Faculty Bibliography

Studies in vivo and in vitro have suggested that the mechanism underlying Alzheimer's disease (AD) neuropathogenesis is initiated by an interaction between the cellular prion protein (PrPC) and amyloid-beta oligomers (Abetao). This PrPC-Abetao complex activates Fyn kinase which, in turn, hyperphosphorylates tau (P-Tau) resulting in synaptic dysfunction, neuronal loss and cognitive deficits. AD transgenic mice lacking PrPC accumulate Abeta, but show normal survival and no loss of spatial learning and memory suggesting that PrPC functions downstream of Abetao production but upstream of intracellular toxicity within neurons. Since AD and traumatic brain injury (TBI)-linked chronic traumatic encephalopathy are tauopathies, we examined whether similar mechanistic pathways are responsible for both AD and TBI pathophysiologies. Using transgenic mice expressing different levels of PrPC, our studies investigated the influence and necessity of PrPC on biomarker (total-tau [T-Tau], P-Tau, GFAP) levels in brain and blood as measured biochemically following severe TBI in the form of severe closed head injury (sCHI). We found that following sCHI, increasing levels of T-Tau and P-Tau in the brain were associated with the PrPC expression levels. A similar relationship between PrPC expression and P-Tau levels following sCHI were found in blood in the absence of significant T-Tau changes. This effect was not seen with GFAP which increased within 24 h following sCHI and progressively decreased by the 7 day time point regardless of the PrPC expression levels. Changes in the levels of all biomarkers were independent of gender. We further enhanced and expanded the quantitation of brain biomarkers with correlative studies using immunohisochemistry. We also demonstrate that a TBI-induced calpain hyperactivation is not required for the generation of P-Tau. A relationship was demonstrated between the presence/absence of PrPC, the levels of P-Tau and cognitive dysfunction. Our studies suggest that PrPC is important in mediating TBI related pathology.

BACKGROUND: Encapsulated non-invasive follicular variant papillary thyroid cancer (ENIFVPTC) has recently been re-termed noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). This designation specifically omits the word "cancer" to encourage conservative management since patients with NIFTP tumors have been shown to derive no benefit from completion thyroidectomy or adjuvant radioactive iodine (RAI) therapy. METHODS: IRB approved retrospective study of consecutive cases of tumors from 2007 to 2015 that met pathologic criteria for NIFTP. The Conservative Management (CM) group included patients managed with lobectomy alone or appropriately indicated total thyroidectomy. Those included in the Aggressive Management (AM) group received either completion thyroidectomy or radioactive iodine or both. RESULTS: From 100 consecutive cases of ENIFVPTC reviewed, 40 NIFTP were included for the final analysis. Of these, 10 (27%) patients treated with initial lobectomy received completion thyroidectomy and 6 of 37 (16%) also received post-surgical adjuvant RAI. The mean per-patient cost of care in the AM group was $17629+/-2865 nearly twice the $8637+/- 309 costs in the CM group, and was largely driven by the cost of completion thyroidectomy and RAI. CONCLUSIONS: The term NIFTP has been recently promulgated to identify a type of thyroid neoplasm, formerly identified as a low-grade cancer, for which initial surgery represents adequate treatment. We believe that since the new NIFTP nomenclature intentionally omits the word "cancer" the clinical indolence of these tumors will be better appreciated, and cost savings will result from a more conservative and appropriate clinical management.

Objective Given the recalcitrant nature of recurrent respiratory papillomatosis, targeted therapies to reduce disease burden are fundamental to improved patient care paradigms. We seek to demonstrate the safety of imiquimod injection into vocal fold mucosa by evaluating the degree of laryngeal edema, histopathologic changes to vocal fold structure, and serologic interferon alpha (IFNalpha) levels following injection. Study Design Preclinical. Setting Academic institution. Subjects and Methods Six New Zealand White rabbits underwent unilateral injection of 100 microg of sterile imiquimod (1 microg/microL), with 100 microL of normal saline injected into the contralateral vocal fold. Direct laryngoscopy was performed on days 3, 7, and 30 following injection. Larynges from 3 rabbits were harvested on postinjection day 7 for histologic analysis. The remaining 3 rabbit larynges were harvested on day 30. Serial serum samples were drawn for IFNalpha quantification via immunoassay. Results No signs of respiratory distress were observed at any point. Vocal fold appearance was not clinically divergent between imiquimod and control conditions via serial direct laryngoscopic evaluation. No inflammatory lesions or scarring were identified following injection. Histology showed no signs of acute inflammatory processes or changes in the control or imiquimod injection groups. Serum IFNalpha increased at days 3 and 7 following imiquimod injection ( P < .0001 and P = .0368, respectively), before returning to baseline by day 14. Conclusions Vocal fold imiquimod injection did not result in notable morbidity in this preclinical model. However, serum IFNalpha concentrations increased transiently. These data are critical to advance the therapeutic utility of this compound, particularly in the setting of recurrent respiratory papillomatosis.

Due to its central location, the nose plays a prominent role in facial aesthetics. As tastes have shifted and techniques have advanced, the accepted "ideal" appearance and proportions of the nose have evolved over time. By assessing the aesthetics of the nasal dorsum through the use of lines and angles, one can more precisely elucidate a goal for the patient's postoperative nasal shape, which should, in turn, guide the surgeon to execute specific operative maneuvers needed to achieve that contour. In assessing the aesthetics of the nasal dorsum, practitioners calculate and observe aspects such as the paired dorsal aesthetic lines, the nasofrontal angle, and the nasofacial angle. There is also additional consideration given to nasal tip position as this must fit harmoniously with the shape of the dorsum. In contrast to the established aesthetic lines and angles, using nasal geometric polygons for the aesthetic evaluation and development of operative goals in rhinoplasty has recently been described in the literature. Constructed ideals, in the form of proportions, lines, and angles, should be used with caution, as there are many factors to consider in the aesthetic analysis of the nasal dorsum, including ethnic differences, and subjective and changing views of beauty.

The production and perception of music is preferentially mediated by cortical areas within the right hemisphere, but little is known about how these brain regions individually contribute to this process. In an experienced singer undergoing awake craniotomy, we demonstrated that direct electrical stimulation to a portion of the right posterior superior temporal gyrus (pSTG) selectively interrupted singing but not speaking. We then focally cooled this region to modulate its activity during vocalization. In contrast to similar manipulations in left hemisphere speech production regions, pSTG cooling did not elicit any changes in vocal timing or quality. However, this manipulation led to an increase in the pitch of speaking with no such change in singing. Further analysis revealed that all vocalizations exhibited a cooling-induced increase in the frequency of the first formant, raising the possibility that potential pitch offsets may have been actively avoided during singing. Our results suggest that the right pSTG plays a key role in vocal sensorimotor processing whose impact is dependent on the type of vocalization produced.

OBJECTIVE: High channel count electrode arrays allow for the monitoring of large-scale neural activity at high spatial resolution. Implantable arrays featuring many recording sites require compact, high bandwidth front-end electronics. In the present study, we investigated the use of a small, light weight, and low cost digital current-sensing integrated circuit for acquiring cortical surface signals from a 61-channel micro-electrocorticographic (ECoG) array. APPROACH: We recorded both acute and chronic ECoG signal from rat auditory cortex using our novel digital current-sensing headstage. For direct comparison, separate recordings were made in the same anesthetized preparations using an analog voltage headstage. A model of electrode impedance explained the transformation between current- and voltage-sensed signals, and was used to reconstruct cortical potential. We evaluated the digital headstage using several metrics of the baseline and response signals. MAIN RESULTS: The digital current headstage recorded neural signal with similar spatiotemporal stastics and auditory frequency tuning compared to the voltage signal. The signal-to-noise ratio of auditory evoked responses (AERs) was significantly stronger in the current signal. Stimulus decoding based on true and reconstructed voltage signals were not significantly different. Recordings from an implanted system showed AERs that were detectable and decodable for 52 days. The reconstruction filter mitigated the thermal current noise of the electrode impedance and enhanced overall SNR. SIGNIFICANCE: We developed and validated a novel approach to headstage acquisition that used current-input circuits to independently digitize 61 channels of ECoG measurements of the cortical field. These low-cost circuits, intended to measure photo-currents in digital imaging, not only provided a signal representing the local cortical field with virtually the same sensitivity and specificity as a traditional voltage headstage but also resulted in a small, light headstage that can easily be scaled to record from hundreds of channels.

Significant technological advances have fostered a movement toward minimally invasive surgical interventions for the management of ventral skull base malignancies. The care of patients with these lesions ideally involves an interdisciplinary skull base team that includes otolaryngologists, neurologic surgeons, radiation oncologists, and medical oncologists. This overview describes considerations essential for diagnosis, prognosis, and preoperative evaluation. Furthermore, surgical nuances, strategies for skull base reconstruction, and nonsurgical options are briefly discussed. Our hope is that this overview may be useful as an up-to-date description of the challenging clinical scenarios associated with these lesions.

The consequences of developmental hearing loss have been reported to include both sensory and cognitive deficits. To investigate these issues in a non-human model, auditory learning and asymptotic psychometric performance were compared between normal hearing (NH) adult gerbils and those reared with conductive hearing loss (CHL). At postnatal day 10, before ear canal opening, gerbil pups underwent bilateral malleus removal to induce a permanent CHL. Both CHL and control animals were trained to approach a water spout upon presentation of a target (Go stimuli), and withhold for foils (Nogo stimuli). To assess the rate of task acquisition and asymptotic performance, animals were tested on an amplitude modulation (AM) rate discrimination task. Behavioral performance was calculated using a signal detection theory framework. Animals reared with developmental CHL displayed a slower rate of task acquisition for AM discrimination task. Slower acquisition was explained by an impaired ability to generalize to newly introduced stimuli, as compared to controls. Measurement of discrimination thresholds across consecutive testing blocks revealed that CHL animals required a greater number of testing sessions to reach asymptotic threshold values, as compared to controls. However, with sufficient training, CHL animals approached control performance. These results indicate that a sensory impediment can delay auditory learning, and increase the risk of poor performance on a temporal task.