animal , Modelos Animales de Enfermedad , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Ratones , Canal de Sodio Activado por Voltaje NAV1.7 , Odorantes/análisis , Trastornos del Olfato/congénito , Trastornos del Olfato/patología , Mucosa Olfatoria/citología , Mucosa Olfatoria/patología , Vías Olfatorias/metabolismo , Vías Olfatorias/patología , Vías Olfatorias/fisiopatología , Percepción Olfatoria/genética , Percepción Olfatoria/fisiología , Neuronas Receptoras Olfatorias/metabolismo , Neuronas Receptoras Olfatorias/patología , Dolor/genética , Dolor/fisiopatología , Fenotipo , Olfato/genética , Olfato/fisiología , Canales de Sodio/deficiencia , Canales de Sodio/metabolismo , Sinapsis/metabolismo , Sinapsis/patología , Orina/químicaRESUMEN
Advanced nasal cancers usually demand partial or total rhinectomy followed by radiotherapy. Reconstruction of the resulting defects can be achieved by means of reconstructive plastic surgery and/or epithetic surgery. The data of 22 patients who had been treated after nasal ablation by means of custom-made silicone nasal epithesis fixed by bone-anchored magnets between 2003 and 2014 were evaluated retrospectively. There were 15 male (68.2 %) and 7 (31.8 %) female patients. The most common etiology that led to epithetic rehabilitation was a squamous cell carcinoma in 16 patients. An operative revision was necessary in two patients due to screw loss. Twenty patients were still alive with no evidence of disease after minimum follow-up of 2 years (90.9 %). Epithetic rehabilitation after nasal ablation to treat nasal malignancies is an interesting alternative to plastic and reconstructive surgery. Bone-anchored fixation using magnets can achieve a stable epithetic fixation after nasal ablation necessitating, in numerous cases, additional adjuvant therapy like radiation.