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  • 1.
    Anniko, Matti
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Takumida, Masaya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Lidian, Adnan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Linder, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Nordang, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Stenqvist, Monika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Exotoxin in the middle ear: risk factor for hearing impairment2005Book (Other academic)
  • 2.
    Cheng, Junping
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Ekberg, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Engström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Nestor, Marika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Jensen, Holger J.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Radioimmunotherapy with astatine-211 using chimeric monoclonal antibody U36 in head and neck squamous cell carcinoma2007In: The Laryngoscope, ISSN 0023-852X, E-ISSN 1531-4995, Vol. 117, no 6, 1013-1018 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: In advanced head and neck squamous cell carcinoma (HNSCC), there is a need for an adjuvant treatment. We aim to evaluate the biodistribution and therapeutic effect of radioimmunotherapy using the alpha emitting, astatine-211-labeled, chimeric monoclonal antibody U36 (U36) on the HNSCC cell line UT-SCC7 in vivo. STUDY DESIGN: Xenograft tumors were inoculated subcutaneously in nude mice. Astatine-211-labeled U36 was injected intravenously with or without blocking of target with nonlabeled U36. METHODS: In the biodistribution experiments, radioactivity was measured in tumors and various organs at set time points. In the therapeutic experiments, two groups (with or without blocking) received therapy, and the tumor growth was compared with that of controls. In addition, one group received nonlabeled U36 only. RESULTS: The biodistribution experiments demonstrated that astatine-211-labeled U36 could target UT-SCC7 xenografts in nude mice. With time, uptake increased in tumors and decreased in normal organs. Nonlabeled U36 did not influence tumor growth. In the two therapy groups, 18 of 20 tumors responded to therapy by decreasing or stabilizing their volumes. Significant difference was seen between the treated groups and the controls (P < .05). CONCLUSION: The study illustrates the specific binding of astatine-211-labeled U36 to HNSCC and suggests radioimmunotherapy with the alpha emitting radionuclide to be a useful treatment modality.

  • 3.
    Cheng, Junping
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Engström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Ekberg, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Nestor, Marika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    The use of closo-dodecaborate-containing linker improves targeting of HNSCC xenografts with radioiodinated chimeric monoclonal antibody U362010In: Molecular Medicine Reports, ISSN 1791-2997, Vol. 3, no 1, 155-160 p.Article in journal (Refereed)
    Abstract [en]

    Radionuclide imaging of head and neck squamous cell carcinoma (HNSCC) using monoclonal antibodies (MAbs) has the potential to contribute to improved diagnosis and staging, thereby making more effective treatment possible. Chimeric monoclonal antibody U36 (cMAb U36), specific to CD44v6 antigen. is a candidate for the targeting of HNSCC. The aim of this study was to compare the influence of indirect iodination via closo-dodecaborate-based linker (DABI) with the influence of direct radioiodination on the biodistribution of the chimeric anti-CD44v6 antibody U36. The study was performed using nude mice bearing UT-SCC7 HNSCC xenografts using the paired-label method. The biodistribution of cMAb U36 labelled directly with I-131 and using DABI with I-125 was compared in the same animals. The influence of DABI on the tumour-to-organ ratio was evaluated. For both conjugates, radioactivity uptake in blood and organs decreased with time, except in tumours and the thyroid. DABI-labelled cMAb U36 was characterised by fast blood clearance and an elevated uptake in the liver and spleen. The use of DABI enabled a 1.5 to 2-fold improvement in the tumour-to-blood and tumour-to-organ ratios in comparison with direct radioiodination, with the exception of the liver and spleen. These results indicate that DABI is a promising linker for the coupling of radioiodine to HNSCC-targeting antibodies.

  • 4.
    Cheng, Junping
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Persson, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Siavaev, Igor
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Kairemo, Kalevi
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Targeting of a head and neck squamous cell carcinoma xenograft model using the chimeric monoclonal antibody U36 radioiodinated with a closo-dodecaborate-containing linker2004In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 124, no 9, 1078-85 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: High rates of local recurrence and distant metastases following surgery of high-grade head and neck squamous cell carcinoma (HNSCC) necessitate the use of adjuvant systemic treatment. Radioimmunotargeting might be a possible treatment modality in this case. The nuclear properties of 131I make it a suitable isotope for treatment of minimal residual disease and small metastases, but the conventional radioiodine label has poor cellular retention and its radiocatabolites accumulate in the thyroid. We attempted to overcome these problems by using closo-dodecaborate derivatives for attachment of radioiodine. MATERIAL AND METHODS: We investigated the feasibility of targeting an SCC25 HNSCC xenograft in vivo using a benzylisothiocyanate derivative of closo-dodecaborate (DABI) as radioiodine linker and the chimeric anti-CD44v6 antibody U36. 125I was used in biodistribution studies. RESULTS: The use of DABI enabled tumor targeting and decreased the radioactivity uptake of the thyroid. CONCLUSION: Tumor localization of DABI-labeled U36 was similar to its para-iodobenzoate-labeled counterpart, presumably due to the strong dependence of targeting efficiency on tumor size.

  • 5.
    Ekberg, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Nestor, Marika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Engström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Nordgren, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wester, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Carlsson, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Expression of EGFR, HER2, HER3, and HER4 in metastatic squamous cell carcinomas of the oral cavity and base of tongue2005In: International Journal of Oncology, ISSN 1019-6439, Vol. 26, no 5, 1177-85 p.Article in journal (Refereed)
    Abstract [en]

    The expressions of all four receptors in the epidermal growth factor receptor family, EGFR. HER2, HER3, and HER4 were evaluated by immunohistochemistry in 19 cases of metastatic squamous cell carcinoma of the oral cavity and base of tongue. EGFR had a similar and high expression in both primary tumours and the corresponding metastases, while the expression in normal epithelium was lower in most cases. HER2 was not expressed to the same extent as EGFR. However, when HER2 was well expressed, it was in most cases expressed to the same extent and intensity in the primary tumours, metastases, and normal epithelium. The expression of HER3 and HER4 varied and was mainly cytoplasmic in all cases studied. No overexpression of HER3 and HER4 in tumours was seen as compared to normal epithelium. In order to further investigate the distribution of HER3, two HER3 expressing cell lines originating from tongue cancer were analysed in vitro, using radiolabelled anti-HER3 antibodies directed to the extracellular domains of the receptor. The results indicated that HER3 was not present in measurable amounts in the cellular membrane. There is a need for improved diagnostics and therapy for the studied type of tumours, e.g. using radiolabelled antibodies or ligands, and EGFR seemed suitable as target since the expression was high, membrane associated and similar in the primary tumours and the corresponding metastases.

  • 6. Ferlito, Alfio
    et al.
    Arnold, Wolfgang
    Rinaldo, A.
    Nidermeyer, H. P.
    Bozorg Grayeli, A.
    Devaney, K.O.
    McKenna, M.J.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Pulec, J. L.
    McCabe, B. F.
    van den Broek, P.
    Shea, J. J.
    Viruses and otosclerosis:  chance association or true causal link?2003In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 123, no 6, 741-746 p.Article in journal (Other (popular science, discussion, etc.))
  • 7. Ferlito, Alfio
    et al.
    Devaney, K.O.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Arnold, Wolfgang
    Rinaldo, A.
    Otological Wegener's granulomatosis at the time of initial presentation:  a potential diagnostic dilemma2003In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 123, no 6, 675-677 p.Article in journal (Other (popular science, discussion, etc.))
  • 8. Ferlito, Alfio
    et al.
    Pellitteri, Phillip K.
    Robbins, K. Thomas
    Shaha, Ashok R.
    Kowalski, Luiz P.
    Silver, Carl E.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Rinaldo, Alessandra
    Medina, Jesus E.
    Bradley, Patrick J.
    Byers, Robert M.
    Management of the neck in cancer of the major salivary glands, thyroid and parathyroid glands2002In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 122, no 6, 673-678 p.Article in journal (Other (popular science, discussion, etc.))
  • 9. Gao, Chaobing
    et al.
    Li, Xiaohong
    Tong, Busheng
    Wu, Kaile
    Liu, Yehai
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Duan, Maoli
    Up-regulated expression of Dicer reveals poor prognosis in laryngeal squamous cell carcinoma2014In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 134, no 9, 959-963 p.Article in journal (Refereed)
    Abstract [en]

    Conclusions: Increased expression of Dicer may be a prognostic biomarker for patients with laryngeal squamous cell carcinoma (LSCC). Objectives: Recent studies have shown that many microRNAs (miRNAs) play an important role in the development and progression of human cancers. Dicer, one of the most important enzymes of the miRNA machinery, performs the final step of biogenesis of miRNAs. This study aimed to investigate the impact of Dicer expression on patient survival in human LSCC. Methods: We detected the expression of Dicer in larynx tissue specimens from 76 LSCC samples and 26 polyps by immunohistochemistry. The clinicopathological and prognostic significance of Dicer expression was investigated in LSCC. Results: Our data showed that the expression of Dicer was significantly higher in the LSCC than in the polyp tissue specimens. Moreover, the expression level of Dicer was significantly associated with the pTNM stage and tumor lymph node metastasis. Kaplan-Meier survival analyses revealed a strong association between tumor Dicer expression and the survival of the patients with LSCC.

  • 10.
    Hägg, Mary
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Influence of lip force on swallowing capacity in stroke patients and in healthy subjects2010In: Acta oto-laryngologica, ISSN 1651-2251, Vol. 130, no 11, 1204-1208 p.Article, review/survey (Refereed)
    Abstract [en]

    Conclusion: In spite of no clinical signs of facial paresis, a pathological lip force (LF) will strongly influence swallowing capacity (SC). Stroke patients with impaired SC suffer a subclinical facial paresis. The results support earlier findings that LF training can be used to treat dysphagia. Objectives: Lip muscle training with an oral screen can improve both LF and SC in stroke patients, irrespective of the presence or absence of facial palsy. The aim was therefore to study the influence of LF on SC. Methods: This prospective study included 22 stroke patients, aged 38-90 years, with dysphagia, 12 with initial unilateral facial paresis and 45 healthy subjects, aged 25-87 years. All were investigated with a Lip Force Meter (LF100), and with an SC test. Results: A significant correlation was found between LF/SC (p = 0.012) in stroke patients but not in healthy subjects. LF/SC was not age-related in stroke patients. LF was not age-dependent in healthy subjects, but SC decreased with increasing age (p < 0.0001). However, SC did not reach a pathological value and a regression analysis showed that 73% of the variation in SC is attributable to LF and age.

  • 11. Ishibashi, Takuya
    et al.
    Takumida, Masaya
    Akagi, Nana
    Hirakawa, Katsuhiro
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Changes in transient receptor potential vanilloid (TRPV) 1, 2, 3 and 4 expression in mouse inner ear following gentamicin challenge2009In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 129, no 2, 116-26 p.Article in journal (Refereed)
    Abstract [en]

    CONCLUSION: It is suggested that transient receptor potential vanilloid (TRPV)-1 and -2 may be of pathological significance for sensory cells and ganglions, while TRPV-3 and -4 may play an important part in neuroprotection of the inner ear. OBJECTIVE: Changes in the expression of TRPV-1, -2, -3, and -4 in gentamicin (GM)-treated mouse inner ear were studied. MATERIALS AND METHODS: CBA/J mice were used in this study. The localization of TRPV-1, -2, -3, and -4 in the inner ear of both untreated and GM-treated CBA/J animals (intratympanic injection of 5 mg GM) was investigated by immunohistochemistry. RESULTS: TRPV-1, -2, and -3 were co-expressed in the inner ear sensory and ganglion cells, while TRPV-4 was also expressed in the stria vascularis and vestibular dark cells. Following GM treatment, the intensity of immunofluorescent reaction to TRPV-1 and TRPV-2 increased, while that to TRPV-3 and TRPV-4 decreased.

  • 12.
    Kareem, Heewa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Sandström, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Elia, Ronny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Gedda, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Lundqvist, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Nestor, Marika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Blocking EGFR in the liver improves the tumor-to-liver uptake ratio of radiolabeled EGF2010In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 31, no 2, 79-87 p.Article in journal (Refereed)
    Abstract [en]

    Overexpression of epidermal growth factor receptor (EGFR) in several types of malignant tumors correlates with disease progression. EGFR could, therefore, be an excellent candidate for targeted radionuclide diagnostics. However, the high natural expression of EGFR in the liver may be problematic. The aim of this study was to improve the tumor-to-liver ratio of radiolabeled epidermal growth factor (EGF) by blocking its uptake by the liver with a nonradiolabeled EGFR-targeting molecule in tumorbearing mice. Intraperitoneally injected nonradiolabeled EGF was first evaluated as a blocking agent, preadministered at various time intervals before intravenous injection of 125I-labeled EGF. The anti-EGFR Affibody molecule (ZEGFR:955)2 was then assessed as a blocking agent of 111In-labeled EGF in a dual isotope study (50, 100, and 200μg, preadministered 30 or 60 min before 111In-EGF). The 30-min preadministration of nonradiolabeled EGF significantly decreased 125I-EGF uptake in the liver, whereas uptake in the tumor remained unchanged. Furthermore, preadministration of only 50μg (ZEGFR:955)2 as a blocking agent 30 min before the 111In-EGF decreased the uptake of 111In-EGF by the liver and increased its uptake by the tumor, thereby increasing the tumor-to-liver ratio sixfold. We conclude that the Affibody molecule (ZEGFR:955)2 shows promise as a blocking agent that could enhance the outcome of radionuclide-based EGFRexpressing tumor diagnostics and imaging.

  • 13. Katagiri, Yoshiaki
    et al.
    Takumida, Masaya
    Hirakawa, Katsuhiro
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Long-term administration of vasopressin can cause Meniere's disease in mice2014In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 134, no 10, 990-1004 p.Article in journal (Refereed)
    Abstract [en]

    Conclusion: A new murine model of Meniere's disease has been developed, based on long-term administration of vasopressin. Induction of vestibular dysfunction in the present animal model can cause additional stress, by reducing inner ear blood flow. Latanoprost, a selective agonist for the FP prostanoid receptor, may become a new remedy for Meniere's disease. Objective: The purpose of this study was to develop a more suitable animal model, with a closer resemblance to the pathophysiological process in Meniere's disease. Methods: Adult CBA/J or ICR mice were treated by subcutaneous injection of vasopressin for 5 days up to 8 weeks. Morphological analyses were performed of the cochlea, vestibular end organs and endolymphatic sac. The effect of latanoprost on the development of endolymphatic hydrops was also examined. Results: All experimental animals showed mild to moderate endolymphatic hydrops, increasing in severity as the vasopressin treatment was prolonged. Animals treated with vasopressin for 8 weeks showed severe endolymphatic hydrops with partial loss of outer hair cells and spiral ganglion cells. These animals also had a reversible vestibular dysfunction following intratympanic injection of epinephrine. Latanoprost inhibited the development of endolymphatic hydrops caused by vasopressin.

  • 14. León, Xavier
    et al.
    Ferlito, Alfio
    Myer, Charles M.
    Saffioti, Umberto
    Shaha, Ashok R.
    Bradley, Patrick J.
    Brandwein, Margaret S.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Elluru, Ravindhra G.
    Rinaldo, Alessandra
    Second primary tumours in head and neck cancer patients2002In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 122, no 7, 765-778 p.Article in journal (Other (popular science, discussion, etc.))
  • 15.
    Lidian, Adnan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Linder, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Nordang, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    BDNF as otoprotectant in toxin-induced hearing loss2013In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 133, no 1, 4-11 p.Article in journal (Refereed)
    Abstract [en]

    Conclusion: Brain-derived neurotrophic factor (BDNF) can prevent auditory brainstem response (ABR) threshold shift changes caused by Pseudomonas aeruginosa exotoxin A (PaExoA). Objective: Peptides of the neurotrophin family are known to prevent neuronal death during embryonic development by interacting with specific membrane receptors. The purpose of this study was to investigate whether a single dose of BDNF is an effective protectant against toxic effects of PaExoA-induced ABR threshold shifts. Materials and Methods: Eight groups of Sprague-Dawley rats were used. There were five control groups (n = 20) as follows. Group A (n = 4) received NaCl solution; group B (n = 3) received 4 mu g BDNF; group C (n = 4) received 1 mu g/20 mu l PaExoA; group D (n = 4) received 2 mu g/20 mu l PaExoA; groupE (n = 5) received 10 mu g/20 mu l PaExoA injected into the round window niche. Three treatment groups (n = 13) received a single dose of PaExoA and 4 mu g of BDNF simultaneously. Group 1 (n = 3) received 1 mu g/20 mu l PaExoA + 4 mu g of BDNF; group 2 (n = 5) received 2 mu g/20 mu l PaExoA + 4 mg BDNF; group 3 (n = 5) received 10 mu g/20 mu l PaExoA+ 4 mu g BDNF. ABR was used to measure efficacy by analyzing threshold shifts before and after injections. Results: A single dose of BDNF prevented changes in ABR thresholds following exposure to increasing concentrations of PaExoA injected into the middle ear.

  • 16.
    Lidian, Adnan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Stenkvist-Asplund, Monika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Linder, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Nordang, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Early hearing protection by brain-derived neurotrophic factor2013In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 133, no 1, 12-21 p.Article in journal (Refereed)
    Abstract [en]

    Conclusion: Brain-derived neurotrophic factor (BDNF) protects the inner ear from PaExoA (exotoxin A from Pseudomonas aeruginosa)-induced sensory neural hearing loss when administered 12 h after exotoxin, but not after 72 h. Objective: BDNF is a peptide in the neurotrophin family with protective effects against noise-induced hair cell loss and toxic inner ear damage following exposure to cisplatin. The exotoxin A (PaExoA) from P. aeruginosa, the most common microorganism in chronic suppurative otitis media, induces sensorineural hearing loss in rats. Previous study showed that, when given simultaneously with the exotoxin, BDNF protected the inner ear from damage. The aim of this study was to determine if BDNF has a protective effect when given 12-72 h after PaExoA. Materials and Methods : Five groups of Sprague-Dawley rats were used. The three control groups (n = 16) were as follows. Group 1 (n = 8) received 15 mu g/20 mu l PaExoA; group 2 (n = 5) received 20 mu g/20 mu l PaExoA; and group 3 (n = 3) received 25 mu g/20 mu l PaExoA injected into the round window niche. There were two treatment groups (n = 12): group A (n = 6) received 15 mu g/20 mu l PaExoA and 4 mu g/20 mu l BDNF 12 h later; group B (n = 6) received 15 mu g/20 mu l PaExoA and 4 mu g/20 mu l BDNF 72 h later. Brainstem response audiometry (ABR) was performed on day 0 (control), and repeated on days 7, 14, 21, 28, and 35 to analyze the thresholds shifts. Results: Exposure to 15 mu g/20 mu l PaExoA caused persistent and significant ABR impairment in controls when measured after 35 days. A single dose of BDNF given 12 h after PaExoA reduced hearing loss significantly, but when BDNF was given 72 h after PaExoA no protective effect was evident.

  • 17. Liu, Yehai
    et al.
    Li, Yifan
    Liu, Zhongmin
    Zhang, Liyong
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Duan, Maoli
    Prognostic significance of matrix metalloproteinase-20 overexpression in laryngeal squamous cell carcinoma2011In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 131, no 7, 769-773 p.Article in journal (Refereed)
    Abstract [en]

    Conclusion: Matrix metalloproteinase (MMP)-20 is overexpressed in laryngeal squamous cell carcinoma (LSCC) compared with the adjacent normal laryngeal epithelium and MMP-20 plays a role in lymph node metastasis. Overexpression of MMP-20 may be used as a significant prognostic factor for lymph node metastasis. All the findings indicate that MMP-20 may play a role in the initiation and progression of LSCC. Objective: The MMPs are a gene family of zinc-dependent endopeptidases that have been implicated in tumor invasion and metastasis, and MMP-20 is a new member of the MMP family. The purpose of this study was to investigate whether MMP-20 is overexpressed in human LSCC and, if so, the significance of its overexpression in relation to clinical parameters. Methods: We analyzed 33 cases of LSCC with RT-PCR and 73 cases of LSCC with immunohistochemistry compared with normal laryngeal epithelium. Results: We found that MMP-20 is overexpresssed in LSCC compared with the adjacent normal laryngeal epithelium.

  • 18. Maeta, Manabu
    et al.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Protective effect of brain-derived neurotrophic factor against the ototoxicity of Pseudomonas aeruginosa exotoxin A2003In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 123, no 1, 14-9 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The protective effect of brain-derived neurotrophic factor (BDNF) against the ototoxicity resulting from exposure of Pseudomonas aeruginosa exotoxin A (PaExoA) to the middle ear was analyzed. The combined effect of BDNF and N(G)-nitro-L-arginine methyl ester (L-NAME) was also investigated. MATERIAL AND METHODS: Six groups of albino rats were instilled through the tympanic membrane into the round window niche with the following solutions: saline; PaExoA; BDNF; L-NAME; PaExoA + BDNF; and PaExoA + BDNF + L-NAME. Frequency-specific (2-31.5 kHz) auditory brainstem responses were used to obtain the hearing thresholds before and 2, 5 and 15 days after instillation. RESULTS: PaExoA penetrated from the middle ear into the cochlea, causing initially mixed hearing loss, followed by persistent sensorineural hearing loss. This impairment was blocked by BDNF at 6, 8 and 10 kHz on Day 2 and at 8 kHz on Day 5. L-NAME given in combination with BDNF did not show any additional protective effect. There were no significant differences in the thickness of the round window membrane between control ears and those in each instillation group. CONCLUSION: Our results suggest that BDNF may protect against cochlear damage caused by PaExoA in the middle turns of the ear.

  • 19. Motohashi, Ray
    et al.
    Takumida, Masaya
    Shimizu, Akira
    Konomi, Ujimoto
    Fujita, Koji
    Hirakawa, Katsuhiro
    Suzuki, Mamoru
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Effects of age and sex on the expression of estrogen receptor alpha and beta in the mouse inner ear2010In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 130, no 2, 204-214 p.Article in journal (Refereed)
    Abstract [en]

    Conclusion: Estrogen receptor (ER) alpha and beta were expressed in the inner ear, and expression decreased with increasing age. ER alpha may alter cochlear and vestibular sensory transduction, and ER beta may have a neuroprotective function in the inner ear. Objective: Expression of ER alpha and ER beta in the mouse inner ear and its alterations with sex and aging were analyzed. Materials and methods: Male and female CBA/J mice aged 8 weeks and 24 months were used. The localization and the intensity of ER alpha and ER beta immunoreactivity in the inner ear of young and old mice of both sexes were investigated by immunohistochemistry. Results: ER alpha and ER beta were co-expressed in the inner ear, i.e. in the nuclei of stria vascularis, outer and inner hair cells, spiral ganglion cells and vestibular ganglion cells, vestibular dark cells and endolymphatic sac. Strial marginal cells, outer hair cells and type II ganglion cells showed less expression of ER alpha. No gender-or age-related difference was noted in the expression pattern of ER alpha or ER beta but fluorescence intensity of ER alpha was stronger in young female mice than in voting male mice. In contrast, ER beta revealed no significant difference. In the old mice, fluorescence intensities of both ER alpha and ER beta were significantly decreased in both sexes.

  • 20. Nakashimo, Yousuke
    et al.
    Takumida, Masaya
    Fukuiri, Takashi
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Hirakawa, Katsuhiro
    Expression of transient receptor potential channel vanilloid (TRPV) 1-4, melastin (TRPM) 5 and 8, and ankyrin (TRPA1) in the normal and methimazole-treated mouse olfactory epithelium2010In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 130, no 11, 1278-1286 p.Article in journal (Refereed)
    Abstract [en]

    Conclusion: It is suggested that TRPV1, 2, 3, and 4, TRPM5 and 8, and TRPA1 may play several roles in the olfactory epithelium (OE), contributing to olfactory chemosensation, olfactory adaptation, olfactory-trigeminal interaction, and OE fluid homeostasis. In patients with olfactory disturbance, TRPV1 and TRPM8 may be closely related to a high rate of recognition of curry and menthol odors, while TRPV2 may also play a crucial role in the regeneration of olfactory receptor neurons. Objective: Expression of TRPV1-4, TRPM5 and 8, and TRPA1 in the normal and methimazole-treated mouse OE was analyzed. Methods: The localization of TRPV1-4, TRPM5 and 8, and TRPA1 in the OE of normal and methimazole-treated CBA/J mice was investigated by immunohistochemistry. Results: Normal OE showed a positive immunofluorescent reaction to TRPV1-4, TRPM5 and 8, and TRPA1. In lamina propria, the nerve fibers displayed TRPV 1, 2, and 3, TRPM8 and TRPA1. In the pathological condition, the expression of TRPV3, TRPV4, TRPM5, and TRPA1 was markedly reduced and took a long time to recover. In contrast, expression of TRPM8 was scarcely affected, even in the pathological condition, while TRPV1 and TRPV2 showed early recovery following methimazole treatment.

  • 21.
    Nestor, Marika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Persson, Mikael
    Cheng, Junping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Tolmachev, Vladimir
    van Dongen, Guus
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Kairemo, Kalevi
    Biodistribution of the chimeric monoclonal antibody U36 radioiodinated with a closo-dodecaborate-containing linker: Comparison with other radioiodination methods2003In: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 14, no 4, 805-10 p.Article in journal (Refereed)
    Abstract [en]

    We have evaluated the applicability of the [(4-isothiocyanatobenzylammonio)undecahydro-closo-dodecaborate (1-)] (DABI) linker molecule for antibody radiohalogenation and compared it to radiohalogenation using the linker N-succinimidyl 4-iodobenzoate (PIB) and to direct radiohalogenation using Chloramine T. These studies were performed to assess the potential of DABI conjugates and to optimize the biological properties of halogen-labeled cMAb U36. The three conjugates were evaluated in vitro for their specificity and affinity and in vivo for their biodistribution patterns in normal mice at 1.5, 6, 24, and 96 h pi. Labeling efficiencies of direct CAT labeling, indirect PIB labeling, and indirect DABI labeling were 90-95%, 60%, and 68%, respectively. This resulted in a PIB:cMAb U36 molar ratio of 1.8-2.5 and a DABI:cMAb U36 molar ratio of 4.1. The in vitro data demonstrated specific binding for all conjugates and similar affinities with values around 1 x 10(8) M(-)(1). However, the in vivo data revealed accumulation of the radioiodine uptake in thyroid for the directly labeled conjugate, with a value 10 times higher than the indirectly labeled conjugates 96 h pi. Both the (125)I-PIB-cMAb U36 and (125)I-DABI-cMAb U36 conjugates yielded a low thyroid uptake with no accumulation, indicating different catabolites for these conjugates. This may favor the use of the indirectly labeled conjugates for future studies. Apart from the specific results obtained, these findings also demonstrate how the right linker molecule will provide additional opportunities to further improve the properties of an antibody-radionuclide conjugate.

  • 22.
    Nestor, Marika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Sundström, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Effect of cetuximab in combination with alpha-radioimmunotherapy in cultured squamous cell carcinomas2011In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 38, no 1, 103-112 p.Article in journal (Refereed)
    Abstract [en]

    Aim

    The monoclonal antibody cetuximab, targeting the epidermal growth factor receptor (EGFR), is a promising molecular targeting agent to be used in combination with radiation for anticancer therapy. In this study, effects of cetuximab in combination with alpha-emitting radioimmunotherapy (RIT) in a panel of cultured human squamous cell carcinomas (SCCs) were assessed.

    Methods

    SCC cell lines were characterized and treated with cetuximab in combination with anti-CD44v6 RIT using the astatinated chimeric monoclonal antibody U36 (211At-cMAb U36). Effects on 211At-cMAb U36 uptake, internalization and cell proliferation were then assessed in SCC cells.

    Results

    Cetuximab in combination with 211At-cMAb U36 mediated increased growth inhibition compared to RIT or cetuximab alone in two cell lines. However, cetuximab also mediated radioprotective effects compared to RIT alone in two cell lines. The radioprotective effects occurred in the cell lines in which cetuximab clearly inhibited cell growth during radiation exposure. Cetuximab treatment also influenced 211At-cMAb-U36 uptake and internalization, suggesting interactions between CD44v6 and EGFR.

    Conclusions

    Results from this study demonstrate the vast importance of further clarifying the mechanisms of cetuximab and radiation response, and the relationship between EGFR and suitable RIT targets. This is important not only in order to avoid potential radioprotective effects, but also in order to find and utilize potential synergistic effects from these combinations.

  • 23.
    Nordang, Leif
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Hearing loss in relation to round window membrane morphology in experimental chronic otitis media2001In: Journal for Oto-Rhino-Laryngology, ISSN 0301-1569, E-ISSN 1423-0275, Vol. 63, no 6, 333-340 p.Article in journal (Refereed)
    Abstract [en]

    The present study was performed to test the effect of single and repeated Pseudomonas aeruginosa exotoxin A (PaExoA) instillations in the middle ear of the rat. The hearing level was examined by the ABR technique, round window membrane (RWM) thickness was measured and morphology was studied by light microscopy. The results showed both reversible and permanent hearing loss (HL). In animals that received a single dose of PaExoA, the RWM thickness doubled initially and remained thickened during the observation period. When PaExoA was instilled on several occasions, RWM thickness doubled, before decreasing to near-control levels. This study confirms the toxicity of PaExoA and the partially reversible HL occurring after a single application of the toxin. The diminished effect of repeated toxin instillations--despite the decreasing thickness of the RWM--is discussed.

  • 24.
    Nordang, Leif
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Linder, Birgitta
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Morphological changes in round window membrane following topical hydrocortisone and dexamethasone treatment2003In: Otology and Neurotology, ISSN 1531-7129, E-ISSN 1537-4505, Vol. 24, no 2, 339-43 p.Article in journal (Refereed)
    Abstract [en]

    HYPOTHESIS: Are all glucocorticoids supposed to have the same effect on the round window membrane? BACKGROUND: Interest in glucocorticoids for topical treatment of inner ear diseases is increasing. The safety of such treatment should therefore be an important consideration before clinical use. METHODS: In this study the authors investigated the morphology of the round window membrane after topical instillation of dexamethasone or hydrocortisone into the middle ear. Twenty Sprague-Dawley rats were used. Five rats received 5 doses, and five rats 10 doses, of 1 microg (20 microl) dexamethasone in the right ear, and five others were given 5 doses, and five rats 10 doses, of 2% (20 microl) hydrocortisone solution, also in the right ear. Membrane morphology was studied in both light microscopy and transmission electron microscopy. The thickness of exposed membranes was measured and compared with that of control membranes. RESULTS: Thickening and microscopically signs of inflammation were observed in hydrocortisone-exposed membranes but not in dexamethasone-exposed membranes, which did not differ morphologically from those in control ears. CONCLUSION: Although hydrocortisone has anti-inflammatory properties, it seems to provoke inflammation in the round window membrane after topical instillation. Dexamethasone had no such effects, however.

  • 25.
    Nordang, Leif
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Oestreicher, E.
    Arnold, Wolfgang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Glutamate is the afferent neurotransmitter in the human cochlea2000In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 120, no 3, 359-362 p.Article in journal (Refereed)
    Abstract [en]

    Glutamate, the most important afferent neurotransmitter in the auditory system, is thought to be the afferent transmitter between the cochlear inner hair cells and afferent neurons, hitherto visualized only in the cochlea of animal species. It has been identified for the first time in sections from the human inner ear. L-glutamate, NMDAR2B and the enzyme glutamine synthetase were identified by using monoclonal antibodies. The distribution pattern of the transmitter L-glutamate in the human cochlea is similar to that observed in other mammals. L-glutamate was identified adjacent to outer and inner hair cells and in the spiral ganglion. Similar distributions were found for glutamine synthetase and the ionotropic NMDA receptor subunit NMDAR2. The identification of neurotransmitters and their receptors in the human cochlea has implications for the pharmacotherapy of inner ear diseases.

  • 26.
    Nordang, Leif
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Stenqvist, Monika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Passage through the round window membrane and inner ear function2004In: Audiological Medicine, ISSN 1651-386X, E-ISSN 1651-3835, Vol. 2, no 3, 165-168 p.Article in journal (Other (popular science, discussion, etc.))
    Abstract [en]

    The round window membrane (RWM) is an anatomical barrier between the aerated middle ear and the fluid (perilymph) compartments of the cochlea. Permeability of the RWM is regarded as an accident and not as a function of the membrane because of its anatomical characteristics, location and the high prevalence of middle ear disease. This paper provides a review of the effects on cochlear function following experimental exposure of bacterial toxins into the round window niche. Hearing loss is correlated with RWM morphology in experimental chronic otitis media. Following exposure to bacterial toxins there is a time‐dependent response of both the middle ear mucosal changes and the morphological alterations in the epithelium of the endolymphatic duct and sac. Otoprotectants, such as nitric oxide inhibitors, dexamethasone and neurotrophic factors, prevent toxic effects of Pseudomonas aeruginosa exotoxin A. In spite of a limited knowledge on the permeability of the RWM the application of therapeutic substances into the round window niche seems still the most suitable clinical approach to treat inner ear disorders.

  • 27. Rucci, Lucio
    et al.
    Ferlito, Alfio
    Bradley, Patrick J.
    Romagnoli, Paolo
    Rinaldo, Alessandra
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Can embryology influence clinicians concerning the "best therapy" for glottic cancer?2002In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 122, no 7, 796-8 p.Article in journal (Refereed)
  • 28. Shimizu, Akira
    et al.
    Takumida, Masaya
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Suzuki, M.
    Calpain and caspase inhibitors protect vestibular sensory cells from gentamicin ototoxicity2003In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 123, no 4, 459-465 p.Article in journal (Other (popular science, discussion, etc.))
    Abstract [en]

    OBJECTIVE: Apoptosis may play an important role in the mechanism of aminoglycoside ototoxicity. Caspases and calpains are regarded to be important factors in the regulation of cell death in the inner ear. We hypothesized that caspase or calpain inhibitors would protect hair cells from aminoglycoside ototoxicity. MATERIAL AND METHODS: In order to test this hypothesis we carried out a pilot study to determine if gentamicin (GM) would induce caspase and calpain immunolabeling in guinea pig hair cells Having confirmed this we carried out the main experiment using guinea pig vestibular organ culture to determine if caspase and calpain would protect the hair cells from GM ototoxicity. RESULTS: Immunoreactivity for caspase-3 and m-calpain was detected in the vestibular sensory cells and ganglia after GM treatment. Both caspase and calpain inhibitors protected hair cells against gentamicin ototoxicity. CONCLUSION: It is suggested that inhibition of apoptosis is essential in order to block aminoglycoside ototoxicity.

  • 29.
    Smit, Jeroen M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Acosta, Rafael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Zeebregts, Clark J.
    Liss, Anders G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Hartman, Ed H.
    Early reintervention of compromised free flaps improves success rate2007In: Microsurgery, ISSN 0738-1085, E-ISSN 1098-2752, Vol. 27, no 7, 612-616 p.Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION AND AIM: To develop a protocolized monitor schedule in microvascular free flap reconstruction, we investigated a possible correlation between the outcome and the interval between clamp release and start of revision. MATERIALS AND METHODS: All the charts of patients treated between 2000 and 2006 with a free flap were evaluated. The patients who underwent a flap revision were further analyzed. RESULTS: A total of 608 free flaps were evaluated; 69 of these flaps were revised. Most vascular complications took place within the first 24 h; the latest complication was observed 8 days after surgery. After 6 days post surgery, the number of revisions decreased considerably. With regard to the salvaged flaps the mean time to start the revision was 46.5 h (SD 39). With regard to the failed revisions, the mean time to start the revision was 82.0 h (SD 47). This difference proved significant (P = 0.006). CONCLUSION: Our data shows that the majority of anastomotic failures occur within the first 24 h. Thereafter, the frequency of failures decreases. We also found that the time between initial reconstruction and start of the salvage procedure influences the outcome of the revision negatively.

  • 30. Stenfors, Lars-Eric
    et al.
    Hellstrom, Sten
    Sade, Jacob
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Folkow, Lars
    Exotoses and cavernous venous formation in the external auditory canal of the hooded seal as functional physiological organ2000In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 120, no 8, 940-943 p.Article in journal (Refereed)
    Abstract [en]

    Exostoses of the external auditory canal (EAC) develop after protracted mechanical, chemical or thermal irritation in particular. This is a common disorder among aquatic sportsmen and has been considered unique to Man. We dissected and photodocumented the EACs of 5 newborn and 3 adult Hooded Seals (Cystophora cristata). Serial sections of the EACs were prepared for light microscopic evaluation after staining with haematoxylin-eosin or toluidine blue. All EACs exhibited a firm, broad-based. mountain peak-shaped exostosis on the floor of the meatus, lateral to the eardrum. In addition, the meatal skin of the bony EAC harboured large venous sinuses. The exostosis and venous sinuses of the seal EAC participate in the protection of the sensitive hearing apparatus, particularly the pars tensa portion of the drum, during divine.

  • 31.
    Stenkvist Asplund, Monika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Lidian, Adnan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Linder, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Takumida, Masaya
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Protective effect of edaravone against tobramycin-induced ototoxicity2009In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 129, no 1, 8-13 p.Article in journal (Refereed)
    Abstract [en]

    CONCLUSION: It is suggested that simultaneous treatment with the radical scavenger edaravone has an effective protective effect against tobramycin ototoxicity in rat. Even if the edaravone treatment is postponed for 7 days, it can still prevent hearing loss, but a 14 day delay cannot protect from ototoxicity. OBJECTIVES: With the aim of alleviating hearing loss caused by aminoglycoside ototoxicity, we performed a trial to assess the hearing protective efficacy of the radical scavenger edaravone. MATERIALS AND METHODS: In part one of the study, 21 male Sprague-Dawley albino rats were used; 2 rats served as controls for the safety of edaravone. Eight rats each received 10 subcutaneous injections (s.c.) of tobramycin (160 mg/kg b.w.) once daily and saline injection intraperitoneally for 2 weeks. Eleven rats were given 10 s.c. tobramycin injections simultaneously with an intraperitoneal injection of edaravone (3 mg/kg b.w.). In part two, tobramycin was injected in 13 rats (as above). Five of these received two edaravone injections 7 days later and four rats similarly 14 days later. Auditory brainstem response (ABR) was used to assess hearing. RESULTS: All rats treated only with tobramycin showed a deterioration of hearing. None of the rats given simultaneous treatment with tobramycin and edaravone demonstrated hearing loss. A 7 day delay in edaravone injection still prevented hearing loss, but a 14 day delay had only a temporary prophylactic effect.

  • 32.
    Stenqvist, Monika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Additive effects of toxin exposure and destruction of semicircular canal on cochlear function: an auditory brainstem response study in the rat2004In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 124, no 1, 13-8 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To ascertain whether the severity of toxin-related hearing loss and the interval between instillation of toxin and surgical trauma affect hearing recovery capacity following semicircular canal (SCC) surgery in the rat. MATERIAL AND METHODS: Twelve rats were injected with Pseudomonas aeruginosa exotoxin A (PaExoA). Auditory brainstem responses (ABRs) were measured 72 h and 3 weeks later. Depending on the severity of hearing loss, the rats were divided into two groups: those with moderate (Group A; n = 6) and severe (Group B; n = 6) hearing loss. Three rats from Group A were then operated on 3 weeks after toxin exposure and the other three 3 months after instillation of toxin. All Group B rats were operated on after 3 months. RESULTS: In Group A, post-surgical hearing loss recovered to a varying degree but rats in Group B showed little or no hearing recovery capacity. This difference was statistically significant. When the six rats with moderately toxin-affected ears were compared, statistical differences in recovery capacity between those operated on at 3 weeks and at 3 months were also detected. The group with a shorter interval showed significantly less hearing recovery of inner ear function following surgical trauma. CONCLUSION: When the toxin causes severe hearing damage there is no capacity for cochlear recovery following additional surgical trauma. When the rat inner ear is moderately affected by PaExoA, the interval between toxin exposure and SCC destruction plays a significant role in the ultimate hearing outcome. Cochlear recovery potential seems to be weakened in close temporal proximity to toxin exposure, but recovers with the passage of time.

  • 33.
    Stenqvist, Monika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Cochlear changes following destruction of semicircular canal in healthy and previously toxin-exposed rats: An electrophysiological and morphological investigation1997In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 117, no 5, 681-8 p.Article in journal (Refereed)
    Abstract [en]

    One group of Sprague-Dawley rats (group A, n = 6) was treated by instilling Pseudomonas aeruginosa exotoxin A (PaExoA), and another (group B, n = 6) treated similarly with Haemophilus influenzae type b endotoxin (HiBEndo). In group A a 20 dB hearing loss was observed, predominantly in the high-frequency region, which was reversible within 1 month. In group B no significant hearing impairment was noted. Between 1 and 6 months later, the lateral and posterior semicircular canals (SCCs) were ablated unilaterally. Control rats (group C, n = 8) were subjected to ablation only. All rats were cochleotomized contralaterally prior to labyrinthine surgery. Frequency-specific evoked potential testing at 2-31.5 kHz tone bursts was performed before and directly after surgery, 6, 24 and 48 hours and 1, 4 and 16 weeks postoperatively. After surgery in 18 rats, thresholds rose immediately, predominantly at 2, 4 and 6 kHz, followed by varying degrees of recovery. Greatest immediate postoperative hearing loss was observed in group A; no rat recovered completely and two rats showed severe permanent threshold elevation. All group B rats recovered completely, except one showing moderate threshold impairment. No permanent hearing loss was observed in group C. This study shows that destruction of SCCs in rats does not necessarily cause permanent hearing loss, even if the fluid spaces are not sealed off. However, previous exposure of the middle ear to PaExoA (but not HiBEndo) renders the cochlea more vulnerable and can result in persistent hearing loss.

  • 34. Takano, Sakurako
    et al.
    Iguchi, Hiroyoshi
    Sakamoto, Hiramori
    Yamane, Hideo
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Blockage pattern of longitudinal flow in Meniere's disease2013In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 133, no 7, 692-698 p.Article in journal (Refereed)
    Abstract [en]

    Conclusion: In the present study, classification of the patterns of 3D CT images of the ductus reuniens (reuniting duct) (RD), saccular duct (SD), and endolymphatic sinus (ES) gave more precise information for assessing the pathological condition of Meniere's disease (MD) than our previous study. Objective: This study attempted to provide more detailed information on MD by classifying the patterns of 3D CT images of the RD, SD, and ES in patients with MD. Methods: We examined the ears of 62 patients with definitely diagnosed unilateral MD based on the criteria of the Committee on Hearing and Equilibrium of the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) using 3D CT. The 3D CT images of bony grooves of RD, SD, and ES (BRD, BSD, and BES) were classified into patterns according to aspects of their patency. Results: BRD could be classified into six types by assessing their patency defined using the criteria in this study. In the ears on the affected side of patients with MD, the BRD, BSD, and BES lost continuity in 3D CT images along their bony routes and were significantly different from normal healthy ears (p<0.01). There were no significant differences among each stage of MD in the distributions of BRD and BES except for BSD.

  • 35. Takumida, Masaya
    et al.
    Akagi, Nana
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Effect of inner ear blood flow changes in Ménière's model mice2009In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 129, no 3, 244-53 p.Article in journal (Refereed)
    Abstract [en]

    CONCLUSIONS: The endolymphatic sac (ES) is important for inner ear fluid homeostasis. A dysfunctional ES can cause vertigo attacks following additional stress such as a sudden change in endolymphatic volume and/or pressure, or restricted inner ear blood flow. OBJECTIVE: The purpose of this study was to elucidate the mechanism of vertigo attacks in Ménière's disease. MATERIALS AND METHODS: Adult CBA/J mice were given an intratympanic injection of lipopolysaccharide and an intraperitoneal injection of aldosterone. These 'model' animals had epinephrine or sodium nitroprusside (SNP) instilled into the middle ear cavity. Cochleae, vestibules, and endolymphatic sacs were studied morphologically by light microscopy. RESULTS: The injection of epinephrine into the model animals reduced the endolymphatic hydrops in the cochlea, but also produced mild hydrops in the vestibule, which was never observed in untreated (control) animals. The ES did not react to epinephrine in the normal way. Injection of SNP did not cause any changes.

  • 36. Takumida, Masaya
    et al.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Expression of canonical transient receptor potential channel (TRPC) 1-7 in the mouse inner ear2009In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 129, no 12, 1351-1358 p.Article in journal (Refereed)
    Abstract [en]

    Conclusion: It is suggested that TRPCs play a functional role in the sensory cell transduction system in the inner ear. Objective: To study expression of TRPC 1-7 in the mouse inner ear. Materials and methods: The localization of TRPC 1-7 in the inner ear of CBA/J mice was investigated by immunohistochemistry. Results: TRPC immunoreactivity was observed generally in the inner ear, e. g. in the lateral wall of the cochlea, organ of Corti, spiral ganglion, vestibular end organs and vestibular ganglion. The immunofluorescent reaction to TRPC 3, 4, 5, and 7 in the stria vascularis was more intense than in the spiral prominence or spiral ligament. In the organ of Corti, TRPC immunoreactivity was observed in the outer hair cells (OHCs), inner hair cells (IHCs) and some supporting cells. TRPC 1-7 were all present in the ganglion cell body, TRPC 1 and 3 showing intense fluorescence, TRPC 2 and 7 moderate fluorescence and TRPC 4, 5 and 6 weak staining in ganglion fibres. In the vestibular end organs, vestibular hair cells (VHCs) showed immunoreactivity to all TRPCs. Nerve fibres in the subepithelial tissue were stained by TRPC 1, 3, 5, 6 and 7. Immunofluorescence to TRPC 1, 3, 4, 5, 6 and 7 was observed in the dark cells. In the vestibular ganglion, TRPC 1-7 were all present in the ganglion cell body. TRPC 1-4 and 7 elicited immunofluorescence in ganglion fibres.

  • 37. Takumida, Masaya
    et al.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Expression of transient receptor potential channel mucolipin (TRPML) and polycystine (TRPP) in the mouse inner ear2010In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 130, no 2, 196-203 p.Article in journal (Refereed)
    Abstract [en]

    Conclusions: TRPML3 may play distinct roles in the inner ear, such as stereociliar organization, sensory cell transduction, and inner ear fluid homeostasis, and TRPP3 may be important for fluid homeostasis in the inner ear. Objective: To study the expression of TRPML1-3 and TPPP2, 3, and 5 in the mouse inner ear. Materials and methods: Localization of TRPML1-3 and TRPP2, 3, and 5 in the inner ear of CBA/J mice was investigated by immunohistochemistry. Results: TRPML1-3 immunoreactivity was evident in the stria vascularis, spiral prominence, and spiral ligament. TRPML immunoreactivity was also observed in outer and inner hair cells, supporting cells, and spiral ganglion cells. The vestibular end organs, vestibular sensory cells, dark cells, and ganglion cells all showed immunoreactivity to TRPML. TRPP2 immunoreactivity was evident in the outer lining of the lateral wall of the cochlea, spiral ganglion cells, vestibular sensory cells, and ganglion cells. TRPP3 immunoreactivity was present in stria vascularis, spiral ganglion cells, vestibular sensory cells, dark cells, and ganglion cells. Faint TRPP5 immunoreactivity was observed in the spiral ganglion cells and vestibular ganglion cells.

  • 38. Takumida, Masaya
    et al.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Functional significance of nitric oxide in the inner ear2004In: In Vivo, ISSN 0258-851X, E-ISSN 1791-7549, Vol. 18, no 3, 345-350 p.Article in journal (Other (popular science, discussion, etc.))
    Abstract [en]

    Significant advances have been made in our understanding of the functional significance of nitric oxide (NO) in the inner ear. The localization of NO synthase and the nitric oxide production site has now been established by immunohistochemistry and the fluorescent indicator of NO. The functional significance of NO in the inner ear, especially as a neurotransmitter, is becoming increasingly clear. Mounting evidence suggests that excessive NO production may play an essential role in inner ear disorders as well. The production of an inducible type of NO synthase may be closely related to this phenomenon. Based on the mechanisms of inner ear disorders, new pharmacological strategies for preventing and/or treating inner ear disorders have also been suggested.

  • 39.
    Takumida, Masaya
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Heat shock protein 70 delays gentamicin-induced vestibular hair cell death2005In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 125, no 7, 23-28 p.Article in journal (Refereed)
    Abstract [en]

    In this study, geranylgeranylacetone (GGA) was shown to induce heat shock protein (HSP)70 in the vestibular end organs of the guinea pig and to alleviate gentamicin (GM) ototoxicity. This was accomplished without thermal preconditioning. In isolated guinea pig vestibular end organs we demonstrated possible prophylactic (preventive) effects of GGA on GM ototoxicity by actively inducing HSP70. When HSP70 was pre-incubated with GGA, its content in sensory cell cytoplasm and transitional dark cells was increased. Pre-incubation of vestibular end organs with GGA gave sensory cells partial protection from GM toxicity. These findings show that administration of GGA can protect vestibular sensory cells from GM ototoxicity and suggest that induction of HSP70 by GGA may be a useful adjunct for the treatment of vestibular disorders.

  • 40.
    Takumida, Masaya
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Isosorbide delays gentamicin-induced vestibular sensory cell death2005In: Journal for Oto-Rhino-Laryngology, ISSN 0301-1569, E-ISSN 1423-0275, Vol. 67, no 5, 276-81 p.Article in journal (Refereed)
    Abstract [en]

    The efficacy of isosorbide for protection from vestibular sensory cell damage was investigated. The effects of isosorbide on gentamicin-induced production of nitric oxide (NO) and reactive oxygen species (ROS) were studied by means of the fluorescence indicators 4,5-diaminofluorescein diacetate and dihydrotetramethylrosamine. The effect on gentamicin-induced vestibular sensory cell damage was examined by using an in vitro LIVE/DEAD system. Isosorbide inhibited the production of both NO and ROS. Isosorbide limited the vestibular sensory cell damage caused by gentamicin. It is, therefore, suggested that isosorbide may help to treat inner ear disorders.

  • 41. Takumida, Masaya
    et al.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Localization of endotoxin in inner ear following inoculation of endotoxin into the middle ear2004In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 124, no 7, 772-777 p.Article in journal (Other (popular science, discussion, etc.))
    Abstract [en]

    Sensorineural hearing loss is known to be a significant sequela of otitis media (OM). The pathophysiology of such hearing loss in OM is thought to be due to transmission of toxins and other bacterial products through the round window membrane, damaging the hair cells of the basal turn of the cochlea. Other routes, such as those involving the oval window, blood vessels and lymphatics, may also be involved. The purpose of this study was to elucidate the routes from the middle ear cavity to the inner ear and also the distribution pattern of endotoxin in the inner ear after injection of fluorescence-labelled endotoxin into the tympanic cavity and detection of fluorescence in the cochleae, vestibular end organs and facial nerves. This fluorescence was far more intense in the lower turns of the cochlea. These findings suggest that endotoxin can reach the inner ear by various routes, e.g. the round window, blood vessels or lymphatics, and/or interscala exchange, resulting in a disturbance not only of the cochlea but also of the vestibular end organs.

  • 42. Takumida, Masaya
    et al.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Localization of prostanoid receptors in the mouse inner ear2011In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 131, no 2, 142-148 p.Article in journal (Refereed)
    Abstract [en]

    Conclusion: EP4, EP2, and IP prostanoid receptors exert an otoprotective function and FP may be important for fluid homeostasis in the inner ear. Objective: To investigate the expression of prostanoid receptors in the normal mouse inner ear. Methods: CBA/J mice were used in this study. The localization of prostanoid receptors, i.e. DP, EP1, EP2, EP3, EP4, FP, IP, and TP, in the inner ear, i.e. the cochlea, vestibular end organs, endolymphatic sac, was studied by immunohistochemical techniques. Results: The EP4, IF, and FP prostanoid receptors were found to be abundantly distributed in many inner ear structures, i.e. stria vascularis, inner and outer hair cells, spiral ganglion cells, vestibular sensory and ganglion cells, and the endolymphatic sac. EP2 and EP3 are also localized in the inner ear whereas DP, EP1, and TP are only weakly expressed.

  • 43. Takumida, Masaya
    et al.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Nitric Oxide in the Inner Ear2002In: Current Opinion in Neurology, ISSN 1350-7540, E-ISSN 1473-6551, Vol. 15, no 1, 11-15 p.Article in journal (Other (popular science, discussion, etc.))
    Abstract [en]

    During the past year significant advances have been made in our understanding of the functional significance of nitric oxide (NO) in the inner ear. NO synthase and the NO production site have now been localized using immunohistochemistry and a new fluorescence indicator for NO. The functional significance of NO in the inner ear, in particular as a neurotransmitter, is becoming increasingly clear. Increasing evidence suggests that excessive NO production may play an essential role in inner ear disorders. The production of an inducible form of NO synthase may be closely related to this phenomenon. Based on the mechanisms of inner ear disorders, new pharmacological strategies for preventing or treating inner ear disorders have been suggested.

  • 44.
    Takumida, Masaya
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Protective effect of edaravone against the ototoxicity of Pseudomonas aeruginosa exotoxin A2006In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 126, no 1, 15-19 p.Article in journal (Refereed)
    Abstract [en]

    CONCLUSION: Our findings suggest that edaravone can protect against cochlear damage caused by Pseudomonas aeruginosa exotoxin A (PaExoA). OBJECTIVE: To analyze the protective effect of a free radical scavenger, edaravone, against the ototoxicity resulting from exposure of the middle ear to PaExoA. MATERIAL AND METHODS: In nine groups of albino rats the following solutions were instilled either via the tympanic membrane into the round window niche [intratympanically (i.t.)] or intravenously (i.v.): edaravone (i.v.); edaravone (i.t.); PaExoA (i.t.) + edaravone (i.t.; simultaneously); PaExoA (i.t.) + edaravone (i.t.; 1 h after); PaExoA (i.t.) + edaravone (i.t.; 24 h after); PaExoA (i.t.) + edaravone (i.v.; simultaneously); PaExoA (i.t.) + edaravone (i.v.; 1 h after); PaExoA (i.t.) + edaravone (i.v.; 24 h after); PaExoA (i.t.) + saline (i.v.). Frequency-specific (2-20 kHz) auditory brainstem responses were measured to determine hearing thresholds before and 2, 5 and 10 days after instillation. RESULTS: PaExoA had penetrated from the middle ear into the cochlea and caused hearing loss. This impairment was blocked by intratympanic injection of edaravone when given simultaneously or 1 h after the first instillation of PaExoA, or by intravenous injection of edaravone when given simultaneously. There were significant differences in protective effect between the intratympanic and intravenous routes.

  • 45.
    Takumida, Masaya
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Radical scavengers: a remedy for presbyacusis. A pilot study2005In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 125, no 12, 1290-5 p.Article in journal (Refereed)
    Abstract [en]

    CONCLUSION: The results of this study suggest that treatment with radical scavengers has the potential to become an effective new therapy for presbyacusis. OBJECTIVE: To assess the efficacy of treatment with the radical scavengers rebamipide and vitamin C for presbyacusis. MATERIAL AND METHODS: Rebamipide (300 mg/day) and vitamin C (600 mg/day) were taken orally for at least 8 weeks by 23 patients with presbyacusis. RESULTS: Hearing levels after treatment were significantly improved at 125, 250, 500 and 8000 Hz but unchanged at 1000, 2000 and 4000 Hz.

  • 46. Takumida, Masaya
    et al.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Radical scavengers for elderly patients with age-related hearing loss2009In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 129, no 1, 36-44 p.Article in journal (Refereed)
    Abstract [en]

    CONCLUSION: The results of this study suggest that treatment with radical scavengers has the potential to become an effective new therapy for age-related hearing loss. OBJECTIVE: To assess the efficacy of treatment with radical scavengers for age-related hearing loss. SUBJECTS AND METHODS: Rebamipide (300 mg/day), alpha-lipoic acid (60 mg/day), and vitamin C (600 mg/day) were given orally for at least 8 weeks to 46 elderly patients with age-related hearing loss. RESULTS: Hearing levels after treatment were significantly improved at all frequencies.

  • 47. Takumida, Masaya
    et al.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Simultaneous detection of both nitric oxide and reactive oxygen species in guinea pig vestibular sensory cells2002In: Journal for Oto-Rhino-Laryngology, ISSN 0301-1569, E-ISSN 1423-0275, Vol. 64, no 2, 143-147 p.Article in journal (Other (popular science, discussion, etc.))
    Abstract [en]

    Gentamicin-induced production of reactive oxygen species (ROS) and of nitric oxide (NO) in the vestibular end organs of the guinea pig was investigated by applying two new fluorescence indicators, 4,5-diaminofluorescein diacetate for direct detection of NO and dihydrotetramethylrosamine for ROS. The vestibular sensory cells produced both NO and ROS after exposure to gentamicin. A nonspecific inhibitor of NO synthase, L-NAME, inhibited the production of NO but did not appear to affect the production of ROS following exposure to gentamicin. In contrast, a radical scavenger, D-methionine, or the neurotrophin BDNF suppressed the production of ROS, in turn stimulating NO production. These findings could indicate that both NO and ROS play an important role in aminoglycoside ototoxicity.

  • 48. Takumida, Masaya
    et al.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Ohtani, M.
    Radical scavengers for Ménière´s disease after failure of conventional therapy: A pilot study2003In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 123, no 6, 697-703 p.Article in journal (Other (popular science, discussion, etc.))
    Abstract [en]

    OBJECTIVE: To perform a trial to assess the efficacy of radical scavengers, i.e. rebamipide, vitamin C and glutathione, for the treatment of Ménière's disease (MD). MATERIAL AND METHODS: Rebamipide (300 mg/day), vitamin C (600 mg/day) and/or glutathione (300 mg/day) were given orally for at least 8 weeks to 25 patients with poorly controlled MD. RESULTS: Of 22 patients, 21 showed marked improvement of vertigo; 12/27 ears showed improvement of hearing disorders; 17/27 ears showed improvement of tinnitus; and 18/25 patients showed improvement of disability. CONCLUSION: This study suggests that treatment using radical scavengers has the potential to become an effective new therapy for MD.

  • 49. Takumida, Masaya
    et al.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Popa, Raul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Zhang, De Ming
    Pharmacological models for innerear therapy with emphasis on nitric oxide2001In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 121, no 1, 16-20 p.Article in journal (Refereed)
    Abstract [en]

    Nitric oxide (NO)-mediated neurotoxicity may be an appropriate pathophysiological model with which to explain a variety of inner ear diseases characterized by acute or progressive hearing loss, tinnitus and vertigo. The localization of NO synthase (NOS) isoforms was examined in the inner ear of the pigmented guinea pig after intratympanic injection of 1 mg lipopolysaccharide (LPS) or 5 mg gentamicin (GM) using an immunohistochemical method, revealing the expression of NOS II in the inner ear. Production of NO in the isolated organ of Corti and utricle or in the isolated vestibular and cochlear hair cells after stimulation with L-arginine, glutamate, GM and LPS was investigated using the fluorescence indicator 4,5-diaminofluorescein diacetate. The fluorescence intensity of the sensory cells was augmented by stimulation with L-arginine, glutamate, GM and LPS. A significant increase in NO production was also noted in the LPS-treated animals. These findings imply that NO from constitutive NOS may mediate ototoxicity in the early phase, whereas NO from NOS II may contribute to the late phase of tissue damage in the inner ear. Based on this hypothesis, reduction of glutamatergic excitotoxicity and inhibition of NOS, scavenging superoxide and scavenging peroxynitrite are thought to attenuate NO-mediated otoneurotoxicity.

  • 50. Takumida, Masaya
    et al.
    Anniko, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Shimizu, Akira
    Watanabe, Hiroshi
    Neuroprotection of vestibular sensory cells from gentamicin ototoxicity obtained using nitric oxide synthase inhibitors, reactive oxygen species scavengers, brain-derived neurotrophic factors and calpain inhibitors2003In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 123, no 1, 8-13 p.Article in journal (Other (popular science, discussion, etc.))
    Abstract [en]

    OBJECTIVE: In order to devise a new treatment for inner ear disorders, the efficacy of a nitric oxide synthase inhibitor (L-N(G)-nitroarginine methylester [L-NAME]), a radical scavenger (D-methionine), a neurotrophin (brain-derived neurotrophic factor [BDNF]) and a calpain inhibitor (leupeptin) for protection from hair cell damage was investigated. MATERIAL AND METHODS: The effects of these drugs on gentamicin-induced production of nitric oxide (NO) and reactive oxygen species (ROS) were studied by means of the fluorescence indicators 4,5-diaminofluorescein diacetate and dihydrotetramethylrosamine. The effect on gentamicin-induced vestibular hair cell damage was examined by using an in vitro LIVE/DEAD system. RESULTS: L-NAME inhibited the production of NO, D-methionine and BDNF restricted the production of ROS and leupeptin inhibited neither NO nor ROS. All the drugs used limited the vestibular hair cell damage caused by gentamicin. The combinations L-NAME + BDNF, L-NAME + leupeptin and D-methionine + BDNF had a significantly stronger preventive effect on hair cell damage. CONCLUSION: It is suggested that combined treatment with a radical inhibitor and either a neurotrophin or calpain inhibitor may help to treat inner ear disorders more effectively.

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