Faculty Bibliography

Proteases sustain hyperexcitability and pain by cleaving protease-activated receptor-2 (PAR₂) on nociceptors through distinct mechanisms. Whereas trypsin induces PAR₂ coupling to Gα_q, Gα_s, and β-arrestins, cathepsin-S (CS) and neutrophil elastase (NE) cleave PAR₂ at distinct sites and activate it by biased mechanisms that induce coupling to Gα_s, but not to Gα_q or β-arrestins. Because proteases activate PAR₂ by irreversible cleavage, and activated PAR₂ is degraded in lysosomes, sustained extracellular protease-mediated signaling requires mobilization of intact PAR₂ from the Golgi apparatus or de novo synthesis of new receptors by incompletely understood mechanisms. We found here that trypsin, CS, and NE stimulate PAR₂-dependent activation of protein kinase D (PKD) in the Golgi of HEK293 cells, in which PKD regulates protein trafficking. The proteases stimulated translocation of the PKD activator Gβγ to the Golgi, coinciding with PAR₂ mobilization from the Golgi. Proteases also induced translocation of a photoconverted PAR₂-Kaede fusion protein from the Golgi to the plasma membrane of KNRK cells. After incubation of HEK293 cells and dorsal root ganglia neurons with CS, NE, or trypsin, PAR₂ responsiveness initially declined, consistent with PAR₂ cleavage and desensitization, and then gradually recovered. Inhibitors of PKD, Gβγ, and protein translation inhibited recovery of PAR₂ responsiveness. PKD and Gβγ inhibitors also attenuated protease-evoked mechanical allodynia in mice. We conclude that proteases that activate PAR₂ by canonical and biased mechanisms stimulate PKD in the Golgi; PAR₂ mobilization and de novo synthesis repopulate the cell surface with intact receptors and sustain nociceptive signaling by extracellular proteases.

Purpose: Non-tuberculous mycobacteria (NTM) can cause clinically significant lung disease and frequent pneumonias. It is unknown whether impaired swallowing contributes to the pathophysiology of NTM. Patients with NTM may exhibit decreased airway protection. Our aim is to determine airway protection and bolus clearance in patients with NTM. Method(s): Videofluoroscopy (VF) was prospectively collected from 98 patients with NTM (67 female; ages 33-88). Two boluses of 3,5,10 ml thin liquid, two 5 cc puree Varibar, cracker were analyzed per subject (N = 980 swallows).Outcome measures included Penetration/Aspiration Scale (PAS) and ordinal ratings of residue in the valleculae and pyriform sinuses. Worst PAS scores categorized subject as unsafe (C 3) or safe (B 2). The correlation between clinical information and the present of penetration/aspiration and pharyngeal residue structures was analyzed. Result(s): Inter-and intra-rater reliability of PAS ratings were assessed using two-way mixed intraclass correlation coefficients (ICC) on 20% of the data with excellent results (intra-rater: ICC 0.98, 95% CI 0.95-0.98 and inter-rater: ICC 0.85, 95% CI 0.69-0.92). The proportion of impaired swallows in the whole dataset was 12.9% (127/980 swallows with PAS scores C 3). There was no correlation between presence of penetration/aspiration and pharyngeal residue with productive cough, pneumonia, smoking history and presence of acid reflux. Conclusions (Including Clinical Relevance): Patients with NTM appear to have impaired swallow function as represented by impaired airway protection. Future work should explore swallowing physiology compared to a control group

BACKGROUND:Long non-coding RNAs (lncRNAs) have important roles in regulating gene expression pertaining to cell proliferation, survival, migration and genomic stability. Dysregulated expression of lncRNAs is implicated in cancer initiation, progression and metastasis. OBJECTIVES/OBJECTIVE:To explore, map and summarize the extent of evidence from clinical studies investigating the differential expression of lncRNAs in oral/tongue squamous cell carcinoma. METHODS:PubMed, Scopus and Web of Science were used as search engines. Clinical, full-length, English language studies were included. PRISMA-ScR protocol was used to evaluate and present results. The present scoping review summarizes relationships of the differential expression of lncRNAs with the presence of tumour and with clinicopathological features including survival. RESULTS:Almost half of the investigated transcripts have been explored in more than one study, yet not always with consistent results. The collected data were also compared to the limited studies investigating oral epithelial dysplasia. Data are not easily comparable, first because of different methods used to define what differential expression is, and second because only a limited number of studies performed multivariate analyses to identify clinicopathological features associated with the differentially expressed lncRNAs. CONCLUSIONS:Standard methods and more appropriate data analyses are needed in order to achieve reliable results from future studies.

OBJECTIVE/UNASSIGNED:To evaluate rates of epiphora after transection and marsupialization of the nasolacrimal duct (NLD) during endoscopic sinus and skull base surgery. INTRODUCTION/UNASSIGNED:The nasolacrimal canal forms part of the medial wall of the maxillary sinus. Transecting the NLD is sometimes necessary for tumor resection or surgical access to maxillary sinus and infratemporal fossa pathology. There is no consensus for the endoscopic management of the NLD when only the duct is transected without involving the nasolacrimal sac. METHODS/UNASSIGNED:Medical records of 29 patients from 2 academic institutions who underwent endoscopic sinus and skull base surgery with transection of the NLD were retrospectively reviewed. Whether the duct was marsupialized or simply transected was recorded, and the postoperative rate of epiphora was calculated. RESULTS/UNASSIGNED:Mean age was 59 years (range, 14-86 years). Mean follow-up was 10.5 months (range, 1-33 months). The NLD was marsupialized in 16 (55%) and simply transected in 13 (45%) patients. Six patients underwent postoperative radiation. No patients in the marsupialization group had epiphora postoperatively, all with Munk score of 0. One patient in the transection group developed postoperative epiphora with Munk score of 1. Pathology included inverted papilloma (8), acute on chronic inflammation (6), B-cell lymphoma (3), juvenile nasopharyngeal angiofibroma (2), squamous cell carcinoma (2), Schneiderian papilloma (2), metastatic melanoma (1), HPV-related carcinoma (1), adenocarcinoma (1), benign epithelial cyst (1), adenoid cystic carcinoma (1), and erosive chronic sinusitis without nasal polyposis (1). CONCLUSION/UNASSIGNED:Management after transection of the NLD varies widely. The duct may be simply transected or marsupialized, or a formal dacryocystorhinostomy can be performed. The surgeon must also choose whether to place a stent. Based on our small series and review of the literature, marsupialization or simple transection of the NLD results in a low rate of postoperative epiphora in the setting of endoscopic sinus and skull base surgery.

BACKGROUND/UNASSIGNED:Improved player safety is an important goal of professional baseball. Prevention of mild traumatic brain injury (concussion) is an area of emphasis because of the potential for long-term as well as short-term sequelae. HYPOTHESIS/UNASSIGNED:A rule change can lower the incidence of concussions and other injuries in professional baseball. STUDY DESIGN/UNASSIGNED:Cohort study; Level of evidence, 3. METHODS/UNASSIGNED:This study included a retrospective review of data entered concurrently into professional baseball's electronic medical record system. All minor and major league teams are required to use this system. All injuries are captured by creation of a new record in the system at the time of the injury. All active minor and major league players from 2011 to 2017 were included. The 30 major league clubs have 1200 roster players and play 162 games per season. The approximately 200 minor league clubs have about 7500 active players and play 56 to 144 games annually that combine for approximately 330,000 athlete-exposures per season. Before the 2014 season, Major League Baseball, in conjunction with its players association, instituted a rule limiting home plate collisions between base runners and catchers that applied to both Major League Baseball and Minor League Baseball. All concussions and other injuries at home plate from 2011 to 2017 were analyzed by mechanism and player position. RESULTS/UNASSIGNED:= .0001). CONCLUSION/UNASSIGNED:This rule change was associated with significant reductions in the numbers of concussions and other injuries caused by collisions at home plate as well as significant decreases in time lost from play.

With an increasing awareness of mental health issues and neurological disorders, "understanding the brain" is one of the biggest current challenges in biological research. This has been recognised by both governments and funding agencies, and it includes the need to understand connectivity of brain regions and coordinated network activity, as well as cellular and molecular mechanisms at play. In this chapter, we will describe how we have taken advantage of different proteomic techniques to unravel molecular mechanisms underlying two modulators of neuronal function: Neurotrophins and antipsychotics.

OBJECTIVES:The purpose of this study was to obtain an electrophysiological analog of masking release using speech-evoked cortical potentials in steady and modulated maskers and to relate this masking release to behavioral measures for the same stimuli. The hypothesis was that the evoked potentials can be tracked to a lower stimulus level in a modulated masker than in a steady masker and that the magnitude of this electrophysiological masking release is of the same order as that of the behavioral masking release for the same stimuli. DESIGN:Cortical potentials evoked by an 80-ms /ba/ stimulus were measured in two steady maskers (30 and 65 dB SPL), and in a masker that modulated between these two levels at a rate of 25 Hz. In each masker, a level series was undertaken to determine electrophysiological threshold. Behavioral detection thresholds were determined in the same maskers using an adaptive tracking procedure. Masking release was defined as the difference between signal thresholds measured in the steady 65-dB SPL masker and the modulated masker. A total of 23 normal-hearing adults participated. RESULTS:Electrophysiological thresholds were uniformly elevated relative to behavioral thresholds by about 6.5 dB. However, the magnitude of masking release was about 13.5 dB for both measurement domains. CONCLUSIONS:Electrophysiological measures of masking release using speech-evoked cortical auditory evoked potentials correspond closely to behavioral estimates for the same stimuli. This suggests that objective measures based on electrophysiological techniques can be used to reliably gauge aspects of temporal processing ability.

Although modern cochlear implants (CIs) use cathodic-leading symmetrical biphasic pulses to stimulate the auditory nerve, a growing body of evidence suggests that anodic-leading pulses may be more effective. The positive polarity has been shown to produce larger electrically evoked compound action potential (ECAP) amplitudes, steeper slope of the amplitude growth function, and broader spread of excitation (SOE) patterns. Polarity has also been shown to influence pitch perception. It remains unclear how polarity affects the relation between physiological SOE and psychophysical pitch perception. Using a within-subject design, we examined the correlation between performance on a pitch-ranking task and spatial separation between SOE patterns for anodic and cathodic-leading symmetric biphasic pulses for 14 CI ears. Overall, there was no effect of polarity on either ECAP SOE patterns, pitch ranking performance, or the relation between the two. This result is likely due the use of symmetric biphasic pulses, which may have reduced the size of the effect previously observed for pseudomonophasic pulses. Further research is needed to determine if a pseudomonophasic stimulus might further improve the relation between physiology and pitch perception.

Iatrogenic facial nerve (FN) injury is one of the most feared complications of otologic surgery. Dehiscence of the bony covering of the FN within the temporal bone increases FN vulnerability to accidental injury. High-resolution computed tomography (HRCT) of the temporal bone is used preoperatively to assess middle ear and mastoid anatomy; however, it is unreliable for detecting facial canal dehiscence. In this study, our aim was to determine if preoperative percutaneous FN stimulation could predict middle ear facial canal dehiscence. Between January 2015 and February 2017, we performed preoperative HRCT and percutaneous FN stimulation on adult patients who underwent otologic surgery at our institution. Stimulation was performed with a monopolar probe placed on the skin over the stylomastoid foramen. Electrical stimuli ranged from 0 to 40 milliamperes (mA). Recordings were made from ipsilateral facial muscles. Dependent variables included threshold to compound muscle action potential (CMAP), threshold to maximum amplitude of CMAP, and maximum amplitude of CMAP for each muscle. A retrospective chart review was performed. Seventy patients met inclusion criteria. Of the 24 with an intraoperatively confirmed dehiscence, 10 were identified preoperatively by the attending surgeon on HRCT. Averages of the lowest recorded threshold to CMAP (5.1mA v. 9.1mA), and an average of the threshold to CMAP (8.9 mA. 11.8 mA) of dehiscent versus non-dehiscent nerves were significantly different (p < .05). In conclusion, percutaneous FN stimulation is a simple and cost-effective tool that can give the surgeon important preoperative information about FN anatomy.