Justin S. Golub

Sustained VEGF delivery via PLGA nanoparticles promotes vascular growth

Technologies to increase tissue vascularity are critically important to the fields of tissue engineering and cardiovascular medicine. Currently, limited technologies exist to encourage angiogenesis and arteriogenesis in a controlled manner. In the present study, we describe an injectable controlled release system consisting of VEGF encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs). The majority of VEGF was released gradually over 2-4 days from the NPs as determined by an ELISA release kinetics experiment. An in vitro aortic ring bioassay was used to verify the bioactivity of VEGF-NPs compared with empty NPs and no treatment. A mouse femoral artery ischemia model was then used to measure revascularization in VEGF-NP-treated limbs compared with limbs treated with naked VEGF and saline. 129/Sv mice were anesthetized with isoflurane, and a region of the common femoral artery and vein was ligated and excised. Mice were then injected with VEGF-NPs, naked VEGF, or saline. After 4 days, three-dimensional microcomputed tomography angiography was used to quantify vessel growth and morphology. Mice that received VEGF-NP treatment showed a significant increase in total vessel volume and vessel connectivity compared with 5 microg VEGF, 2.5 microg VEGF, and saline treatment (all P < 0.001). When the yield of the fabrication process was taken into account, VEGF-NPs were over an order of magnitude more potent than naked VEGF in increasing blood vessel volume. Differences between the VEGF-NP group and all other groups were even greater when only small-sized vessels under 300 mum diameter were analyzed. In conclusion, sustained VEGF delivery via PLGA NPs shows promise for encouraging blood vessel growth in tissue engineering and cardiovascular medicine applications.

Inhibition Of Notch Activity Promotes Nonmitotic Regeneration of Hair Cells in the Adult Mouse Utricles

The capacity of adult mammals to regenerate sensory hair cells is not well defined. To explore early steps in this process, we examined reactivation of a transiently expressed developmental gene, Atoh1, in adult mouse utricles after neomycin-induced hair cell death in culture. Using an adenoviral reporter for Atoh1 enhancer, we found that Atoh1 transcription is activated in some hair cell progenitors (supporting cells) 3 d after neomycin treatment. By 18 d after neomycin, the number of cells with Atoh1 transcriptional activity increased significantly, but few cells acquired hair cell features (i.e., accumulated ATOH1 or myosin VIIa protein or developed stereocilia). Treatment with DAPT, an inhibitor of γ-secretase, reduced notch pathway activity, enhanced Atoh1 transcriptional activity, and dramatically increased the number of Atoh1-expressing cells with hair cell features, but only in the striolar/juxtastriolar region. Similar effects were seen with TAPI-1, an inhibitor of another enzyme required for notch activity (TACE). Division of supporting cells was rare in any control or DAPT-treated utricles. This study shows that mature mammals have a natural capacity to initiate vestibular hair cell regeneration and suggests that regional notch activity is a significant inhibitor of direct transdifferentiation of supporting cells into hair cells following damage.

Prevalence of Perceived Dysphonia in a Geriatric Population

OBJECTIVES: To characterize geriatric dysphonia, including its prevalence, quality‐of‐life impairment, and association with overall health status.

Burnout in Residents of Otolaryngology–head and Neck Surgery: A National Inquiry into the Health of Residency Training

Purpose To characterize resident burnout on a national scale with a large sample size and to identify associated modifiable factors to minimize burnout and improve the quality of residency education. Method A survey was mailed to all 1,364 U.S. residents of otolaryngology–head and neck surgery in September 2005. The main outcome measures were the Maslach Burnout Inventory–Human Services Study, demographic information, and potential burnout predictors, including stressors, satisfaction, self-efficacy, and support systems. Results The response rate was 50% (684/1,364). Current second-year through fifth-year residents were included for further analysis (514). Burnout was extremely common among otolaryngology residents. High burnout was seen in 10% of residents (51), moderate burnout in 76% (391), and low burnout in 14% (72). The strongest associated demographic factor was work hours (P < .001). Hours worked was predictive of emotional exhaustion, with exhaustion scores rising by 0.19 for each hour worked (P < .001). Furthermore, there was an 8% (41 resident) reported violation rate of the Accreditation Council for Graduate Medical Education (ACGME) 80-hour-workweek limitation. Satisfaction with the balance between personal and professional life, relationship stability, and satisfaction with career choice were negatively associated with burnout (all P < .001). Conclusions Burnout is widely prevalent among U.S. otolaryngology residents and is present at greater levels than those seen in chairs or faculty of the same specialty. Work hours predict emotional exhaustion, and adherence to the ACGME 80-hour workweek may help protect against burnout and its deleterious consequences in residents of all specialties.

Hair Cell Replacement in Adult Mouse Utricles after Targeted Ablation of Hair Cells with Diphtheria Toxin

We developed a transgenic mouse to permit conditional and selective ablation of hair cells in the adult mouse utricle by inserting the human diphtheria toxin receptor (DTR) gene into the Pou4f3 gene, which encodes a hair cell-specific transcription factor. In adult wild-type mice, administration of diphtheria toxin (DT) caused no significant hair cell loss. In adult Pou4f3+/DTR mice, DT treatment reduced hair cell numbers to 6% of normal by 14 days post-DT. Remaining hair cells were located primarily in the lateral extrastriola. Over time, hair cell numbers increased in these regions, reaching 17% of untreated Pou4f3+/DTR mice by 60 days post-DT. Replacement hair cells were morphologically distinct, with multiple cytoplasmic processes, and displayed evidence for active mechanotransduction channels and synapses characteristic of type II hair cells. Three lines of evidence suggest replacement hair cells were derived via direct (nonmitotic) transdifferentiation of supporting cells: new hair cells did not incorporate BrdU, supporting cells upregulated the pro-hair cell gene Atoh1, and supporting cell numbers decreased over time. This study introduces a new method for efficient conditional hair cell ablation in adult mouse utricles and demonstrates that hair cells are spontaneously regenerated in vivo in regions where there may be ongoing hair cell turnover.

Burnout in academic faculty of otolaryngology-head and neck surgery.

Objective/Hypothesis: To characterize burnout in academic faculty of otolaryngology—head and neck surgery. To identify associated modifiable factors to reduce burnout and improve the health of the field.

Comparison of an oropharyngeal pH probe and a standard dual pH probe for diagnosis of laryngopharyngeal reflux.

Objectives: We compared the ability of an oropharyngeal (OP) aerosol-detecting pH probe and a standard dual pH probe in measuring laryngopharyngeal reflux (LPR). Methods: Fifteen subjects with LPR symptoms had 24-hour simultaneous placement of the OP probe and a standard dual pH probe. Acid exposure was defined as a 10% pH decrease below baseline for the OP probe or a pH of less than 4 at the upper esophageal sphincter (UES) probe of the dual pH probe. Results: The mean duration of acid exposure was 650 seconds (SD, 619) or 0.75% of the total time for the OP probe and 438 seconds (SD, 511) or 0.51% of the total time for the UES probe. When we excluded meals and sleep, the mean duration of acid exposure was 271 seconds (SD, 356) or 0.31% of the total time for the OP probe and 271 seconds (SD, 359) or 0.31% of the total time for the UES probe. The correlation coefficient (R) between the two probes for measurement of the duration of acid exposure was 0.50 (p < 0.05). When we excluded meals and the supine position, the R was notably higher, at 0.95 (p < 0.0001). Conclusions: The OP probe reliably documented LPR events when meals and sleep were eliminated and was better tolerated than the standard dual probe.

Prosthetic implantation of the human vestibular system

Hypothesis A functional vestibular prosthesis can be implanted in human such that electrical stimulation of each semicircular canal produces canal-specific eye movements while preserving vestibular and auditory function. Background A number of vestibular disorders could be treated with prosthetic stimulation of the vestibular end organs. We have previously demonstrated in rhesus monkeys that a vestibular neurostimulator, based on the Nucleus Freedom cochlear implant, can produce canal-specific electrically evoked eye movements while preserving auditory and vestibular function. An investigational device exemption has been obtained from the FDA to study the feasibility of treating uncontrolled Ménière’s disease with the device. Methods The UW/Nucleus vestibular implant was implanted in the perilymphatic space adjacent to the three semicircular canal ampullae of a human subject with uncontrolled Ménière’s disease. Preoperative and postoperative vestibular and auditory function was assessed. Electrically evoked eye movements were measured at 2 time points postoperatively. Results Implantation of all semicircular canals was technically feasible. Horizontal canal and auditory function were largely, but not totally, lost. Electrode stimulation in 2 of 3 canals resulted in canal-appropriate eye movements. Over time, stimulation thresholds increased. Conclusion Prosthetic implantation of the semicircular canals in humans is technically feasible. Electrical stimulation resulted in canal-specific eye movements, although thresholds increased over time. Preservation of native auditory and vestibular function, previously observed in animals, was not demonstrated in a single subject with advanced Ménière’s disease.

Spectral and temporal measures in hybrid cochlear implant users: on the mechanism of electroacoustic hearing benefits.

Objective Compare auditory performance of Hybrid and standard cochlear implant users with psychoacoustic measures of spectral and temporal sensitivity and correlate with measures of clinical benefit. Study Design Cross-sectional study. Setting Tertiary academic medical center. Patients Hybrid cochlear implant users between 12 and 33 months after implantation. Hybrid recipients had preservation of low-frequency hearing. Interventions Administration of psychoacoustic, music perception, and speech reception in noise tests. Main Outcome Measures Performance on spectral-ripple discrimination, temporal modulation detection, Schroeder-phase discrimination, Clinical Assessment of Music Perception, and speech reception in steady-state noise tests. Results Clinical Assessment of Music Perception pitch performance at 262 Hz was significantly better in Hybrid users compared with standard implant controls. There was a near significant difference on speech reception in steady-state noise. Surprisingly, neither Schroeder-phase discrimination at 2 frequencies nor temporal modulation detection thresholds across a range of frequencies revealed any advantage in Hybrid users. This contrasts with spectral-ripple measures that were significantly better in the Hybrid group. The spectral-ripple advantage was preserved even when using only residual hearing. Conclusion These preliminary data confirm existing data demonstrating that residual low-frequency acoustic hearing is advantageous for pitch perception. Results also suggest that clinical benefits enjoyed by Hybrid recipients are due to improved spectral discrimination provided by the residual hearing. No evidence indicated that residual hearing provided temporal information beyond that provided by electric stimulation.

Professional Burnout Among Microvascular and Reconstructive Free-Flap Head and Neck Surgeons in the United States

OBJECTIVES To determine the prevalence of professional burnout among microvascular free-flap (MVFF) head and neck surgeons and to identify modifiable risk factors with the intent to reduce MVFF surgeon burnout. DESIGN A cross-sectional, observational study. SETTING A questionnaire mailed to MVFF surgeons in the United States. PARTICIPANTS A total of 60 MVFF surgeons. MAIN OUTCOMES MEASURES Professional burnout was quantified using the Maslach Burnout Inventory- Human Services Study questionnaire, which defines burnout as the triad of high emotional exhaustion (EE), high depersonalization (DP), and low personal accomplishment. Additional data included demographic information and subjective assessment of professional stressors, satisfaction, self-efficacy, and support systems using Likert score scales. Potential risk factors for burnout were determined via significant association (P < .05) by Fisher exact tests and analyses of variance. RESULTS Of the 141 mailed surveys, 72 were returned, for a response rate of 51%, and 60 of the respondents were practicing MVFF surgeons. Two percent of the responding MVFF surgeons experienced high burnout (n = 1); 73%, moderate burnout (n = 44); and 25%, low burnout (n = 15). Compared with other otolaryngology academic faculty and department chairs, MVFF surgeons had similar or lower levels of burnout. On average, MVFF surgeons had low to moderate EE and DP scores. High EE was associated with excess workload, inadequate administration time, work invading family life, inability to care for personal health, poor perception of control over professional life, and frequency of irritable behavior toward loved ones (P < .001). On average, MVFF surgeons experienced high personal accomplishment. CONCLUSIONS Most MVFF surgeons experience moderate professional burnout secondary to moderate EE and DP. This may be a problem of proper balance between professional obligations and personal life goals. Most MVFF surgeons, nonetheless, experience a high level of personal accomplishment in their profession.