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1.
Am J Otolaryngol ; 44(4): 103904, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37148847

RESUMO

OBJECTIVE: Otolaryngology (OTO) is a competitive specialty, and medical school factors outside an applicant's control, such as presence of OTO student resources and an affiliated OTO residency program, can impact the competitiveness of a student's application. This study sought to evaluate the extent of OTO resources United States (U.S.) allopathic medical schools provide to help their students be successful, and to evaluate for medical school factors which may bias toward inequitable distribution of student OTO resources. METHODS: A 48-question cross-sectional survey evaluating the extent of OTO resources was distributed by email to LCME accredited U.S. allopathic medical schools in 2020 and 2021. RESULTS: Schools with residency programs and where faculty were employed through an OTO or surgery department were more likely to have an Otolaryngology Interest Group (OIG), an Otolaryngology Medical Student Education Director (OMSED), and were more likely to provide opportunities for OTO research.


Assuntos
Internato e Residência , Otolaringologia , Estudantes de Medicina , Humanos , Estados Unidos , Faculdades de Medicina , Estudos Transversais , Otolaringologia/educação
2.
J Neurophysiol ; 119(1): 73-83, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28978765

RESUMO

Roughly half of all vestibular nucleus neurons without eye movement sensitivity respond to both angular rotation and linear acceleration. Linear acceleration signals arise from otolith organs, and rotation signals arise from semicircular canals. In the vestibular nerve, these signals are carried by different afferents. Vestibular nucleus neurons represent the first point of convergence for these distinct sensory signals. This study systematically evaluated how rotational and translational signals interact in single neurons in the vestibular nuclei: multisensory integration at the first opportunity for convergence between these two independent vestibular sensory signals. Single-unit recordings were made from the vestibular nuclei of awake macaques during yaw rotation, translation in the horizontal plane, and combinations of rotation and translation at different frequencies. The overall response magnitude of the combined translation and rotation was generally less than the sum of the magnitudes in responses to the stimuli applied independently. However, we found that under conditions in which the peaks of the rotational and translational responses were coincident these signals were approximately additive. With presentation of rotation and translation at different frequencies, rotation was attenuated more than translation, regardless of which was at a higher frequency. These data suggest a nonlinear interaction between these two sensory modalities in the vestibular nuclei, in which coincident peak responses are proportionally stronger than other, off-peak interactions. These results are similar to those reported for other forms of multisensory integration, such as audio-visual integration in the superior colliculus. NEW & NOTEWORTHY This is the first study to systematically explore the interaction of rotational and translational signals in the vestibular nuclei through independent manipulation. The results of this study demonstrate nonlinear integration leading to maximum response amplitude when the timing and direction of peak rotational and translational responses are coincident.


Assuntos
Neurônios/fisiologia , Aceleradores de Partículas , Percepção , Rotação , Núcleos Vestibulares/fisiologia , Animais , Macaca fascicularis , Masculino , Núcleos Vestibulares/citologia
3.
J Neurophysiol ; 116(4): 1871-1884, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27489364

RESUMO

After vestibular labyrinth injury, behavioral measures of vestibular performance recover to variable degrees (vestibular compensation). Central neuronal responses after unilateral labyrinthectomy (UL), which eliminates both afferent resting activity and sensitivity to movement, have been well-studied. However, unilateral semicircular canal plugging (UCP), which attenuates angular-velocity detection while leaving afferent resting activity intact, has not been extensively studied. The current study reports response properties of yaw-sensitive non-eye-movement rhesus macaque vestibular neurons after compensation from UCP. The responses at a series of frequencies (0.1-2 Hz) and peak velocities (15-210°/s) were compared between neurons recorded before and at least 6 wk after UCP. The gain (sp/s/°/s) of central type I neurons (responding to ipsilateral yaw rotation) on the side of UCP was reduced relative to normal controls at 0.5 Hz, ±60°/s [0.48 ± 0.30 (SD) normal, 0.32 ± 0.15 ipsilesion; 0.44 ± 0.2 contralesion]. Type II neurons (responding to contralateral yaw rotation) after UCP have reduced gain (0.40 ± 0.27 normal, 0.35 ± 0.25 ipsilesion; 0.25 ± 0.18 contralesion). The difference between responses after UCP and after UL is primarily the distribution of type I and type II neurons in the vestibular nuclei (type I neurons comprise 66% in vestibular nuclei normally; 51% ipsilesion UCP; 59% contralesion UCP; 38% ipsilesion UL; 65% contralesion UL) and the magnitude of the responses of type II neurons ipsilateral to the lesion. These differences suggest that the need to compensate for unilateral loss of resting vestibular nerve activity after UL necessitates a different strategy for recovery of dynamic vestibular responses compared to after UCP.


Assuntos
Neurônios/fisiologia , Propriocepção/fisiologia , Rotação , Canais Semicirculares/fisiologia , Núcleos Vestibulares/fisiologia , Potenciais de Ação , Animais , Feminino , Macaca mulatta , Masculino , Microeletrodos , Modelos Animais , Estimulação Física
4.
Proc Natl Acad Sci U S A ; 110(44): 17999-8004, 2013 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-24127575

RESUMO

Signals from the bilateral vestibular labyrinths work in tandem to generate robust estimates of our motion and orientation in the world. The relative contributions of each labyrinth to behavior, as well as how the brain recovers after unilateral peripheral damage, have been characterized for motor reflexes, but never for perceptual functions. Here we measure perceptual deficits in a heading discrimination task following surgical ablation of the neurosensory epithelium in one labyrinth. We found large increases in heading discrimination thresholds and large perceptual biases at 1 wk postlesion. Repeated testing thereafter improved heading perception, but vestibular discrimination thresholds remained elevated 3 mo postlesion. Electrophysiological recordings from the contralateral vestibular and cerebellar nuclei revealed elevated neuronal discrimination thresholds, elevated neurometric-to-psychometric threshold ratios, and reduced trial-by-trial correlations with perceptual decisions ["choice probabilities" (CPs)]. The relationship between CP and neuronal threshold was shallower, but not significantly altered, suggesting that smaller CPs in lesioned animals could be largely attributable to greater neuronal thresholds. Simultaneous recordings from pairs of neurons revealed that correlated noise among neurons was also reduced following the lesion. Simulations of a simple pooling model, which takes into account the observed changes in tuning slope and correlated noise, qualitatively accounts for the elevated psychophysical thresholds and neurometric-to-psychometric ratios, as well as the decreased CPs. Thus, cross-labyrinthine interactions appear to play important roles in enhancing neuronal and perceptual sensitivity, strengthening interneuronal correlations, and facilitating correlations between neural activity and perceptual decisions.


Assuntos
Comportamento de Escolha/fisiologia , Percepção de Movimento/fisiologia , Orientação/fisiologia , Vestíbulo do Labirinto/lesões , Análise de Variância , Animais , Núcleos Cerebelares/fisiologia , Simulação por Computador , Movimentos da Cabeça/fisiologia , Funções Verossimilhança , Macaca mulatta , Núcleos Vestibulares/fisiologia
5.
J Neurosci ; 33(3): 1198-210a, 2013 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-23325256

RESUMO

The cerebellar interpositus nucleus (IN) contributes to controlling voluntary limb movements. We hypothesized that the vestibular signals within the IN might be transformed into coordinates describing the body's movement, appropriate for controlling limb movement. We tested this hypothesis by recording from IN neurons in alert squirrel monkeys during vestibular and proprioceptive stimulation produced during (1) yaw head-on-trunk rotation about the C1-C2 axis while in an orthograde posture and (2) lateral side-to-side flexion about the C6-T3 axis while in a pronograde posture. Neurons (44/67) were sensitive to vestibular stimulation (23/44 to rotation and translation, 14/44 to rotation only, 7/44 to translation only). Most neurons responded during contralateral movement. Neurons (29/44) had proprioceptive responses; the majority (21/29) were activated during neck rotation and lateral flexion. In all 29 neurons with convergent vestibular and neck proprioceptive input those inputs functionally canceled each other during all combined sensory stimulation, whether in the orthograde or pronograde posture. These results suggest that two distinct populations of IN neurons exist, each of which has vestibular sensitivity. One population carries vestibular signals that describe the head's movement in space as is traditional for vestibular signals without proprioceptive signals. A second population of neurons demonstrated precise matching of vestibular and proprioceptive signals, even for complicated stimuli, which activated the semicircular canals and otolith organs and involved both rotation and flexion in the spine. Such neurons code body (not head) motion in space, which may be the appropriate platform for controlling limb movements.


Assuntos
Núcleos Cerebelares/fisiologia , Movimentos da Cabeça/fisiologia , Pescoço/fisiologia , Neurônios/fisiologia , Propriocepção/fisiologia , Núcleos Vestibulares/fisiologia , Animais , Movimentos Oculares/fisiologia , Feminino , Movimento/fisiologia , Postura/fisiologia , Rotação , Saimiri , Canais Semicirculares/fisiologia
6.
J Neurophysiol ; 111(12): 2445-64, 2014 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-24671533

RESUMO

Vestibular signals are pervasive throughout the central nervous system, including the cortex, where they likely play different roles than they do in the better studied brainstem. Little is known about the parieto-insular vestibular cortex (PIVC), an area of the cortex with prominent vestibular inputs. Neural activity was recorded in the PIVC of rhesus macaques during combinations of head, body, and visual target rotations. Activity of many PIVC neurons was correlated with the motion of the head in space (vestibular), the twist of the neck (proprioceptive), and the motion of a visual target, but was not associated with eye movement. PIVC neurons responded most commonly to more than one stimulus, and responses to combined movements could often be approximated by a combination of the individual sensitivities to head, neck, and target motion. The pattern of visual, vestibular, and somatic sensitivities on PIVC neurons displayed a continuous range, with some cells strongly responding to one or two of the stimulus modalities while other cells responded to any type of motion equivalently. The PIVC contains multisensory convergence of self-motion cues with external visual object motion information, such that neurons do not represent a specific transformation of any one sensory input. Instead, the PIVC neuron population may define the movement of head, body, and external visual objects in space and relative to one another. This comparison of self and external movement is consistent with insular cortex functions related to monitoring and explains many disparate findings of previous studies.


Assuntos
Córtex Cerebral/fisiologia , Percepção de Movimento/fisiologia , Neurônios/fisiologia , Lobo Parietal/fisiologia , Animais , Escuridão , Movimentos Oculares/fisiologia , Feminino , Cabeça/fisiologia , Macaca mulatta , Masculino , Microeletrodos , Pescoço/fisiologia , Estimulação Física , Propriocepção/fisiologia , Rotação , Percepção Visual/fisiologia , Volição
7.
J Neurophysiol ; 112(1): 9-21, 2014 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-24717349

RESUMO

After vestibular labyrinth injury, behavioral deficits partially recover through the process of vestibular compensation. The present study was performed to improve our understanding of the physiology of the macaque vestibular system in the compensated state (>7 wk) after unilateral labyrinthectomy (UL). Three groups of vestibular nucleus neurons were included: pre-UL control neurons, neurons ipsilateral to the lesion, and neurons contralateral to the lesion. The firing responses of neurons sensitive to linear acceleration in the horizontal plane were recorded during sinusoidal horizontal translation directed along six different orientations (30° apart) at 0.5 Hz and 0.2 g peak acceleration (196 cm/s(2)). This data defined the vector of best response for each neuron in the horizontal plane, along which sensitivity, symmetry, detection threshold, and variability of firing were determined. Additionally, the responses of the same cells to translation over a series of frequencies (0.25-5.0 Hz) either in the interaural or naso-occipital orientation were obtained to define the frequency response characteristics in each group. We found a decrease in sensitivity, increase in threshold, and alteration in orientation of best responses in the vestibular nuclei after UL. Additionally, the phase relationship of the best neural response to translational stimulation changed with UL. The symmetry of individual neuron responses in the excitatory and inhibitory directions was unchanged by UL. Bilateral central utricular neurons still demonstrated two-dimension tuning after UL, consistent with spatio-temporal convergence from a single vestibular end-organ. These neuronal data correlate with known behavioral deficits after unilateral vestibular compromise.


Assuntos
Orelha Interna/fisiologia , Neurônios/fisiologia , Orientação , Núcleos Vestibulares/fisiologia , Potenciais de Ação , Animais , Movimentos Oculares , Feminino , Macaca mulatta , Masculino , Reflexo , Rotação , Limiar Sensorial , Núcleos Vestibulares/citologia
8.
J Neurophysiol ; 112(4): 870-89, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-24848470

RESUMO

The vestibular system operates in a push-pull fashion using signals from both labyrinths and an intricate bilateral organization. Unilateral vestibular lesions cause well-characterized motor deficits that are partially compensated over time and whose neural correlates have been traced in the mean response modulation of vestibular nuclei cells. Here we compare both response gains and neural detection thresholds of vestibular nuclei and semicircular canal afferent neurons in intact vs. unilateral-lesioned macaques using three-dimensional rotation and translation stimuli. We found increased stimulus-driven spike count variability and detection thresholds in semicircular canal afferents, although mean responses were unchanged, after contralateral labyrinth lesion. Analysis of trial-by-trial spike count correlations of a limited number of simultaneously recorded pairs of canal afferents suggests increased noise correlations after lesion. In addition, we also found persistent, chronic deficits in rotation detection thresholds of vestibular nuclei neurons, which were larger in the ipsilesional than the contralesional brain stem. These deficits, which persisted several months after lesion, were due to lower rotational response gains, whereas spike count variability was similar in intact and lesioned animals. In contrast to persistent deficits in rotation threshold, translation detection thresholds were not different from those in intact animals. These findings suggest that, after compensation, a single labyrinth is sufficient to recover motion sensitivity and normal thresholds for the otolith, but not the semicircular canal, system.


Assuntos
Potenciais Somatossensoriais Evocados , Percepção de Movimento , Canais Semicirculares/fisiologia , Núcleos Vestibulares/fisiologia , Vestíbulo do Labirinto/fisiologia , Animais , Macaca mulatta , Masculino , Neurônios Aferentes/fisiologia , Rotação , Canais Semicirculares/citologia , Limiar Sensorial , Núcleos Vestibulares/citologia , Vestíbulo do Labirinto/citologia
9.
J Neurophysiol ; 109(10): 2571-84, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23446694

RESUMO

The rotational vestibulo-ocular reflex in primates is linear and stabilizes gaze in space over a large range of head movements. Best evidence suggests that position-vestibular-pause (PVP) and eye-head velocity (EHV) neurons in the vestibular nuclei are the primary mediators of vestibulo-ocular reflexes for rotational head movements, yet the linearity of these neurons has not been extensively tested. The current study was undertaken to understand how varying magnitudes of yaw rotation are coded in these neurons. Sixty-six PVP and 41 EHV neurons in the rostral vestibular nuclei of 7 awake rhesus macaques were recorded over a range of frequencies (0.1 to 2 Hz) and peak velocities (7.5 to 210°/s at 0.5 Hz). The sensitivity (gain) of the neurons decreased with increasing peak velocity of rotation for all PVP neurons and EHV neurons sensitive to ipsilateral rotation (type I). The sensitivity of contralateral rotation-sensitive (type II) EHV neurons did not significantly decrease with increasing peak velocity. These data show that, like non-eye-movement-related vestibular nuclear neurons that are believed to mediate nonlinear vestibular functions, PVP neurons involved in the linear vestibulo-ocular reflex also behave in a nonlinear fashion. Similar to other sensory nuclei, the magnitude of the vestibular stimulus is not linearly coded by the responses of vestibular neurons; rather, amplitude compression extends the dynamic range of PVP and type I EHV vestibular neurons.


Assuntos
Movimentos Oculares , Neurônios/fisiologia , Rotação , Núcleos Vestibulares/fisiologia , Animais , Movimentos da Cabeça , Macaca mulatta , Neurônios/classificação , Reflexo Vestíbulo-Ocular , Núcleos Vestibulares/citologia
10.
J Neurophysiol ; 110(8): 1822-36, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23864379

RESUMO

After vestibular labyrinth injury, behavioral measures of vestibular function partially recover through the process of vestibular compensation. The present study was performed to improve our understanding of the physiology of macaque vestibular nucleus neurons in the compensated state (>6 wk) after unilateral labyrinthectomy (UL). The responses of neurons to sinusoidal yaw rotation at a series of frequencies (0.1-2.0 Hz) and peak velocities (7.5-210°/s) were examined to determine how the behavior of these cells differed from those in animals with intact labyrinths. The sensitivity of neurons responding to ipsilateral rotation (type I) did not differ between the intact and injured sides after UL, although this sensitivity was lower bilaterally after lesion than before lesion. The sensitivity of neurons that increase firing with contralateral rotation (type II) was higher ipsilateral to the UL than before lesion or in the nucleus contralateral to the UL. UL did not increase asymmetry in the responses of individual type I or II neurons to ipsilateral vs. contralateral rotation, nor does it change the power law relationship between neuronal firing and level of stimulation. Increased sensitivities of contralesional type I neurons to the remaining vestibular nerve input and increased efficacy of inhibitory vestibular commissures projecting to the ipsilesional vestibular nucleus appear to be responsible for recovery of dynamic function of central vestibular neurons in compensated animals. The portion of type I neurons on the ipsilesional side is reduced in compensated animals, which likely accounts for the asymmetries in vestibular reflexes and perception that characterize vestibular function after UL.


Assuntos
Potenciais de Ação , Orelha Interna/fisiologia , Neurônios/fisiologia , Rotação , Núcleos Vestibulares/fisiologia , Animais , Orelha Interna/inervação , Orelha Interna/cirurgia , Macaca mulatta , Limiar Sensorial , Núcleos Vestibulares/citologia
11.
Ann Otol Rhinol Laryngol ; 132(11): 1412-1417, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37010056

RESUMO

OBJECTIVES: With an ever-expanding medical knowledge base and requirements for clinical training, medical schools struggle to incorporate subspecialty education, such as otolaryngology (OTO), into curricula. This study aims to assess the current state of OTO education, and evaluate factors contributing to the extent of OTO teaching in United States (U.S.) medical schools. METHODS: A 48-question survey evaluated the extent and practices of OTO teaching. The survey was distributed by email to all 155 LCME accredited U.S. allopathic medical schools in 2020 and 2021. RESULTS: Sixty-eight unique responses were received (43.9% of U.S. allopathic medical schools). 36.8% (n = 25) of schools reported having formal expectations of OTO knowledge in their core curriculum. Only 1 school (1.5%) had a required OTO rotation; the majority of schools offered an optional third or fourth year clerkship rotation (76.5% and 95.6%, respectively). Schools with residency programs and who employ their faculty through an OTO or surgery department were more likely to have otolaryngologists teach basic science lectures and the Head & Neck exam, offer an optional third year rotation, and have formal expectations of rotating students. CONCLUSIONS: Medical schools with residency programs and who employ their faculty through an OTO or surgery department have more robust OTO curricula. Despite the ubiquity of OTO presentations across specialties, incorporation of OTO knowledge in U.S. medical school curricula remains variable, and at times limited.


Assuntos
Internato e Residência , Otolaringologia , Estados Unidos , Humanos , Faculdades de Medicina , Estudos Transversais , Currículo , Otolaringologia/educação
12.
Cancer ; 118(5): 1276-87, 2012 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-21773970

RESUMO

BACKGROUND: Radiotherapy with its advantage of organ preservation has been used to treat laryngeal cancer (LC) for several decades. However, the impact of radiation on overall survival (OS) in a large population-based study has not been evaluated to date. METHODS: The authors analyzed all patients who had localized and/or regional glottic and supraglottic cancer in the Surveillance, Epidemiology, and End Results Program by comparing treatment trends and OS for the periods 1988 to 1993, 1994 to 1999, and 2000 to 2006. Kaplan-Meier and logistic regression analyses were conducted to evaluate OS and the influence of patient demographics on treatment received. RESULTS: Among 13,808 patients with LC, radiotherapy use increased over the 3 periods for localized glottic cancer (LGC) (94%, 97%, and 98% during 1988-1993, 1994-1999, and 2000-2006, respectively; P < .001); for regional glottic cancer (RGC) (53%, 66%, and 75%, respectively; P < .001), for localized supraglottic cancer (LSGC) (61%, 83%, and 94%, respectively), and for regional supraglottic cancer (RSGC) (43%, 55%, and 78%, respectively; P < .001). No significant decrease in 5-year OS was observed during the 3 periods (LGC: 73%, 76%, and 78%, respectively; RGC: 57%, 51%, and 56%, respectively; LSGC: 33%, 35%, and 39%, respectively; and RSGC: 36%, 36%, and 43%, respectively). Blacks were significantly less likely to receive radiotherapy than whites (odds ratio: LGC, 0.42; RGC, 0.76; RSGC, 0.68; all P < .05). Those in the lowest tertile of median household income, compared with highest tertile, received radiotherapy less frequently (odds ratio: LGC, 0.42; RGC, 0.57; RSGC, 0.57; all P < .001). CONCLUSIONS: The current results indicated that the increased use of radiation with its advantage of speech preservation had no adverse impact on the survival of patients with LC. Black race and low income status had significant, inverse relations with the receipt of radiotherapy.


Assuntos
Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/radioterapia , Neoplasias Laríngeas/mortalidade , Neoplasias Laríngeas/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/etnologia , Estudos de Coortes , Feminino , Humanos , Neoplasias Laríngeas/epidemiologia , Neoplasias Laríngeas/etnologia , Masculino , Pessoa de Meia-Idade , População , Radioterapia/métodos , Radioterapia/estatística & dados numéricos , Programa de SEER , Análise de Sobrevida , Resultado do Tratamento , Estados Unidos/epidemiologia
13.
Exp Brain Res ; 215(1): 77-87, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21947173

RESUMO

Translational motion induces retinal image slip which varies with object distance. The brain must know binocular eye position in real time in order to scale eye movements so as to minimize retinal slip. Two potential sources of eye position information are orbital proprioception and an internal representation of eye position derived from central ocular motor signals. To examine the role of orbital proprioceptive information, the position of the left eye was perturbed by microstimulation of the left abducens nerve during translational motion to the right or left along the interaural axis in two rhesus macaques. Microstimulation rotated the eye laterally, activating eye muscle proprioceptors, while keeping central motor commands undisturbed. We found that microstimulation-induced eye position changes did not affect the translational VOR in the abductive (lateral rectus) direction, but it did influence the responses in the adductive (medial rectus) direction. Our findings demonstrate that proprioceptive inputs appear to be involved in the TVOR responses at least during ipsilateral head movements and proprioceptive influences on the TVOR may involve vergence-related signals to the oculomotor nucleus. However, internal representation of eye position, derived from central ocular motor signals, likely plays the dominant role in providing eye position information for scaling eye movements during translational motion, particularly in the abducent direction.


Assuntos
Orientação/fisiologia , Estimulação Luminosa/métodos , Propriocepção/fisiologia , Acompanhamento Ocular Uniforme/fisiologia , Animais , Movimentos Oculares/fisiologia , Movimentos da Cabeça/fisiologia , Macaca mulatta , Reflexo Vestíbulo-Ocular/fisiologia
14.
Int J Radiat Oncol Biol Phys ; 109(4): 1028-1039, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33181249

RESUMO

PURPOSE: In a combined retrospective and prospective study, human salivary glands were investigated after radiation treatment for head and neck cancers. The aim was to assess acinar cell loss and morphologic changes after radiation therapy and to determine whether irradiated salivary glands have regenerative potential. METHODS AND MATERIALS: Irradiated human submandibular and parotid salivary glands were collected from 16 patients at a range of time intervals after completion of radiation therapy (RT). Control samples were collected from 14 patients who had not received radiation treatments. Tissue sections were analyzed using immunohistochemistry to stain for molecular markers. RESULTS: Human submandibular and parotid glands isolated less than 1 year after RT showed a near complete loss of acinar cells. However, acinar units expressing functional secretory markers were observed in all samples isolated at later intervals after RT. Significantly lower acinar cell numbers and increased fibrosis were found in glands treated with combined radiation and chemotherapy, in comparison to glands treated with RT alone. Irradiated samples showed increased staining for duct cell keratin markers, as well as many cells coexpressing acinar- and duct cell-specific markers, in comparison to nonirradiated control samples. CONCLUSIONS: After RT, acinar cell clusters are maintained in human submandibular glands for years. The surviving acinar cells retain proliferative potential, although significant regeneration does not occur. Persistent DNA damage, increased fibrosis, and altered cell identity suggest mechanisms that may impair regeneration.


Assuntos
Células Acinares/efeitos da radiação , Neoplasias de Cabeça e Pescoço/radioterapia , Glândula Submandibular/efeitos da radiação , Células Acinares/patologia , Plasticidade Celular , Proliferação de Células/efeitos da radiação , Quimiorradioterapia/efeitos adversos , Dano ao DNA , Humanos , Estudos Prospectivos , Radioterapia/efeitos adversos , Dosagem Radioterapêutica , Estudos Retrospectivos , Glândula Submandibular/efeitos dos fármacos , Glândula Submandibular/patologia , Vimentina/análise
15.
Commun Biol ; 4(1): 361, 2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33742114

RESUMO

Radiation therapy for head and neck cancers causes salivary gland dysfunction leading to permanent xerostomia. Limited progress in the discovery of new therapeutic strategies is attributed to the lack of in vitro models that mimic salivary gland function and allow high-throughput drug screening. We address this limitation by combining engineered extracellular matrices with microbubble (MB) array technology to develop functional tissue mimetics for mouse and human salivary glands. We demonstrate that mouse and human salivary tissues encapsulated within matrix metalloproteinase-degradable poly(ethylene glycol) hydrogels formed in MB arrays are viable, express key salivary gland markers, and exhibit polarized localization of functional proteins. The salivary gland mimetics (SGm) respond to calcium signaling agonists and secrete salivary proteins. SGm were then used to evaluate radiosensitivity and mitigation of radiation damage using a radioprotective compound. Altogether, SGm exhibit phenotypic and functional parameters of salivary glands, and provide an enabling technology for high-content/throughput drug testing.


Assuntos
Células Acinares/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Ensaios de Triagem em Larga Escala , Lesões por Radiação/prevenção & controle , Glândulas Salivares/efeitos dos fármacos , Análise Serial de Tecidos , Xerostomia/prevenção & controle , Células Acinares/metabolismo , Células Acinares/efeitos da radiação , Animais , Sinalização do Cálcio/efeitos dos fármacos , Células Cultivadas , Feminino , Humanos , Hidrogéis , Masculino , Camundongos Endogâmicos C57BL , Microbolhas , Pessoa de Meia-Idade , Glândula Parótida/efeitos dos fármacos , Glândula Parótida/metabolismo , Glândula Parótida/efeitos da radiação , Fenótipo , Polietilenoglicóis/química , Lesões por Radiação/etiologia , Lesões por Radiação/metabolismo , Glândulas Salivares/metabolismo , Glândulas Salivares/efeitos da radiação , Xerostomia/etiologia , Xerostomia/metabolismo
16.
FEBS Lett ; 594(2): 376-382, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31538335

RESUMO

To develop treatments for salivary gland dysfunction, it is important to understand how human salivary glands are maintained under normal homeostasis. Previous data from our lab demonstrated that murine salivary acinar cells maintain the acinar cell population through self-duplication under conditions of homeostasis, as well as after injury. Early studies suggested that human acinar cells are mitotically active, but the identity of the resultant daughter cells was not clear. Using markers of cell cycle activity and mitosis, as well as an ex vivo 5-Ethynyl-2´-deoxyuridine assay, we show that human salivary gland acinar cells divide to generate daughter acinar cells. As in mouse, our data indicate that human salivary gland homeostasis is supported by the intrinsic mitotic capacity of acinar cells.


Assuntos
Células Acinares/citologia , Diferenciação Celular/genética , Mitose/genética , Glândulas Salivares/crescimento & desenvolvimento , Animais , Ciclo Celular/genética , Diferenciação Celular/efeitos dos fármacos , Desoxiuridina/análogos & derivados , Desoxiuridina/farmacologia , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Humanos , Camundongos , Glândulas Salivares/citologia
17.
Arch Oral Biol ; 97: 122-130, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30384153

RESUMO

OBJECTIVE: The objective of this study was to characterize the mechanism by which salivary gland cells (SGC) aggregate in vitro. DESIGN: Timelapse microscopy was utilized to analyze the process of salivary gland aggregate formation using both primary murine and human salivary gland cells. The role of cell density, proliferation, extracellular calcium, and secretory acinar cells in aggregate formation was investigated. Finally, the ability of cells isolated from irradiated glands to form aggregates was also evaluated. RESULTS: Salivary gland cell self-organization rather than proliferation was the predominant mechanism of aggregate formation in both primary mouse and human salivary gland cultures. Aggregation was found to require extracellular calcium while acinar lineage cells account for ∼80% of the total aggregate cell population. Finally, aggregation was not impaired by irradiation. CONCLUSIONS: The data reveal that aggregation occurs as a result of heterogeneous salivary gland cell self-organization rather than from stem cell proliferation and differentiation, contradicting previous dogma. These results suggest a re-evaluation of aggregate formation as a criterion defining salivary gland stem cells.


Assuntos
Células Acinares/citologia , Glândulas Salivares/citologia , Células Acinares/efeitos da radiação , Animais , Cálcio/fisiologia , Contagem de Células , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Humanos , Camundongos , Glândulas Salivares/efeitos da radiação
18.
J Neurosci ; 27(36): 9742-56, 2007 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-17804635

RESUMO

Recent studies have shown that most neurons in the dorsal medial superior temporal area (MSTd) signal the direction of self-translation (i.e., heading) in response to both optic flow and inertial motion. Much less is currently known about the response properties of MSTd neurons during self-rotation. We have characterized the three-dimensional tuning of MSTd neurons while monkeys passively fixated a central, head-fixed target. Rotational stimuli were either presented using a motion platform or simulated visually using optic flow. Nearly all MSTd cells were significantly tuned for the direction of rotation in the absence of optic flow, with more neurons preferring roll than pitch or yaw rotations. The preferred rotation axis in response to optic flow was generally the opposite of that during physical rotation. This result differs sharply from our findings for translational motion, where approximately half of MSTd neurons have congruent visual and vestibular preferences. By testing a subset of neurons with combined visual and vestibular stimulation, we also show that the contributions of visual and vestibular cues to MSTd responses depend on the relative reliabilities of the two stimulus modalities. Previous studies of MSTd responses to motion in darkness have assumed a vestibular origin for the activity observed. We have directly verified this assumption by recording from MSTd neurons after bilateral labyrinthectomy. Selectivity for physical rotation and translation stimuli was eliminated after labyrinthectomy, whereas selectivity to optic flow was unaffected. Overall, the lack of MSTd neurons with congruent rotation tuning for visual and vestibular stimuli suggests that MSTd does not integrate these signals to produce a robust perception of self-rotation. Vestibular rotation signals in MSTd may instead be used to compensate for the confounding effects of rotatory head movements on optic flow.


Assuntos
Percepção de Forma/fisiologia , Percepção de Movimento/fisiologia , Rotação , Lobo Temporal/fisiologia , Vestíbulo do Labirinto/fisiologia , Animais , Movimentos Oculares/fisiologia , Fixação Ocular/fisiologia , Macaca mulatta , Masculino , Estimulação Luminosa , Estimulação Física , Visão Binocular/fisiologia
19.
Curr Biol ; 15(18): 1657-62, 2005 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-16169488

RESUMO

Our inner ear is equipped with a set of linear accelerometers, the otolith organs, that sense the inertial accelerations experienced during self-motion. However, as Einstein pointed out nearly a century ago, this signal would by itself be insufficient to detect our real movement, because gravity, another form of linear acceleration, and self-motion are sensed identically by otolith afferents. To deal with this ambiguity, it was proposed that neural populations in the pons and midline cerebellum compute an independent, internal estimate of gravity using signals arising from the vestibular rotation sensors, the semicircular canals. This hypothesis, regarding a causal relationship between firing rates and postulated sensory contributions to inertial motion estimation, has been directly tested here by recording neural activities before and after inactivation of the semicircular canals. We show that, unlike cells in normal animals, the gravity component of neural responses was nearly absent in canal-inactivated animals. We conclude that, through integration of temporally matched, multimodal information, neurons derive the mathematical signals predicted by the equations describing the physics of the outside world.


Assuntos
Cerebelo/fisiologia , Sensação Gravitacional/fisiologia , Percepção de Movimento/fisiologia , Canais Semicirculares/fisiologia , Animais , Eletrofisiologia , Macaca fascicularis , Neurônios Aferentes/fisiologia
20.
J Vis Exp ; (135)2018 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-29781993

RESUMO

Hyposalivation is commonly observed in the autoimmune reaction of Sjögren's syndrome or following radiation injury to the major salivary glands. In these cases, questions remain regarding disease pathogenesis and effective interventions. An optimized technique that allows functional assessment of the salivary glands is invaluable for investigating exocrine gland biology, dysfunction, and therapeutics. Here, we present a step by step approach to performing pilocarpine stimulated saliva secretion, including tracheostomy and the dissection of the three major murine salivary glands. We also detail the appropriate murine head and neck anatomy accessed during these techniques. This approach is scalable, allowing for multiple mice to be processed simultaneously, thus improving the efficiency of the work flow. We aim to improve the reproducibility of these methods, each of which has further applications within the field. In addition to saliva collection, we discuss metrics for quantifying and normalizing functional capacity of these tissues. Representative data are included from submandibular glands with depressed salivary gland function 2 weeks following fractionated radiation (4 doses of 6.85 Gy).


Assuntos
Pilocarpina/uso terapêutico , Glândulas Salivares/diagnóstico por imagem , Xerostomia/diagnóstico por imagem , Animais , Fracionamento da Dose de Radiação , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pilocarpina/farmacologia , Xerostomia/radioterapia
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