The inferior colliculus (IC) is a major center of integration in the ascending as well as descending auditory pathways, where both excitatory and inhibitory amino acid neurotransmitters play a key role. When normal input to the auditory system is decreased, the balance between excitation and inhibition in the IC is disturbed. We examined global changes in gene expression in the rat IC 3 and 21 days following bilateral deafening, using Affymetrix GeneChip arrays and focused our analysis on changes in expression of neurotransmission-related genes. Over 1400 probe sets in the Affymetrix Rat Genome U34A Array were identified as genes that were differentially expressed. These genes encoded proteins previously reported to change as a consequence of deafness, such as calbindin, as well as proteins not previously reported to be modulated by deafness, such as clathrin. A subset of 19 differentially expressed genes was further examined using quantitative RT-PCR at 3, 21 and 90 days following deafness. These included several GABA, glycine, glutamate receptor and neuropeptide-related genes.Expression of genes for GABA-A receptor subunits b2, b3, and c2, plus ionotropic glutamate receptor subunits AMPA 2, AMPA 3, and kainate 2, increased at all three times. Expression of glycine receptor a1 initially declined and then later increased, while a2 increased sharply at 21 days. Glycine receptor a3 increased between 3 and 21 days, but decreased at 90 days. Of the neuropeptide-related genes tested with qRT-PCR, tyrosine hydroxylase decreased approximately 50% at all times tested. Serotonin receptor 2C increased at 3, 21, and 90 days. The 5B serotonin receptor decreased at 3 and 21 days and returned to normal by 90 days. Of the genes tested with qRT-PCR, only glycine receptor a2 and serotonin receptor 5B returned to normal levels of expression at 90 days. Changes in GABA receptor b3, GABA receptor c2, glutamate receptor 2/3, enkephalin, and tyrosine hydroxylase were further confirmed using immunocytochemistry.

After 2-week treatment period, bilastine 20 mg once daily was effective and tolerable in Japanese patients with PAR, and exhibited a rapid onset of action.

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There is increasing evidence of activity-related plasticity in auditory pathways. The present study examined the effects of decreased activity on immunolocalization of the inhibitory neurotransmitter glycine in the cochlear nucleus of the rat after bilateral cochlear ablation. Specifically, glycine-immunoreactive puncta adjacent to somatic profiles were compared in normal hearing animals and animals deafened for 14 days. The number of glycine-immunoreactive puncta surrounding somatic profiles of spherical and globular bushy cells, glycineimmunoreactive type I stellate multipolar cells, radiate neurons (type II stellate multipolar cells), and fusiform cells decreased significantly. In addition, the number of glycine immunopositive tuberculoventral (vertical or corn) cells in the deep layer of the dorsal cochlear nucleus also decreased significantly. These results suggest that decreased inhibition reported in cochlear nucleus after deafness may be due to decreases in glycine. Keywords hearing; auditory; ablation; neurotransmitterThere is increasing evidence of plasticity in the mature auditory system, with decreased activity from deafness or increased activity from noise overstimulation capable of inducing marked changes (recently reviewed by Syka, 2002). Activity-induced changes in the auditory brain stem range from changes in gene expression (e.g., Holt et al., 2005) to changes in neuronal response profiles (Francis and Manis, 2000). One of the most striking deafness-related changes in the auditory brain stem is a decrease in inhibition and an increase in spontaneous or evoked excitation, found in both the inferior colliculus (IC) and the cochlear nucleus (CN; Gerken, 1979;Willott and Lu, 1982;Bledsoe et al., 1995;Kaltenbach, 2000;Mossop et al., 2000;Salvi et al., 2000;Willott and Turner, 2000;© 2005 Wiley-Liss, Inc. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptShaddock Palombi et al., 2001), often leading to a change in the tonotopic map Nagase et al., 2000;Snyder et al., 2000). In the IC, the decreased inhibition seems associated with decreases in the inhibitory amino acid neurotransmitter γ-aminobutyric acid (GABA), with studies showing decreased GABA release (Bledsoe et al., 1995) and decreases in the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD) as well as GABA binding (Bauer et al., 2000;Milbrandt et al., 2000;Mossop et al., 2000;Caspary et al., 2002). In the CN, however, many studies suggest that glycine is the major inhibitory transmitter (Altschuler et al., 1986;Wu and Oertel, 1986;Caspary et al., 1987Caspary et al., , 1994Wenthold et al., 1987;Adams and Mugnaini, 1990;Bledsoe et al., 1990;Wickesberg and Oertel, 1990;Helfert et al., 1992;Kolston et al., 1992; Zook, 1992, 1999;Grothe and Sanes, 1993;Wickesberg et al., 1994;Wu and Kelly, 1994;Sato et al., 1995;Golding and Oertel, 1996;Juiz et al., 1996;Harty and Manis, 1998;Doucet et al., 1999;Godfrey et al., 2000;Zheng et al., 2000). Decreases in glycine-immunoreactive neurons and puncta (...

Thyroid-like low-grade nasopharyngeal papillary adenocarcinoma (LGNPPA) is extremely rare; only four cases have been reported. Herein are presented the case reports of two Japanese male patients with thyroid-like LGNPPA. Macroscopically, these tumors were pedunculated polypoid masses on the roof of the nasopharynx. Microscopically, they were characterized by papillary and glandular epithelial proliferation. The papillae were complex and tightly packed with hyalinized fibrovascular cores and lined by columnar and pseudostratified cells with intervening spindle-shaped cells. Both cell types had round to oval vesicular nuclei with tiny nucleoli and mildly eosinophilic cytoplasm. Mitotic figures were not evident and necrosis was not observed. Psammoma bodies were seen focally in one of the patients. Transition from normal surface epithelium to tumor cells was identified in both cases. On immunohistochemistry the tumor cells were positive for cytokeratin (CK)7, CK19, thyroid transcription factor-1 (TTF-1) and vimentin. They were negative for CK5/6, CK20, thyroglobulin, S-100 protein and CD15. In situ hybridization for EBV was negative. Nasopharyngeal tumors with similar morphological appearance should be examined for TTF-1 immunoreactivity, and patients should be clinically followed to determine the course of this unusual disease and the significance of TTF-1 expression.

Two-pore domain potassium channels ( ) play an important role in setting resting membrane potential by regulating background leakage of potassium ions, which in turn controls neuronal excitability. To determine whether these channels contribute to activity-dependent plasticity following deafness, we used quantitative real-time PCR to examine the expression of 10 subunits in the rat cochlear nucleus at 3 days, 3 weeks and 3 months after bilateral cochlear ablation. There was a large sustained decrease in the expression of TASK-5, a subunit that is predominantly expressed in auditory brain stem neurons, and in the TASK-1 subunit which is highly expressed in several types of cochlear nucleus neurons. TWIK-1 and THIK-2 also showed significant decreases in expression that were maintained across all time points. TWIK-2, TREK-1 and TREK-2 showed no significant change in expression at 3 days but showed large decreases at 3 weeks and 3 months following deafness. TRAAK and TASK-3 subunits showed significant decreases at 3 days and 3 weeks following deafness, but these differences were no longer significant at 3 months. Dramatic changes in expression of subunits suggest these channels may play a role in deafness-associated changes in the excitability of cochlear nucleus neurons.

Objectives/Hypothesis: Dupilumab, which blocks the shared receptor component for interleukin-4 and interleukin-13, reduced polyp size, sinus opacification, and symptom severity, and was well tolerated in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) in the SINUS-52 study (NCT02898454). We assessed dupilumab in patients enrolled at Japanese centers.Methods: Patients on a background of mometasone furoate nasal spray, received dupilumab 300 mg every 2 weeks (q2w) for 52 weeks (Arm A); dupilumab 300 mg q2w for 24 weeks, followed by every 4 weeks (q4w) for 28 weeks (Arm B); or placebo (Arm C). Co-primary endpoints were week 24 nasal polyp score (NPS), nasal congestion (NC) score, and sinus Lund-Mackay CT (LMK-CT) scores. Symptoms, sense of smell, health-related quality of life, and safety were assessed during the 52-week treatment period.Results: Of 49 patients enrolled in Japan, 45 completed the study. Week 24 least squares (LS) mean improvement versus placebo were as follows: NPS

Background:The human monoclonal antibody dupilumab blocks interleukin (IL)-4 andIL-13, key and central drivers of type 2 inflammation. Dupilumab, on background mometasone furoate nasal spray (MFNS), improved outcomes in the phase III SINUS-52 study (NCT02898454) in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP). This posthoc analysis of SINUS-52 examined whether eosinophilic status of CRSwNP was a predictor of dupilumab efficacy.Methods: Patients were randomized 1:1:1 to dupilumab 300 mg every 2 weeks (q2w) until week 52; dupilumab 300 mg q2w until Week 24, then 300 mg every 4 weeks until week 52; or placebo (MFNS) until week 52. Coprimary endpoints were change from baseline in nasal polyps score (NPS), nasal congestion (NC), and Lund-Mackay score assessed by CT (LMK-CT) at week 24. Patients (n = 438) were stratified by eosinophilic chronic rhinosinusitis (ECRS) status according to the Japanese Epidemiological Survey of Refractory Eosinophilic Rhinosinusitis algorithm.Results: Dupilumab significantly improved NPS, NC, and LMK-CT scores versus placebo at week 24 in all ECRS subgroups (p < 0.001), with improvements maintained or increased at week 52 (p < 0.001). There was no significant interaction between ECRS subgroup (non-/mild or moderate/severe) and dupilumab treatment effect for all endpoints at weeks 24 and 52 (p > 0.05), except LMK-CT at week 24 (p = 0.0275). Similar results were seen for the secondary endpoints. Dupilumab was well tolerated across all ECRS subgroups. Conclusion:Dupilumab produced consistent improvement in symptoms of severe CRSwNP irrespective of ECRS status. Therefore, blood eosinophil level may not be a suitable biomarker for dupilumab efficacy in CRSwNP.