Reprofiling synthetic glucocorticoid-induced leucine zipper fusion peptide as a novel and effective hair growth promoter.

Hair is a biofilament with unique multi-dimensional values. In human, in addition to physiologic impacts, hair loss and hair related disorders can affect characteristic features, emotions, and social behaviors. Despite significant advancement, there is a dire need to explore alternative novel therapies with higher efficacy, less side effects and lower cost to promote hair growth to treat hair deficiency. Glucocorticoid-induced leucine zipper (GILZ) is a protein rapidly induced by glucocorticoids. Studies from our group and many others have suggested that a synthetic form of GILZ, TAT-GILZ, a fusion peptide of trans-activator of transcription and GILZ, can function as a potent regulator of inflammatory responses, re-establishing and maintaining the homeostasis. In this study, we investigate whether TAT-GILZ could promote and contribute to hair growth. For our pre-clinical model, we used 9-12 week-old male BALB/c and nude (athymic, nu/J) mice. We applied TAT-GILZ and/or TAT (vehicle) intradermally to depilated/hairless mice. Direct observation, histological examination, and Immunofluorescence imaging were used to assess the effects and compare different treatments. In addition, we tested two current treatment for hair loss/growth, finasteride and minoxidil, for optimal evaluation of TAT-GILZ in a comparative fashion. Our results showed, for the first time, that synthetic TAT-GILZ peptide accelerated hair growth on depilated dorsal skin of BALB/c and induced hair on the skin of athymic mice where hair growth was not expected. In addition, TAT-GILZ was able to enhance hair follicle stem cells and re-established the homeostasis by increasing counter inflammatory signals including higher regulatory T cells and glucocorticoid receptors. In conclusion, our novel findings suggest that reprofiling synthetic TAT-GILZ peptide could promote hair growth by increasing hair follicle stem cells and re-establishing homeostasis.

Migraine-Associated Otalgia: An Underappreciated Entity.

BACKGROUND AND OBJECTIVES: Otalgia can be primary/otogenic or secondary as a referred pain from another site, which can be difficult to establish owing to various causes and the complex innervation of the ear. In our center, we observed a large group of patients with unexplained otalgia that had a higher prevalence of migraine. We hypothesized that migraine may cause secondary otalgia. This study then aimed to determine the prevalence of migraine-associated otalgia and evaluate the efficacy of migraine treatment. SUBJECTS AND METHODS: This 2-year retrospective study was conducted at a busy otology clinic. Patients were identified using diagnostic codes corresponding to otalgia. The prevalence of migraine-associated otalgia was determined, and the efficacy of migraine treatment was evaluated in these patients. The interventions included prophylactic and abortive migraine treatments. Statistical analysis was conducted to compare between the pre- and post-treatment symptoms. RESULTS: A total of 208 patients with otalgia were identified. Sixty-four out of ninety patients with unexplained otalgia met the criteria for migraine; of them, 30 patients had an adequate follow-up and were thus included in the evaluation of treatment efficacy. Otalgia improved in 87% of the patients who received migraine treatment. After treatment, the mean pain score and headache frequency significantly decreased from 7 to 2 and from 27 to 9 days per month, respectively (p<0.001). CONCLUSIONS: Migraine should be considered as a source of secondary otalgia, and patients should receive treatment as they often respond to migraine treatment.

Congenital cytomegalovirus (CMV) for the pediatric otolaryngologist.

Cytomegalovirus (CMV) is a double-stranded DNA virus and a member of the herpesvirus family. It is the most common congenital viral infection. For symptomatic infections, symptoms can vary widely but tends to have a predilection for the central nervous system and for the reticuloendothelial system. Sensorineural hearing loss (SNHL) is by far the most common sequelae of congenital CMV infection. For this reason, it is imperative to understand the screening, diagnosis, and possible treatment options for congenital CMV induced SNHL. This literature review explores the association of CMV with hearing loss, screening for congenital CMV infections, possible treatments options, and the development of a possible vaccine.

The Pathology of the Vestibular System in CANVAS.

OBJECTIVE: To describe the site of lesion responsible for the severe, bilateral, symmetrical, selective loss of vestibular function in Cerebellar Ataxia with Neuronopathy and Vestibular Areflexia Syndrome (CANVAS), an adult-onset recessively-inherited ataxia, characterized by progressive imbalance due to a combination of cerebellar, somatosensory, and selective vestibular impairment with normal hearing. METHODS: Histologic examination of five temporal bones and the brainstems from four CANVAS patients and the brainstem only from one more, each diagnosed and followed from diagnosis to death by one of the clinician authors. RESULTS: All five temporal bones showed severe loss of vestibular ganglion cells (cell counts 3-16% of normal), and atrophy of the vestibular nerves, whereas vestibular receptor hair cells and the vestibular nuclei were preserved. In contrast, auditory receptor hair cells, the auditory ganglia (cell counts 51-100% of normal), and the auditory nerves were relatively preserved. In addition, the cranial sensory ganglia (geniculate and trigeminal), present in two temporal bones, also showed severe degeneration. CONCLUSIONS: In CANVAS there is a severe cranial sensory ganglionopathy neuronopathy (ganglionopathy) involving the vestibular, facial, and trigeminal ganglia but sparing the auditory ganglia. These observations, when coupled with the known spinal dorsal root ganglionopathy in CANVAS, indicate a shared pathogenesis of its somatosensory and cranial nerve manifestations. This is the first published account of both the otopathology and neuropathology of CANVAS, a disease that involves the central as well as the peripheral nervous system.

Comparison of Temporal Bone Parameters before Cochlear Implantation in Patients with and without Facial Nerve Stimulation.

BACKGROUND AND OBJECTIVES: Facial nerve stimulation (FNS) is a complication of cochlear implantation (CI). This study compared the thickness and density of the bone separating the upper basal turn of the cochlea (UBTC) and the labyrinthine segment of the facial nerve (LSFN) on preoperative computed tomography (CT) in patients with and without FNS after CI. SUBJECTS AND METHODS: Adult patients who underwent CI from January 2011 to February 2017 with preoperative CT at a tertiary referral hospital were considered for this retrospective case-control study. Patients were divided into two groups: with FNS (n=4) and without FNS (n=53). The density and thickness of the bone between the LSFN and UBTC were measured on preoperative CT. Charts were reviewed for other parameters. RESULTS: A statistically significant difference was seen in the thickness (p=0.007) but not in the density (p=0.125) of the bone between the UBTC and LSFN. Four patients had FNS at the mid-range electrode arrays, and one of them additionally had FNS at the basal arrays. CONCLUSIONS: Decreased thickness of the bone between the UBTC and LSFN can explain postoperative FNS, confirming the histologic and radiologic findings in previous studies, which indicated that the thickness of the temporal bone between the LSFN and UBTC is less in patients who experience FNS. While the density in this region was also less, it was not statistically significant.

A 3D benign paroxysmal positional vertigo model for study of otolith disease.

OBJECTIVE: To develop a three-dimensional study tool of the membranous labyrinth in order to study the pathophysiology, diagnostic workup and treatment of benign paroxysmal positional vertigo (BPPV). BPPV is the most common cause of peripheral vertigo. Its diagnosis and treatment depend on an understanding of the anatomy of the vestibular labyrinth and its position relative to the head. To date, many illustrations have been made to explain principals of diagnosis and treatment of BPPV, but few have been based on anatomical studies of the membranous labyrinth. METHODS: A cadaveric human membranous labyrinth was axially sectioned at 20 µm resolution, stained and segmented to create a high-resolution digital model. The model was cloned to create an enantiomeric pair of labyrinths. These were associated a 3D model of a human skull, segmented from MRI data, and were oriented according to established anatomic norms. Canal markers representing otoliths were created to mark canalith position during movement of the model within the 3D environment. RESULTS: The model allows visualization of true membranous labyrinth anatomy in both ears simultaneously. The dependent portion of each semicircular duct and of the utricle can easily be visualized in any head position. Moveable markers can mark the expected progress of otolith debris with changes in head position and images can be captured to document simulations. The model can be used to simulate pathology as well as diagnostic maneuvers and treatment procedures used for BPPV. The model has great potential as a teaching tool. CONCLUSION: A simple model based on human anatomy has been created to allow careful study of BPPV pathophysiology and treatment. Going forward, this tool could offer insights that may lead to more accurate diagnosis and treatment of BPPV.

Computed tomography appearance of normal nonossified thyroid cartilage: implication for tumor invasion diagnosis.

OBJECTIVE: The objective of this study was to determine the density and homogeneity of the nonossified thyroid cartilage (NOTC) on contrast-enhanced computed tomography (CT) providing preliminary information for future evaluation of cartilage invasion using dual-energy CT. METHODS: One hundred normal-larynx CT scans were evaluated for the density and homogeneity of NOTC. RESULTS: The density of the NOTC was homogeneous in all cases. Nonossified thyroid cartilage had higher mean density than contiguous muscle, but there was overlap. In 47 cases, a lucent area was observed at the junction of the ossified and NOTC but not within the NOTC itself. In 11 cases, ossification was observed in only 1 cortex of the thyroid cartilage. Cartilage at the anterior commissure was not ossified in 7 cases. CONCLUSIONS: Nonossified thyroid cartilage has a homogeneous appearance on contrast-enhanced CT scans, but showed some normal variations that could be mistakenly reported as tumor invasion.

Intracochlear inflammatory response to cochlear implant electrodes in humans.

HYPOTHESIS: This study evaluates the types and degrees of tissue response adjacent to the electrode of multichannel cochlear implants. BACKGROUND: Cochlear implant electrodes have been classified as biocompatible prostheses. Nevertheless, in some reports, electrode extrusion, chronic inflammation, and even soft failure of the implant system have been attributed to a tissue response to the electrode. METHODS: All celloidin-embedded temporal bones with multichannel cochlear implants from the temporal bone collection of the Massachusetts Eye and Ear Infirmary were included in the study. A total of 28 temporal bones from 21 subjects were identified and processed for histology. The severity of cellular response including eosinophil and lymphocytic infiltration, giant cell reaction, new bone formation, and fibrosis were scored on a scale from 0 to 3 at three 1-mm segments along the electrode: first 1 mm at the cochleostomy, last 1 mm from the tip of the electrode, and midway between these proximal and distal segments. The values were compared using the Wilcoxon test. RESULTS: A granulomatous reaction to the electrode was observed in 27 (96.4%) temporal bones. Eosinophil infiltration was observed in 7 (25%) temporal bones, suggesting an allergic reaction. The Inflammatory response to the electrode was significantly greater at the basal turn of cochlea close to the cochleostomy (p < 0.05) than distal to it. CONCLUSION: An inflammatory response is common after cochlear implantation, and it is more robust at the cochleostomy than distal to it, suggesting the role of trauma of insertion as a contributing factor.

Within-subject comparison of word recognition and spiral ganglion cell count in bilateral cochlear implant recipients.

OBJECTIVES: Although published reports have not demonstrated a positive correlation between the number of residual spiral ganglion cells (SGCs) and word recognition scores in patients with unilateral multichannel cochlear implants, this study was designed to retest this hypothesis in patients with bilateral multichannel cochlear implants. MATERIALS AND METHODS: From a pool of 133 temporal bones, all subjects with bilateral multichannel cochlear implants who were deafened bilaterally by the same etiology were studied. A total of 12 temporal bones from 6 subjects were identified and processed after death for histology. The SGCs were counted using standard techniques. The differences between left and right SGC counts as well as the differences in word recognition scores were calculated for each subject. Correlation analysis was performed between the differences of SGC counts and the differences of word recognition scores. RESULTS: Differences in SGC counts were highly correlated with the differences in word recognition scores (R = 0.934, p = 0.006). CONCLUSION: This study suggests higher residual SGCs predicted better performance after implantation in a given patient. The results also support attempts to identify factors which may promote survival of SGCs.

The pathologic basis of facial nerve stimulation in otosclerosis and multi-channel cochlear implantation.

HYPOTHESIS: Unintentional electrical stimulation of the facial nerve by cochlear implants occurs when advanced otosclerosis invades the endosteum of both the upper basal turn of the cochlea (UBTC) and the facial nerve canal (FNC) and all the bone between these 2 structures. BACKGROUND: A complication of cochlear implantation is facial nerve stimulation (FNS) known to be more common in otosclerosis. Otosclerotic involvement of the enchondral bone of the otic capsule results in areas of bone resorption, new bone formation, vascular proliferation, and a connective tissue stroma. This may reduce impedance, shunting current to the facial nerve. The cause of FNS has not been fully elucidated, and remarkable differences in FNS rates have been reported using different types of electrode arrays. METHODS: Thirteen implanted temporal bones from 11 patients with otosclerosis, 10 with straight, and 3 with perimodiolar electrodes, were histologically processed after death. The data were analyzed using Fisher's exact test. RESULTS: In the straight electrode group (n = 10), only those subjects with temporal bones showing involvement by otosclerosis of the UBTC and of FNC endosteum and the bone between these 2 structures (n = 4; 40%) showed FNS during life (p = 0.005), which was consistent with the location of problematic electrodes during life. None of the cases in the perimodiolar group had FNS even with endosteal involvement by otosclerosis. CONCLUSION: FNS is a common complication of cochlear implantation in patients with otosclerosis and occurs most commonly with straight electrode implants where the endosteum of both UBTC and FNC and the intervening bone are otosclerotic.

Histopathology of the inner ear in patients with xeroderma pigmentosum and neurologic degeneration.

INTRODUCTION: Xeroderma pigmentosum (XP) is a rare autosomal recessive disease caused by mutations resulting in defective repair of DNA damage. XP patients have a markedly increased risk of ultraviolet-induced neoplasms and premature aging of sun-exposed tissue. Approximately 25% of XP patients in the United States have neurologic abnormalities including progressive sensorineural hearing loss (SNHL). OBJECTIVE: To describe the temporal bone histopathology in 2 individuals with XP (XPA and XPD) with neurologic degeneration and to discuss the possible causes of deafness in these patients. METHODS: Temporal bones were removed at autopsy and studied using light microscopy. RESULTS: In the case with XPD, the organ of Corti was missing throughout the cochlea, whereas the case with XPA demonstrated scattered presence of sensory cells in the middle and apical turns. In both cases, there was moderate-to-severe patchy atrophy of the stria vascularis in all turns, and cochlear neurons were severely atrophied compared with age-matched controls, with loss of both peripheral dendrites and central axons. There was severe degeneration of Scarpa's ganglion in the case with XPA. CONCLUSION: Two cases of XP with neurologic degeneration are reported. The case with XPD demonstrated a more severe audiologic phenotype than XPA, although both had similar findings such as atrophy of the organ of Corti, stria vascularis, and spiral ganglia leading to severe or profound SNHL by the third decade of life. It is not clear if the neuronal degeneration in the inner ear was primary or secondary to loss of neuroepithelial cells.

Effect of monopolar and bipolar electric stimulation on survival and size of human spiral ganglion cells as studied by postmortem histopathology.

The spiral ganglion cell (SGC) is the target of electrical stimulation in cochlear implants. This study is designed to test the hypothesis that chronic electrical stimulation tends to preserve SGCs in implanted hearing-impaired ears. A total of 26 pairs of temporal bones were studied from 26 individuals who in life suffered bilateral profound hearing impairment that was symmetric (in degree of impairment and etiology) across ears and then underwent unilateral cochlear implantation. The subjects were divided in two groups by stimulus configuration: bipolar (n = 16) or monopolar (n = 10). The temporal bones were prepared for histological review by standard methods and two measures of SGC status were made by cochlear segment: count and maximal cross-sectional area. Within-subject comparison of the measures between the implanted-stimulated and the unimplanted ears showed: (1) for both stimulus configurations, the mean (across subjects and segments) of the count difference (implanted ear - unimplanted ear) was significantly less than zero; (2) the mean (across subject) count difference for cochlear segments I, II and III (segments with electrode contacts in the implanted ear) was significantly less negative than the mean difference for cochlear segment IV (no electrode in implanted ear) for bipolar but not for monopolar stimulation; (3) neither implantation-stimulation nor stimulus configuration significantly influenced the measures of maximum cross-sectional cell area. The SGC count results are consistent with the hypothesis that implantation results in a propensity across the whole cochlea for SGCs to degenerate and with chronic bipolar stimulation ameliorating this propensity in those cochlear segments with electrodes present.

[N,N'-Bis(2,6-dichloro-benzyl-idene)propane-1,3-diamine-κ(2)N,N']dibromidozinc.

In the title compound, [ZnBr(2)(C(17)H(14)Cl(4)N(2))], the Zn(II) ion is bonded to two bromide ions and two N atoms of the diimine ligand and displays a moderately distorted tetra-hedral coordination geometry. The Schiff base ligand acts as a chelating ligand and coordinates to the Zn(II) atom via two N atoms.

Interaural comparison of spiral ganglion cell counts in profound deafness.

OBJECTIVES: This study is designed to measure the degree to which spiral ganglion cell (SGC) survival in the left and right ears is similar in profoundly hearing-impaired human patients with symmetric (right/left) etiology and sensitivity. This is of interest because a small difference between ears would imply that one ear could be used as a control ear in temporal bone studies evaluating the impact on SGC survival of a medical intervention in the other ear. MATERIALS AND METHODS: Forty-two temporal bones from 21 individuals with bilaterally symmetric profound hearing impairment were studied. Both ears in each individual were impaired by the same etiology. Rosenthal's canal was reconstructed in two dimensions and segmental and total SGCs were counted. Correlation analysis and t-tests were used to compare segmental and total counts of left and right ears. Statistical power calculations illustrate how the results can be used to estimate the effect size (right/left difference in SGC count) that can be reliably identified as a function of sample size. RESULTS: Left counts (segmental and total) were significantly correlated with those in the right ears (p < 0.01) and the coefficients of determination for segments 1 to 4 and total count were respectively 0.64, 0.91, 0.93, 0.91 and 0.98. The hypothesis that mean segmental and total counts of right and left are the same could not be rejected by paired t-test. CONCLUSION: The variance in the between-ear difference across the temporal bones studied indicates that useful effect sizes can be reliably identified using subject numbers that are practical for temporal bone studies. For instance, there is 95% likelihood that an interaural difference in SGC count of approximately 1000 cells associated with a treatment/manipulation of one ear will be reliably detected in a bilaterally-symmetric profound hearing loss population of temporal bones from approximately 10 subjects.