Bone conduction transmission and head‐shadow effects were determined with transcranial completely‐in‐the‐canal (TCCIC) CROS hearing aids. Five subjects with documented profound unilateral hearing loss and experience with traditional CROS/BICROS fittings (TCROS) were tested with a CIC hearing aid placed in their poorer ear. Peak SPL was measured at the tympanic membrane and ranged from 105–115 dB SPL at 2000 Hz. Pure‐tone crossover thresholds and functional gain tested at frequencies from 250–8000 Hz varied considerably more than the SPL measures. The pure‐tone results indicated that sensitivity in the better ear was moderately associated with functional gain across frequency. Speech recognition was then tested in the sound field in two conditions: direct (noise in the poorer ear, speech in the better ear) and indirect (noise in the better ear, speech in the poorer ear) at S/Ns of −6, 0, +6, +12, and quiet. The TCCIC fittings were more effective than TCROS aids across S/Ns, particularly in the direct condition. In the indirect condition, the two fittings performed similarly. When data were pooled across conditions, the TCCIC aids provided better word recognition than the TCROS aids, particularly for those subjects with greater sensitivity in the better ear.

It is estimated that nearly 50,000 individuals in the United States will be diagnosed with head and neck cancer in 2017 (American Cancer Society www.cancer.org). Ninety percent of oral cancers are head and neck squamous cell carcinoma (HNSCC). Major obstacles in the treatment of HNSCC are recurrence and treatment resistance, which contributes to increased mortality. Therefore, there is increased need to determine genetic alterations in HNSCC that may be ideal novel drug targets, and biomarkers to improve diagnostic and prognostic testing. Abnormal localization and overexpression of base excision repair protein and transcriptional regulator Apurinic/Apyrimidic endonuclease (APE1) has been associated with treatment resistance and poor prognosis. Therefore, we explored mechanisms for how APE1 contributes to treatment resistance and increased mortality in HNSCC. Because oxidative stress heavily influences APE1’s expression and transcriptional regulatory activities, we examined genes involved in oxidative stress management, including SOD3 and NRF2. PPARGC1A, a NRF2 transcriptional co-activator, was also examined as our lab previously observed a link between APE1 and PPARGC1A expression. This previous work also revealed that APE1 suppressed gene expression of tumor suppressor, decorin (DCN). To examine possible mechanisms for how APE1 regulates expression of tumor suppressors and antioxidants, digital image analysis of immunohistochemistry staining was used to identify alterations in protein expression. Nuclear and total cellular protein expression of APE1, DCN, NRF2, PPARGC1A, and SOD3 were quantified in regions of proximal benign, carcinoma in situ (CIS) and invasive HNSCC. Patient survival analysis revealed that increased APE1, DCN, and PPARGC1A protein levels were significantly associated with reduced survival in CIS, benign, and invasive tissues respectively. Using multivariate analysis of protein expression, we identified that increased APE1 protein levels in the CIS of primary tumors were associated with the presence of cancer invaded lymph nodes. Elevated DCN and SOD3 protein levels in benign tissue were associated with poorly differentiated tumors as was reduced PPARGC1A in CIS. Most importantly, potential prognostic biomarkers for use in early cancer development were identified. Identifying poor prognosis in early cancer development allows the possibility of improved treatment strategies, which could prevent invasive cancer development, and increase patient survival.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / In the presence of nasal obstruction, nasal patency may be reduced, and nasal breathing is replaced by mouth breathing (MB). Orofacial, and otorhinolaringologic changes are present in this breathing mode, as well as head posture misalignment, as a compensatory mechanism for the nasal airflow impairment. Some characteristics are typically found, but MB diagnosis is still controversial among multidisciplinary assessments. This study was conduct to identify variables associated with mouth breathing diagnosis in children, based on multidisciplinary domains, including anamnesis, speech therapy, otorhinolaryngologic, occlusal and physiotherapeutic assessments. It also aimed to compare nasal patency and otorhinolaryngologic-orofacial features and craniocervical posture in children. Six-12 year-old children, both sexes underwent muldisciplinary evaluation constituted by: anamnesis; speech therapy evaluation, according to MBGR protocol; clinical and endoscopic otorhinolaryngologic (OTRL) examination; occlusal and physical therapy assessments (nasal patency and body posture). Nasal patency was measured, by means of Peak Nasal Inspiratory Flow absolute (PNIF) values and Nasal Obstruction Symptom Evaluation (NOSE) scale. Craniocervical posture was evaluated with biophotogrametric measures (software SAPO, v.0.68), such as: Cervical Distance (CD); Head Horizontal Alignment (HHA), Flexion-Extension Head Position (FE) and Lumbar Distance (LD). Mann-Whitney, Kruskal-Wallis, Spearman Correlation Coefficient and Multiple Logistic Regression were used for data analysis. One hundred thirty three children took part in the study. Significant lower values of PNIF and %PNIF in children with restless sleep (p=0.006 and p=0.002), nasal obstruction report (p=0.027 and p=0.023) and runny nose (p=0.004 and p=0.012), unsystematic lip closure during mastication (p=0.040 and 0.026), masticatory speed reduced (p=0.006 and p= 0.008) and altered solid food swallowing (p=0.006 and p=0.001) were found. Significant lower PNIF was found in children with pale inferior turbinate (p=0.040). PNIF and %PNIF was significantly higher in children with mild everted lip (p=0.008 and p=0.000). PNIF was significantly higher in children with tongue width increased (p=0.027) and lower in children with hard palate width reduced (p=0.037). PNIF was significantly lower in children with altered speech (p=0.004). FE was significantly higher in children with nasal patency decreased (p=0.023). Negative and weak correlation between FE and %PNIF (r=-0.266; p=0.002) and positive and weak correlation between CD and PNIF (r=0.209; p=0.016) were found. NOSE scores were negatively correlated with PNIF (r= -0.179; p=0.039). It was found association of MB diagnosis in each professional domain with: nasal obstruction report (OR =5.55), time of pacifier sucking (OR=1.25), convex facial type (OR=3.78), obtuse nasal angle (OR=4.30), half-open or open lip posture (OR=4.13), tongue positioned on the mouth floor (OR=5.88), hard palate width reduced (OR=2.99), unexpected contraction of orbicularis and mentalis muscles during mastication (OR= 2.97), obstructive pharyngeal tonsills (OR=8.37), Angle Class II malocclusion (OR= 10.85) and regular gingival maintenance (OR=2.89). Nasal patency was lower in children with restless sleep, rhinitis signs and symptoms, hard palate width reduced and with changes in mastication, deglutition and speech functions. Children with decreased nasal patency presented greater head extension and, this postural deviation is prone to increase as nasal airflow decreases, indicating the relationship between craniocervical posture and nasal patency. Nasal obstruction report, time of pacifier sucking, convex facial type, obtuse nasal angle, half-open or open lip posture, tongue positioned on the mouth floor, hard palate width reduced, unexpected contraction during mastication, obstructive pharyngeal tonsils, Angle Class II malocclusion and regular gingival maintenance were associated with MB diagnosis / Na presença de uma obstrução nasal, a permeabilidade pode estar reduzida e a respiração nasal é substituída pela respiração oral (RO). Alterações orofaciais e otorrinolaringológicas são associadas a essa condição, bem como alterações na postura da cabeça, como mecanismo compensatório a redução do fluxo nasal. Algumas características são tipicamente associadas a RO, mas seu diagnóstico ainda permanece controverso. Este estudo foi conduzido para identificar variáveis associadas com o diagnóstico de respiração oral em crianças, baseado nos domínios multidisciplinares. Também se propôs a comparar a permeabilidade nasal e as características orofaciais, fonoaudiológicas e postura craniocervical em crianças. Um total de 133 crianças de seis a 12 anos de idade, de ambos os sexos, submeteram-se avaliação multidisciplinar constituída de: anamnese; avaliação fonoaudiológica, de acordo com o protocolo MBGR; exame OTRL clínico e endoscópico; avaliações oclusal e fisioterapêutica (permeabilidade nasal e postura corporal). A permeabilidade nasal foi medida por meio do Pico de Fluxo Inspiratório Nasal (PFIN) e valores da escala Nasal Obstruction Symptom Evaluation (NOSE). A postura corporal foi avaliada com medidas biofotogramétricas (Software SAPO, v.0.68) como: Distância Cervical (DC); Alinhamento Horizontal da Cabeça (AHC); Ângulo de Flexo-Extensão da Cabeça (FE) e Distância Lombar (DL). Para a análise dos dados foram utilizados os testes U de Mann-Whitney, Kruskal-Wallis, Correlação de Spearmann e Regressão Logística Múltipla. PFIN e %PFIN foram menores nas crianças com sono agitado (p=0,006 e p=0,002), relato de obstrução nasal (p=0,027 e p=0,023), rinorreia (p=0,004 e p=0,012), fechamento labial assistemático na mastigação (p=0,040 e p=0,026), velocidade mastigatória reduzida (p=0,006 e p= 0,008), com alteração na deglutição de sólidos (p=0,006 e p=0,001) e somente PFIN naquelas com largura de palato reduzida (p=0,037) e alteração da fala (p=0,004). Foram encontrados valores menores de PFIN nas crianças com palidez das conchas nasais inferiores (p=0,040). PFIN e %PFIN foram maiores nas crianças com lábio levemente evertido (p=0,008 e p=0,000) e somente o PFIN naquelas com largura aumentada da língua (p=0,027). FE foi maior nas crianças com permeabilidade nasal diminuída (p=0,023). Foi encontrada correlação negativa e fraca entre FE e %PFIN (r=-0,266; p=0,002) e positiva e fraca entre DC e PFIN (r=0,209; p=0,016). Os escores da escala NOSE foram negativamente correlacionados com PFIN (r= -0,179; p=0,039). Foi observada associação do diagnóstico de respiração com: relato de obstrução nasal (OR =5,55), tempo de uso de chupeta (OR=1,25), tipo facial convexo (OR=3,78), ângulo nasolabial obtuso (OR=4,30), postura de lábios entreabertos ou abertos (OR=4,13), postura de língua no assoalho da boca (OR=5,88), largura do palato duro reduzida (OR=2,99), contrações não esperadas dos músculos orbiculares e mentual durante a mastigação (OR= 2,97), tonsilas faríngeas obstrutivas (OR=8,37), má oclusão classe II de Angle (OR= 10,85) e conservação gengival regular (OR=2,89). A permeabilidade nasal foi menor em crianças com sono agitado, sinais e sintomas de rinite, largura reduzida do palato duro e alterações nas funções de mastigação, deglutição e fala. Crianças com permeabilidade nasal reduzida apresentaram maior extensão da cabeça e esta alteração postural tende a aumentar à medida que o fluxo nasal diminui, indicando uma relação entre a postura craniocervical e permeabilidade nasal. Foram associadas com a RO as variáveis: relato de obstrução nasal; tempo de uso de chupeta; tipo facial convexo; ângulo nasolabial obtuso; postura de lábios entreabertos ou abertos; postura de língua no assoalho da boca; largura reduzida do palato duro; contrações não esperadas na mastigação; tonsilas faríngeas obstrutivas, má oclusão classe II de Angle e conservação gengival regular.

The endoplasmic reticulum (ER) is a multi-functional cellular compartment that functions in protein folding, lipid biosynthesis, and calcium homeostasis. Perturbations to ER function lead to the dysregulation of ER homeostasis, causing the accumulation of unfolded and misfolded proteins in the cell. This is a state of ER stress. ER stress elicits a cytoprotective, adaptive signaling cascade to mitigate stress, the Unfolded Protein Response (UPR). As long as the UPR can moderate stress, cells can produce the proper amount of proteins and maintain a state of homeostasis. If the UPR, however, is dysfunctional and fails to achieve this, cells will undergo apoptosis. Diabetes mellitus is a group of metabolic disorders characterized by persistent high blood glucose levels. The pathogenesis of this disease involves pancreatic β-cell dysfunction: an abnormality in the primary function of the β-cell, insulin production and secretion. Activation of the UPR is critical to pancreatic β-cell survival, where a disruption in ER stress signaling can lead to cell death and consequently diabetes. There are several models of ER stress leading to diabetes. Wolcott-Rallison syndrome, for example, occurs when there is a mutation in the gene encoding one of the master regulators of the UPR, PKR-like ER kinase (PERK). In this dissertation, we show that Wolfram Syndrome 1 (WFS1), an ER transmembrane protein, is a component of the UPR and is a downstream target of two of the master regulators of the UPR, Inositol Requiring 1 (IRE1) and PERK. WFS1 mutations lead to Wolfram syndrome, a non-autoimmune form of type 1 diabetes accompanied by optical atrophy and other neurological disorders. It has been shown that patients develop diabetes due to the selective loss of their pancreatic β-cells. Here we define the underlying molecular mechanism of β-cell loss in Wolfram syndrome, and link this cell loss to ER stress and a dysfunction in a component of the UPR, WFS1. We show that WFS1 expression is localized to the β-cell of the pancreas, it is upregulated during insulin secretion and ER stress, and its inactivation leads to chronic ER stress and apoptosis. This dissertation also reveals the previously unknown function of WFS1 in the UPR. Positive regulation of the UPR has been extensively studied, however, the precise mechanisms of negative regulation of this signaling pathway have not. Here we report that WFS1 regulates a key transcription factor of the UPR, activating transcription factor 6 (ATF6), through the ubiquitin-proteasome pathway. WFS1 expression decreases expression levels of ATF6 target genes and represses ATF6-mediated activation of the ER stress response (ERSE) promoter. WFS1 recruits and stabilizes an E3 ubiquitin ligase, HMG-CoA reductase degradation protein 1 (HRD1), on the ER membrane. The WFS1-HRD1 complex recruits ATF6 to the proteasome and enhances its ubiquitination and proteasome-mediated degradation, leading to suppression of the UPR under non-stress conditions. In response to ER stress, ATF6 is released from WFS1 and activates the UPR to mitigate ER stress. This body of work reveals a novel role for WFS1 in the UPR, and a novel mechanism for regulating ER stress signaling. These findings also indicate that hyperactivation of the UPR can lead to cellular dysfunction and death. This supports the notion that tight regulation of ER stress signaling is crucial to cell survival. This unanticipated role of WFS1 for a feedback loop of the UPR is relevant to diseases caused by chronic hyperactivation of ER stress signaling network such as pancreatic β-cell death in diabetes and neurodegeneration.