Browsing by Author "Yates, Charles"

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    Audiologic Improvement Following MCF Approach for Spontaneous Cerebrospinal Fluid Leaks
    (Wolters Kluwer, 2019-09) Alwani, Mohamedkazim; Bandali, Elhaam; Van Buren, Lauren; Yates, Charles; Nelson, Rick; Otolaryngology -- Head and Neck Surgery, School of Medicine
    Objective: To determine the audiologic improvement after middle cranial fossa (MCF) approach to repair spontaneous cerebrospinal fluid (sCSF) leaks. Study Design: Retrospective cohort study. Setting: Tertiary referral center. Patients: Twenty-four consecutive patients (27 ears) with temporal bone sCSF leak over a 4-year period. Patient age, sex, ethnicity, body mass index (BMI), location of CSF leak, recurrence of CSF leak, and presence of encephalocele(s) were recorded. Intervention: Audiometric testing in patients undergoing MCF repair of temporal bone sCSF leak. Main Outcome Measures: Comparison of preoperative and postoperative pure-tone average (PTA), air-bone gap (ABG), and word recognition score (WRS) in the sCSF leak ear. Results: Out of 27 ears, 55% had multiple tegmen defects and 82% had more than or equal to 1 encephaloceles. There were no recurrent CSF leaks at a median follow up of 4 months. The mean (SD) preoperative PTA and ABG were 40.58 [15.67] and 16.44 [6.93] dB, respectively. There was significant improvement in mean PTA (10.28 [8.01] dB; p < 0.001; Cohen d = 0.95) and ABG (9.31 [7.16] dB; p < 0.001; Cohen d = 0.88) after sCSF repair. Mean WRS improved (by 3.07 [6.11] %; p = 0.024; Cohen d = 0.46) from a mean preoperative WRS of 93.16 [9.34]% to a mean postoperative WRS of 96.26 [6.49]%. Conclusions: MCF approach for repair of sCSF leaks yields significant improvement in conductive hearing loss and is highly effective in management of the entire lateral skull base where multiple bony defects are often identified.
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    PAK1 inhibition reduces tumor size and extends the lifespan of mice in a genetically engineered mouse model of Neurofibromatosis Type 2 (NF2)
    (Oxford University Press, 2021) Hawley, Eric; Gehlhausen, Jeffrey; Karchugina, Sofiia; Chow, Hoi-Yee; Araiza-Olivera, Daniela; Radu, Maria; Smith, Abbi; Burks, Ciersten; Jiang, Li; Li, Xiaohong; Bessler, Waylan; Masters, Andrea; Edwards, Donna; Burgin, Callie; Jones, David; Yates, Charles; Clapp, D. Wade; Chernoff, Jonathan; Park, Su-Jung; Biochemistry and Molecular Biology, School of Medicine
    Neurofibromatosis Type II (NF2) is an autosomal dominant cancer predisposition syndrome in which germline haploinsufficiency at the NF2 gene confers a greatly increased propensity for tumor development arising from tissues of neural crest derived origin. NF2 encodes the tumor suppressor, Merlin, and its biochemical function is incompletely understood. One well-established function of Merlin is as a negative regulator of group A serine/threonine p21-activated kinases (PAKs). In these studies we explore the role of PAK1 and its closely related paralog, PAK2, both pharmacologically and genetically, in Merlin-deficient Schwann cells and in a genetically engineered mouse model (GEMM) that develops spontaneous vestibular and spinal schwannomas. We demonstrate that PAK1 and PAK2 are both hyper activated in Merlin-deficient murine schwannomas. In preclinical trials, a pan Group A PAK inhibitor, FRAX-1036, transiently reduced PAK1 and PAK2 phosphorylation in vitro, but had insignificant efficacy in vivo. NVS-PAK1-1, a PAK1 selective inhibitor, had a greater but still minimal effect on our GEMM phenotype. However, genetic ablation of Pak1 but not Pak2 reduced tumor formation in our NF2 GEMM. Moreover, germline genetic deletion of Pak1 was well tolerated, while conditional deletion of Pak2 in Schwann cells resulted in significant morbidity and mortality. These data support the further development of PAK1-specific small molecule inhibitors and the therapeutic targeting of PAK1 in vestibular schwannomas and argue against PAK1 and PAK2 existing as functionally redundant protein isoforms in Schwann cells.
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    Prevalence of Obstructive Sleep Apnea (OSA) in Spontaneous Cerebrospinal Fluid (CSF) Leaks: A Prospective Cohort Study
    (Wolters Kluwer, 2018-07) Rabbani, Cyrus; Saltagi, Mohamad; Manchanda, Shalini; Yates, Charles; Nelson, Rick; Otolaryngology -- Head and Neck Surgery, School of Medicine
    Objective: To determine the prevalence of obstructive sleep apnea (OSA) in a prospective cohort of patients with spontaneous CSF (sCSF) leaks of the temporal bone. Study Design: Prospective cohort study. Setting: Tertiary referral center. Patients: Consecutive sCSF leak patients (21) over a 3-year period. Four patients presented with a history of OSA and 17 patients were prospectively offered polysomnogram (PSG) testing during the initial clinic encounter. Intervention: Level I PSG. Main Outcome Measures: Patient characteristics (age, sex, body mass index), apnea hypopnea index (AHI), presence of snoring, and presence of hypoxia (oxygen saturation <88% for >5 min). OSA was defined as mild (AHI ≥5 and <15/h), moderate (AHI ≥15 and <30/h), and severe (AHI ≥30/h). Results: The prevalence of OSA in sCSF leak patients is 83.3%. PSG studies were performed on 18 of the 21 patients. There were 15 women and 6 men with an average age (standard deviation) of 56.3 (11.2) years and an average body mass index of 35.3 (7.7) kg/m2. Objectively, the AHI ranged from mild to severe (range = 5.7–92, median = 19.8). Snoring was present in 61% of patients and hypoxia was present in 39% of patients. sCSF leak patients with OSA were significantly older than sCSF leak patients without OSA (56.7 [8.3] versus 42.7 [14.5] yr, p = 0.03). Conclusions: OSA is highly prevalent among patients with sCSF leaks. All patients with sCSF leaks should undergo formal PSG testing. Future studies are needed to determine the role of OSA in the development of sCSF leaks.