Faculty Bibliography

BACKGROUND: Understanding normal volume asymmetry is essential for accurate assessment of limb volume changes following breast cancer (BC) treatment in which lymphatic function is disrupted. The purposes of this study were to evaluate for differences in dominant and nondominant limb volumes and to evaluate for interactions between the effects of dominance and side of cancer on limb volume. METHODS AND RESULTS: This study evaluated preoperative limb volumes of 397 women enrolled in a prospective, longitudinal study of neuropathic pain and lymphedema. Volume was calculated from circumference. Limb resistance was measured with bioimpedance. Women were dichotomized into two groups: those whose cancer was on their dominant side and those whose cancer was on their nondominant side. Analyses of variance were used to evaluate for differences. In 47%, BC occurred on the side of the dominant limb. Except for the 30 to 40 centimeter (cm) limb volume segment, a main effect of dominance was found for all measures. The volume of the dominant limb was significantly greater than that of the nondominant limb. No main effects were found for side of cancer. A statistically significant interaction was found only at the 0 to 10 cm limb volume segment. CONCLUSIONS: Prior to BC treatment, the dominant limb demonstrated lower bioimpedance resistance (-2.09%) and greater total limb volume (1.12%) than the nondominant limb. Segmental volume differences were greatest at the proximal forearm segment (2.31%) and least at the proximal arm segment (0.21%). This study provides evidence that preoperative volume assessment is important due to normal variability associated with limb dominance.

BACKGROUND: The aim of this study was to create benchmarks for evaluating clinical outcomes and complications of transoral robotic surgeries (TORS) in a multicenter setting. METHODS: 243 TORS for obstructive sleep apnea/hypopnea syndrome (OSAHS) operations, carried out between 2008 and 2012, were analyzed at 7 different centers. The average hospitalization was 3.5 days. The mean patient age was 50 +/- 12 years, the average BMI at the time of the procedure was 28.53 +/- 3.87 and the majority of the patients were men (81%). RESULTS: The mean preoperative and postoperative apnea/hypopnea index was 43.0 +/- 22.6 and 17.9 +/- 18.4, respectively (p < 0.001). The mean preoperative and postoperative Epworth Sleepiness Scale score was 12.34 +/- 5.19 and 5.7 +/- 3.49, respectively (p < 0.001). The mean pre- and postoperative lowest O2 saturation was 79.5 +/- 8.77 and 83.9 +/- 6.38%, respectively (p < 0.001). CONCLUSIONS: Patients undergoing TORS as part of a multilevel approach for the treatment of OSAHS have a reasonable expectation of success with minimal long-term morbidity.

BACKGROUND: Current augmentative and reconstructive rhinoplasties use auto logous tissue grafts or synthetic bioinert materials to repair nasal trauma or attain an aesthetic shape. Autologous grafts are associated with donor-site trauma and morbidity. Synthetic materials are widely used but often yield an unnatural appearance and are prone to infection or dislocation. There is an acute clinical need for the generation of native tissues to serve as rhinoplasty grafts without the undesirable features that are associated with autologous grafts or current synthetic materials. METHODS: Bioactive scaffolds were developed that not only recruited cells in the nasal dorsum in vivo, but also induced chondrogenesis of the recruited cells. Bilayered scaffolds were fabricated with alginate-containing gelatin microspheres encapsulating cytokines atop a porous poly(lactic-co-glycolic acid) base. Microspheres were fabricated to contain recombinant human transforming growth factor-beta3 at doses of 200, 500, or 1000 ng, with phosphate-buffered saline-loaded microspheres used as a control. A rat model of augmentation rhinoplasty was created by implanting scaffolds atop the native nasal cartilage surface that was scored to induce cell migration. Tissue formation and chondrogenesis in the scaffolds were evaluated by image analysis and histologic staining with hematoxylin and eosin, toluidine blue, Verhoeff elastic-van Geison, and aggrecan immunohistochemistry. RESULTS: Sustained release of increasing doses of transforming growth factor-beta3 for up to the tested 10 weeks promoted orthotopic cartilage-like tissue formation in a dose-dependent manner. CONCLUSIONS: These findings represent the first attempt to engineer cartilage tissue by cell homing for rhinoplasty, and could potentially serve as an alternative material for augmentative and reconstructive rhinoplasty.

Background: Impaired NMDA receptor signaling is believed to contribute to schizophrenia and other psychiatric disorders. NMDA receptors are critical for neural development as well as learning, memory, and cognitive processes in adults. Thus disruption of NMDA receptor activation and synaptic transmission might lead to schizophrenia. Drugs that act as NMDA receptor antagonists (e.g., ketamine) lead to schizophrenic-like symptoms, and human genetic studies have highlighted de novo mutations in NMDA receptors and associated proteins in humans with schizophrenia. However, little is known about how NMDA receptor activation is directly involved in cognitive processes such as perception and memory. Here I will present new work in mouse models showing the connections between a gene implicated in schizophrenia (CNTNAP2), NMDA receptor activation, and control of local circuit dynamics by synaptic plasticity and regulation of excitatory-inhibitory balance in mouse sensory cortex. Methods: We performed electrophysiological experiments in brain slices and in vivo. Some behavioral experiments to examine perception and seizures were also performed. For in vitro experiments, brain slices of wild-type and Cntnap2 mutant animals were made. Synaptic transmission (strength of inhibition relative to strength of excitation) and long-term synaptic plasticity (pairing pre- and postsynaptic spikes to examine spike-timing-dependent plasticity) were assessed with whole-cell current-clamp and voltage-clamp recordings. Methods are similar to our past studies in brain slices (Froemke et al., Nature 2005; Southwell et al., Science 2010). For in vivo experiments, animals were anesthetized and head-fixed, and whole-cell recordings made in auditory or visual cortex. Sensory stimuli (pure tones/vocalizations or light flashes/ sequences, respectively) were presented to the animals; response strength and short- and long-term plasticity were measured. Methods are similar to our past studies in vivo (Froemke et al., Nature 2007; Froemke et al., Nature Neurosci 2013). Results: In Cntnap2 mutant animals, we found that: 1) NMDA receptor amplitude was decreased relative to AMPA receptor transmission, 2) long-term synaptic plasticity was impaired, 3) GABAergic inhibition was imbalanced and uncorrelated to excitation, and 4) sensory responses were unreliable and more variable than in wild-type animals. Each of these latter results (#2-4) might come as a direct consequence of impaired NMDA receptor activation (#1). However, treatment with D-serine could selectively rescue and boost NMDA receptor currents in Cntnap2 mutant mice, suggesting that glycine site modulation could improve synaptic and local circuit function in these animals. Conclusions: Many of the disruptions in Cntnap2 mutant mice (serving as a genetic model of schizophrenia) could have as a root cause reductions in current flux through NMDA receptors. However, glycine site agonists may provide a reasonable therapeutic approach for enhancing NMDA receptor function and improving cognitive processes, especially in the context of trainingbased approaches to recruit mechanisms of longterm synaptic plasticity and rebalancing inhibition with excitation

BACKGROUND: It is desirable to detect neoplastic thyroid disease before proceeding with surgical therapy for hyperparathyroidism so that both conditions can be treated with a single operation. METHODS: Between March 1998 and June 2009, 227 patients with primary hyperparathyroidism were treated with surgical therapy. Of these, 217 were evaluated preoperatively with a modified 4-dimensional CT and ultrasonography. The medical records of these patients were reviewed in order to document the incidence and significance of thyroid pathology in this cohort of patients. RESULTS: Thyroid nodules were identified in 159 of the 217 patients (73.3%). Nine of 217 patients (4.1%) were treated with either a partial or a total thyroidectomy at the time of parathyroidectomy. Three of these patients had papillary thyroid carcinoma, 1 had a Hurthle cell carcinoma, and 1 had an incidental micropapillary thyroid carcinoma. CONCLUSION: The rate of clinically significant thyroid malignancy in patients undergoing surgical treatment of primary hyperparathyroidism was 1.8%.

Lrp4, the muscle receptor for neuronal Agrin, is expressed in the hippocampus and areas involved in cognition. The function of Lrp4 in the brain, however, is unknown, as Lrp4-/- mice fail to form neuromuscular synapses and die at birth. Lrp4-/- mice, rescued for Lrp4 expression selectively in muscle, survive into adulthood and showed profound deficits in cognitive tasks that assess learning and memory. To learn whether synapses form and function aberrantly, we used electrophysiological and anatomical methods to study hippocampal CA3-CA1 synapses. In the absence of Lrp4, the organization of the hippocampus appeared normal, but the frequency of spontaneous release events and spine density on primary apical dendrites were reduced. CA3 input was unable to adequately depolarize CA1 neurons to induce long-term potentiation. Our studies demonstrate a role for Lrp4 in hippocampal function and suggest that patients with mutations in Lrp4 or auto-antibodies to Lrp4 should be evaluated for neurological deficits.

Surgical resection in oral cancer patients can result in altered speech, swallowing, and patient perception of quality of life (QOL). Oral surgery can result in reduced lingual range of motion (ROM). However, few studies have quantified the degree of lingual restriction after surgery. This pilot study describes a new measurement system to define tongue ROM in surgically treated tongue cancer patients. This measurement system was validated by comparing results in these treated surgical patients versus healthy individuals. This scale was further validated by correlating ROM with performance status, oral outcomes, and patient-rated QOL. Thirty-six patients who underwent oral tongue surgery and 31 healthy individuals were included. Tongue ROM was assessed using a novel ROM assessment system. This novel system was examined in these patients versus healthy subjects. This measurement tool was further validated by correlating tongue ROM in treated patients with performance status, oral outcomes, and patient-rated QOL. Tongue ROM was found to be significantly lower in the surgically treated patients than in the healthy individuals (p = 0.0001). Tongue ROM correlated with performance status, oral outcomes, and all QOL measures. This new tongue ROM measurement system defined tongue deficits in surgically treated oral cancer patients. This tool was validated by comparing results to those in healthy individuals, as well as by correlating tongue ROM to performance status, oral outcomes, and QOL. This measurement tool can be used to define baseline and postsurgery tongue ROM in oral cancer patients, as well as track change over time with recovery and therapy. Future studies should examine use of this measurement tool with other populations demonstrating tongue deficits.

OBJECTIVE: Is conscious sedation an effective, safe, and efficient anesthetic choice in patients undergoing select neurotologic and otologic procedures? STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: Six patients underwent eight neurotologic procedures including cerebrospinal fluid leak and encephalocele repair, and primary and revision cochlear implant surgery. Patients were deemed poor candidates for general anesthesia secondary to medical comorbidities. These were compared to 11 control patients who underwent same procedures under general anesthesia with intubation. INTERVENTION: Dexmedetomidine infusion was utilized as the primary agent for conscious sedation in this high-risk patient population because, unlike other commonly used sedatives, it preserves normal respirations while providing adequate analgesia. MAIN OUTCOME MEASURES: Preoperative Physiological and Operative Severity Score for the enUmeration of Mortality and Morbidity (P-POSSUM) scores were calculated for the study group. We measured total anesthesia, and perioperative and recovery times. Cost of anesthetic agents was considered and any adverse effects were noted. Patient satisfaction with the operative experience was assessed with telephone surveys. RESULTS: P-POSSUM scores were high for the study group. Postoperative anesthesia was shorter for the study patients undergoing conscious sedation. Difference in cost of anesthetic agents was negligible. The adverse effects were few and as expected for the type of procedure. Patients reported satisfaction and comfort with their operative experience. CONCLUSION: Select neurotologic and otologic procedures can be safely, effectively, and efficiently performed under conscious sedation with dexmedetomidine infusion as the primary anesthetic choice for patients who are deemed poor medical candidates for general endotracheal anesthesia.