Faculty Bibliography

Varicocele is the most common correctible cause of male infertility and is present in 15% to 20% of the male population. Despite its prevalence, the pathophysiology of varicocele remains under investigation. One of the largest obstacles in studying varicocele is that it is almost exclusively found in humans. This has necessitated the creation of an animal model of varicocele. The most commonly used animal model involves the creation of a varicocele in a rodent by partially occluding the left renal vein. This model has provided a significant amount of data on varicocele, and a modification of this model utilizing microsurgery appears even more promising. Animal models have proven critical to investigating the pathophysiology of varicocele.

BACKGROUND:Autoimmune inner ear disease (AIED) is a rare disease that results in progressive sensorineural hearing loss. Patients with AIED initially respond to corticosteroids; however, many patients become unresponsive to this treatment over time, and there is no effective alternative therapy for these individuals. METHODS:We performed a phase I/II open-label, single-arm clinical trial of the IL-1 receptor antagonist anakinra in corticosteroid-resistant AIED patients. Given that the etiology of corticosteroid resistance is likely heterogeneous, we used a Simon 2-stage design to distinguish between an unacceptable (≤10%) and an acceptable (≥30%) response rate to anakinra therapy. Subjects received 100 mg anakinra by subcutaneous injection for 84 days, followed by a 180-day observational period. RESULTS:Based on patient responses, the Simon 2-stage rule permitted premature termination of the trial after 10 subjects completed the 84-day drug period, as the target efficacy for the entire trial had been achieved. Of these 10 patients, 7 demonstrated audiometric improvement, as assessed by pure tone average (PTA) and word recognition score (WRS). In these 7 responders, reduced IL-1β plasma levels correlated with clinical response. Upon discontinuation of treatment, 3 subjects relapsed, which correlated with increased IL-1β plasma levels. CONCLUSION/CONCLUSIONS:We demonstrated that IL-1β inhibition in corticosteroid-resistant AIED patients was effective in a small cohort of patients and that IL-1β plasma levels associated with both clinical hearing response and disease relapse. These results suggest that a larger phase II randomized clinical trial of IL-1β inhibition is warranted. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov NCT01267994. FUNDING/BACKGROUND:NIH, Merrill & Phoebe Goodman Otology Research Center, and Long Island Hearing & Speech Society.

Design: The relationship of the recurrent laryngeal nerve to the superior parathyroid gland during consecutive thyroidectomies was prospectively evaluated. When one structure was noted, careful dissection was performed to locate the other structure, to preserve their natural anatomical relationship. Patients: In total, 103 consecutive thyroid lobectomies were performed on 73 patients. The distance from the superior parathyroid gland to the recurrent laryngeal nerve was recorded. Results: In 88 cases (88.9 per cent), the superior parathyroid gland was identified within 5 mm of the recurrent laryngeal nerve. In 62 cases (62.6 per cent), the gland was within 1 mm of the recurrent laryngeal nerve. The height of the thyroid lobe was positively associated with the distance between the two structures (p = 0.001), as was the incidence of cancer (p = 0.033). The incidence of recurrent laryngeal nerve paresis was less than 4 per cent. Conclusion: In most cases, the recurrent laryngeal nerve was found in close proximity to the superior parathyroid gland. In a thyroid gland with a large height, or in a cancerous lobe, this relationship is less reliable.

With a cochlear implant, when stimulation from multiple channels is interleaved, the perceived loudness is greater than the loudness associated with any of the individual channels presented in isolation. This phenomenon is known as loudness summation. This study examined if loudness summation with monopolar and tripolar stimulation were equivalent at two loudnesses and two spacing configurations. Results suggest that loudness summation is similar for monopolar and tripolar modes. However, larger summation differences were observed for softer sounds and louder sounds with a larger spatial separation. The results are consistent with the idea that loudness summation is dependent on channel interaction and have implications for implementing current-focused processing strategies.

Long (31.5 mm) electrode arrays are inserted deeper into the cochlea than the typical 1.25 turn insertion. With these electrode arrays, the apical electrodes are closer to (and possibly extend past) the end of the spiral ganglion. Using multi-dimensional scaling with patients implanted with a 31.5 mm electrode array, the perceptual space between electrodes was measured. The results suggest that deeper insertion increases the range of place pitches, but the perceptual differences between adjacent electrodes become smaller in the apex.

A non-parametric bootstrapping statistical method is introduced and investigated for estimating confidence intervals resulting from information transfer (IT) analysis of confusion matrices. Confidence intervals can be used to statistically compare ITs from two or more confusion matrices obtained in an experiment. Information transfer is a nonlinear analysis and does not satisfy many of the assumptions of a parametric method. The bootstrapping method accurately estimated IT confidence intervals as long as the confusion matrices contained a sufficiently large number of presentations per stimulus category, which is also a condition for reduced bias in IT analysis.

OBJECTIVES: Auditory brainstem implants (ABI) use the same processing strategy as was developed for cochlear implants (CI). However, the cochlear nucleus (CN), the stimulation site of ABIs, is anatomically and physiologically more complex than the auditory nerve and consists of neurons with differing roles in auditory processing. The aim of this study was to evaluate the hypotheses that ABI users are less able than CI users to access speech spectro-temporal information delivered by the existing strategies and that the sites stimulated by different locations of CI and ABI electrode arrays differ in encoding of temporal patterns in the stimulation. DESIGN: Six CI users and four ABI users of Nucleus implants with ACE processing strategy participated in this study. Closed-set perception of aCa syllables (16 consonants) and bVd words (11 vowels) was evaluated via experimental processing strategies that activated one, two, or four of the electrodes of the array in a CIS manner as well as subjects' clinical strategies. Three single-channel strategies presented the overall temporal envelope variations of the signal on a single-implant electrode located at the high-, medium-, and low-frequency regions of the array. Implantees' ability to discriminate within electrode temporal patterns of stimulation for phoneme perception and their ability to make use of spectral information presented by increased number of active electrodes were assessed in the single- and multiple-channel strategies, respectively. Overall percentages and information transmission of phonetic features were obtained for each experimental program. RESULTS: Phoneme perception performance of three ABI users was within the range of CI users in most of the experimental strategies and improved as the number of active electrodes increased. One ABI user performed close to chance with all the single and multiple electrode strategies. There was no significant difference between apical, basal, and middle CI electrodes in transmitting speech temporal information, except a trend that the voicing feature was the least transmitted by the basal electrode. A similar electrode-location pattern could be observed in most ABI subjects. CONCLUSIONS: Although the number of tested ABI subjects was small, their wide range of phoneme perception performance was consistent with previous reports of overall speech perception in ABI patients. The better-performing ABI user participants had access to speech temporal and spectral information that was comparable to that of average CI user. The poor-performing ABI user did not have access to within-channel speech temporal information and did not benefit from an increased number of spectral channels. The within-subject variability between different ABI electrodes was less than the variability across users in transmission of speech temporal information. The difference in the performance of ABI users could be related to the location of their electrode array on the CN, anatomy, and physiology of their CN or the damage to their auditory brainstem due to tumor or surgery.

BACKGROUND: Hyaluronan (HA) is a ligand for the CD44 receptor which is crucial to cancer cell proliferation and metastasis. High levels of CD44 expression in many cancers have encouraged the development of HA-based carriers for anti-cancer therapeutics. PURPOSE: The objective of this study was to determine whether HA conjugation of anticancer drugs impacts CD44-specific HA-drug uptake and disposition by human head and neck cancer cells. METHODS: The internalization and cellular disposition of hyaluronan-doxorubicin (HA-DOX), hyaluronan-cisplatin (HA-Pt), and hyaluronan-cyanine7 (HA-Cy7) conjugates were investigated by inhibiting endocytosis pathways, and by inhibiting the CD44-mediated internalization pathways that are known to mediate hyaluronan uptake in vitro. RESULTS: Cellular internalization of HA was regulated by CD44 receptors. In mouse xenografts, HA conjugation significantly enhanced tumor cell uptake compared to unconjugated drugs. DISCUSSION: The results suggested that the main mechanism of HA-based conjugate uptake may be active transport via CD44 in conjunction with a clathrin-dependent endocytic pathway. Other HA receptors, hyaluronan-mediated motility receptor (RHAMM) and lymphatic vessel endothelial hyaluronan receptor (LYVE-1), did not play a significant role in conjugate uptake. CONCLUSIONS: HA conjugation significantly increased CD44-mediated drug uptake and extended the residence time of drugs in tumor cells.