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  • 1.
    Agrawal, Sumit
    et al.
    Western Univ, Dept Otolaryngol Head & Neck Surg, London, ON, Canada.
    Schart-Moren, Nadine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Liu, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Ladak, Hanif M.
    Western Univ, Dept Otolaryngol Head & Neck Surg, London, ON, Canada;Western Univ, Dept Med Biophys, London, ON, Canada;Western Univ, Dept Elect & Comp Engn, London, ON, Canada.
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Li, Hao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    The secondary spiral lamina and its relevance in cochlear implant surgery2018In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 123, no 1, p. 9-18Article in journal (Refereed)
    Abstract [en]

    Objective: We used synchrotron radiation phase contrast imaging (SR-PCI) to study the 3D microanatomy of the basilar membrane (BM) and its attachment to the spiral ligament (SL) (with a conceivable secondary spiral lamina [SSL] or secondary spiral plate) at the round window membrane (RWM) in the human cochlea. The conception of this complex anatomy may be essential for accomplishing structural preservation at cochlear implant surgery.

    Material and methods: Sixteen freshly fixed human temporal bones were used to reproduce the BM, SL, primary and secondary osseous spiral laminae (OSL), and RWM using volume-rendering software. Confocal microscopy immunohistochemistry (IHC) was performed to analyze the molecular constituents.

    Results: SR-PCI reproduced the soft tissues including the RWM, Reissner's membrane (RM), and the BM attachment to the lateral wall (LW) in three dimensions. A variable SR-PCI contrast enhancement was recognized in the caudal part of the SL facing the scala tympani (ST). It seemed to represent a SSL allied to the basilar crest (BC). The SSL extended along the postero-superior margin of the round window (RW) and immunohistochemically expressed type II collagen.

    Conclusions: Unlike in several mammalian species, the human SSL is restricted to the most basal portion of the cochlea around the RW. It anchors the BM and may influence its hydro-mechanical properties. It could also help to shield the BM from the RW. The microanatomy should be considered at cochlear implant surgery.

  • 2.
    Boström, Marja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Khalifa, Shaden
    Boström, Henrik
    Liu, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Friberg, Ulla
    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.
    Effects of Neurotrophic Factors on Growth and Glial Cell Alignment of Cultured Adult Spiral Ganglion Cells2009In: Audiology & neuro-otology, ISSN 1420-3030, E-ISSN 1421-9700, Vol. 15, no 3, p. 175-186Article in journal (Refereed)
    Abstract [en]

    Adult spiral ganglion cells were cultured in chorus to assess the influence of the neurotrophins brain-derived neurotrophic factor, neurotrophin 3 and glial cell line-derived neurotrophic factor (GDNF) on neurite growth and Schwann cell alignment. Over 1500 measurements were collected using each factor at 10 ng/ml and all three in combination. Evaluation was made with GDNF at concentrations of up to 100 ng/ml. Neurite dimensions were assessed at days 5, 7, 9 and 11 using a computer-based program (Axon Analyzer). GDNF had a strong effect on spiral ganglion cell growth almost attaining the level of all three factors in combination. GDNF increased glial cell alignment and nerve bundle formation. Results show the potential of GDNF to maintain and possibly restore auditory nerve integrity.

  • 3.
    Cai, Yixiao
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Edin, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Alexsson, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Gudjonsson, Olafur
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Liu, Wei
    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.
    Karlsson, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Li, Hao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Strategy towards independent electrical stimulation from cochlear implants: Guided auditory neuron growth on topographically modified nanocrystalline diamond2016In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 31, p. 211-220Article in journal (Refereed)
    Abstract [en]

    Cochlear implants (CI) have been used for several decades to treat patients with profound hearing loss. Nevertheless, results vary between individuals, and fine hearing is generally poor due to the lack of discrete neural stimulation from the individual receptor hair cells. A major problem is the deliverance of independent stimulation signals to individual auditory neurons. Fine hearing requires significantly more stimulation contacts with intimate neuron/electrode interphases from ordered axonal re-growth, something current CI technology cannot provide.

    Here, we demonstrate the potential application of micro-textured nanocrystalline diamond (NCD) surfaces on CI electrode arrays. Such textured NCD surfaces consist of micrometer-sized nail-head-shaped pillars (size 5 5 lm2) made with sequences of micro/nano-fabrication processes, including sputtering, photolithography and plasma etching.

    The results show that human and murine inner-ear ganglion neurites and, potentially, neural progenitor cells can attach to patterned NCD surfaces without an extracellular matrix coating. Microscopic methods revealed adhesion and neural growth, specifically along the nail-head-shaped NCD pillars in an ordered manner, rather than in non-textured areas. This pattern was established when the inter-NCD pillar distance varied between 4 and 9 lm.

    The findings demonstrate that regenerating auditory neurons show a strong affinity to the NCD pillars, and the technique could be used for neural guidance and the creation of new neural networks. Together with the NCD’s unique anti-bacterial and electrical properties, patterned NCD surfaces could provide designed neural/electrode interfaces to create independent electrical stimulation signals in CI electrode arrays for the neural population.

  • 4. Eckhard, A
    et al.
    Dos Santos, A
    Liu, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Bassiouni, M
    Arnold, H
    Gleiser, C
    Hirt, B
    Harteneck, C
    Müller, M
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Löwenheim, H
    Regulation of the perilymphatic-endolymphatic water shunt in the cochlea by membrane translocation of aquaporin-52015In: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 467, no 12, p. 2571-2588Article in journal (Refereed)
    Abstract [en]

    Volume homeostasis of the cochlear endolymph depends on radial and longitudinal endolymph movements (LEMs). LEMs measured in vivo have been exclusively recognized under physiologically challenging conditions, such as experimentally induced alterations of perilymph osmolarity or endolymph volume. The regulatory mechanisms that adjust LEMs to the physiological requirements of endolymph volume homeostasis remain unknown. Here, we describe the formation of an aquaporin (AQP)-based "water shunt" during the postnatal development of the mouse cochlea and its regulation by different triggers. The final complementary expression pattern of AQP5 (apical membrane) and AQP4 (basolateral membrane) in outer sulcus cells (OSCs) of the cochlear apex is acquired at the onset of hearing function (postnatal day (p)8-p12). In vitro, hyperosmolar perfusion of the perilymphatic fluid spaces or the administration of the muscarinic agonist pilocarpine in cochlear explants (p14) induced the translocation of AQP5 channel proteins into the apical membranes of OSCs. AQP5 membrane translocation was blocked by the muscarinic antagonist atropine. The muscarinic M3 acetylcholine (ACh) receptor (M3R) was identified in murine OSCs via mRNA expression, immunolabeling, and in vitro binding studies using an M3R-specific fluorescent ligand. Finally, the water shunt elements AQP4, AQP5, and M3R were also demonstrated in OSCs of the human cochlea. The regulation of the AQP4/AQP5 water shunt in OSCs of the cochlear apex provides a molecular basis for regulated endolymphatic volume homeostasis. Moreover, its dysregulation or disruption may have pathophysiologic implications for clinical conditions related to endolymphatic hydrops, such as Ménière's disease.

  • 5. Eckhard, Andreas
    et al.
    Gleiser, Corinna
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Arnold, Heinz
    Liu, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Mack, Andreas
    Müller, Marcus
    Löwenheim, Hubert
    Hirt, Bernhard
    Co-localisation of Kir4.1 and AQP4 in rat and human cochleae reveals a gap in water channel expression at the transduction sites of endocochlear K+ recycling routes2012In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 350, no 1, p. 27-43Article in journal (Refereed)
    Abstract [en]

    Sensory transduction in the cochlea depends on perilymphatic-endolymphatic potassium (K+) recycling. It has been suggested that the epithelial supporting cells (SCs) of the cochlear duct may form the intracellular K+ recycling pathway. Thus, they must be endowed with molecular mechanisms that facilitate K+ uptake and release, along with concomitant osmotically driven water movements. As yet, no molecules have been described that would allow for volume-equilibrated transepithelial K+ fluxes across the SCs. This study describes the subcellular co-localisation of the Kir4.1 K+ channel (Kir4.1) and the aquaporin-4 water channel (AQP4) in SCs, on the basis of immunohistochemical double-labelling experiments in rat and human cochleae. The results of this study reveal the expression of Kir4.1 in the basal or basolateral membranes of the SCs in the sensory domain of the organ of Corti that are adjacent to hair cells and in the non-sensory domains of the inner and outer sulci that abut large extracellular fluid spaces. The SCs of the inner sulcus (interdental cells, inner sulcus cells) and the outer sulcus (Hensen’s cells, outer sulcus cells) display the co-localisation of Kir4.1 and AQP4 expression. However, the SCs in the sensory domain of the organ of Corti reveal a gap in the expression of AQP4. The outer pillar cell is devoid of both Kir4.1 and AQP4. The subcellular co-localisation of Kir4.1 and AQP4 in the SCs of the cochlea described in this study resembles that of the astroglia of the central nervous system and the glial Mueller cells in the retina.

  • 6.
    Edin, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Liu, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Boström, Marja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Magnusson, Peetra U.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Differentiation of human neural progenitor cell-derived spiral ganglion-like neurons: a time-lapse video study2014In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 134, no 5, p. 441-447Article in journal (Refereed)
    Abstract [en]

    Conclusions: Human neural progenitor cells can differentiate into spiral ganglion-like cells when exposed to inner ear-associated growth factors. The phenotype bears resemblance to human sphere-derived neurons. Objective: To establish an in vitro model for the human auditory nerve to replace and complement in vivo animal experiments and ultimately human in vivo transplantation. Methods: Human neural progenitors were differentiated under conditions developed for in vitro survival of human primary spiral ganglion culture with media containing growth factors associated with inner ear development. Differentiation was documented using time-lapse video microscopy. Time-dependent marker expression was evaluated using immunocytochemistry with fluorescence and laser confocal microscopy. Results: Within 14 days of differentiation, neural progenitors adopted neural phenotype and expressed spiral ganglion-associated markers.

  • 7.
    Edin, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Liu, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Li, Hao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Atturo, Francesca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Magnusson, Peetra U
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    3-D gel culture and time-lapse video microscopy of the human vestibular nerve2014In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 134, no 12, p. 1211-1218Article in journal (Refereed)
    Abstract [en]

    UNLABELLED: Abstract Conclusions: Human inner ear neurons have an innate regenerative capacity and can be cultured in vitro in a 3-D gel. The culture technique is valuable for experimental investigations of human inner ear neuron signaling and regeneration.

    OBJECTIVES: To establish a new in vitro model to study human inner ear nerve signaling and regeneration.

    METHODS: Human superior vestibular ganglion (SVG) was harvested during translabyrinthine surgery for removal of vestibular schwannoma. After dissection tissue explants were embedded and cultured in a laminin-based 3-D matrix (Matrigel™). 3-D growth cone (GC) expansion was analyzed using time-lapse video microscopy (TLVM). Neural marker expression was appraised using immunocytochemistry with fluorescence and laser confocal microscopy.

    RESULTS: Tissue explants from adult human SVG could be cultured in 3-D in a gel, indicating an innate potential for regeneration. Cultured GCs were found to expand dynamically in the gel. Growth cone expansion and axonal Schwann cell alignment were documented using TLVM. Neurons were identified morphologically and through immunohistochemical staining.

  • 8. Guo, Rui
    et al.
    Zhang, HongLei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Chen, Wei
    Zhu, XiaoQuan
    Liu, Wei
    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.
    The inferior cochlear vein: surgical aspects in cochlear implantation2016In: European Archives of Oto-Rhino-Laryngology, ISSN 0937-4477, E-ISSN 1434-4726, Vol. 273, no 2, p. 355-361Article in journal (Refereed)
    Abstract [en]

    The patency of the inferior cochlear vein (ICV) may be challenged in cochlear implantation (CI) due to its location near the round window (RW). This may be essential to consider during selection of different trajectories for electrode insertion aiming at preserving residual hearing. Venous blood from the human cochlea is drained through the ICV. The vein also drains blood from the modiolus containing the spiral ganglion neurons. Surgical interference with this vein could cause neural damage influencing CI outcome. We analyzed the topographical relationship between the RW and ICV bony channel and cochlear aqueduct (CA) from a surgical standpoint. Archival human temporal bones were further microdissected to visualize the CA and its accessory canals (AC1 and AC2). This was combined with examinations of plastic and silicone molds of the human labyrinth. Metric analyses were made using photo stereomicroscopy documenting the proximal portion of the AC1, the internal aperture of the CA and the RW. The mean distance between the AC1 and the anterior rim of the RW was 0.81 mm in bone specimens and 0.67 mm assessed in corrosion casts. The AC1 runs from the floor of the scala tympani through the otic capsule passing parallel to the CA to the posterior cranial fossa. The mean distance between the CA and AC1 canal was 0.31 and 0.25 mm, respectively.

  • 9.
    Hayashi, Hisamitsu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery. Gifu Univ, Grad Sch Med, Dept Otolaryngol, 1-1 Yanagido, Gifu 5011194, Japan.
    Edin, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Li, Hao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Liu, Wei
    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.
    The effect of pulsed electric fields on the electrotactic migration of human neural progenitor cells through the involvement of intracellular calcium signaling2016In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1652, p. 195-203Article in journal (Refereed)
    Abstract [en]

    Endogenous electric fields (EFs) are required for the physiological control of the central nervous system development. Application of the direct current EFs to neural stem cells has been studied for the possibility of stem cell transplantation as one of the therapies for brain injury. EFs generated within the nervous system are often associated with action potentials and synaptic activity, apparently resulting in a pulsed current in nature. The aim of this study is to investigate the effect of pulsed EF, which can reduce the cytotoxicity, on the migration of human neural progenitor cells (hNPCs). We applied the mono-directional pulsed EF with a strength of 250mV/mm to hNPCs for 6h. The migration distance of the hNPCs exposed to pulsed EF was significantly greater compared with the control not exposed to the EF. Pulsed EFs, however, had less of an effect on the migration of the differentiated hNPCs. There was no significant change in the survival of hNPCs after exposure to the pulsed EF. To investigate the role of Ca(2+) signaling in electrotactic migration of hNPCs, pharmacological inhibition of Ca(2+) channels in the EF-exposed cells revealed that the electrotactic migration of hNPCs exposed to Ca(2+) channel blockers was significantly lower compared to the control group. The findings suggest that the pulsed EF induced migration of hNPCs is partly influenced by intracellular Ca(2+) signaling.

  • 10.
    Hayashi, Hisamitsu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery. Gifu Univ, Grad Sch Med, Dept Otolaryngol, Gifu, Gifu 5011194, Japan.
    Schrott-Fischer, Annelies
    Med Univ Innsbruck, Dept Otolaryngol, A-6020 Innsbruck, Austria.
    Glueckert, Rudolf
    Med Univ Innsbruck, Dept Otolaryngol, A-6020 Innsbruck, Austria.
    Liu, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Salvenmoser, Willi
    Univ Innsbruck, Inst Zool, A-6020 Innsbruck, Austria.
    Santi, Peter
    Univ Minnesota, Dept Otolaryngol, Minneapolis, MN 55455 USA.
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Molecular organization and fine structure of the human tectorial membrane: is it replenished?2015In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 362, no 3, p. 513-527Article in journal (Refereed)
    Abstract [en]

    Auditory sensitivity and frequency resolution depend on the physical properties of the basilar membrane in combination with outer hair cell-based amplification in the cochlea. The physiological role of the tectorial membrane (TM) in hair cell transduction has been controversial for decades. New insights into the TM structure and function have been gained from studies of targeted gene disruption. Several missense mutations in genes regulating the human TM structure have been described with phenotypic expressions. Here, we portray the remarkable gradient structure and molecular organization of the human TM. Ultrastructural analysis and confocal immunohistochemistry were performed in freshly fixed human cochleae obtained during surgery. Based on these findings and recent literature, we discuss the role of human TMs in hair cell activation. Moreover, the outcome proposes that the α-tectorin-positive amorphous layer of the human TM is replenished and partly undergoes regeneration during life.

  • 11.
    Hellberg, Victoria
    et al.
    Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..
    Gahm, Caroline
    Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..
    Ehrsson, Hans
    Karolinska Univ Hosp, Karolinska Pharm, Stockholm, Sweden..
    Liu, Wei
    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.
    Laurell, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    In Response to Immunohistochemical Localization of OCT2 in the Cochlea of Various Species2016In: The Laryngoscope, ISSN 0023-852X, E-ISSN 1531-4995, Vol. 126, no 6, p. E232-E232Article in journal (Refereed)
  • 12.
    Hellberg, Victoria
    et al.
    Karolinska Univ Hosp, Dept Clin Sci Intervent & Technol, S-14186 Stockholm, Sweden..
    Gahm, Caroline
    Karolinska Univ Hosp, Dept Clin Sci Intervent & Technol, S-14186 Stockholm, Sweden..
    Liu, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Ehrsson, Hans
    Karolinska Univ Hosp, Karolinska Pharm, S-14186 Stockholm, Sweden..
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Laurell, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Immunohistochemical localization of OCT2 in the cochlea of various species2015In: The Laryngoscope, ISSN 0023-852X, E-ISSN 1531-4995, Vol. 125, no 9, p. E320-E325Article in journal (Refereed)
    Abstract [en]

    ObjectiveTo locate the organic cation transporter 2 (OCT2) in the cochlea of three different species and to modulate the ototoxicity of cisplatin in the guinea pig by pretreatment with phenformin, having a known affinity for OCT2. Study DesignImmunohistochemical and in vivo study. MethodsSections from the auditory end organs were subjected to immunohistochemical staining in order to identify OCT2 in cochlea from untreated rats, guinea pigs, and a pig. In the in vivo study, guinea pigs were given phenformin intravenously 30 minutes before cisplatin administration. Electrophysiological hearing thresholds were determined, and hair cells loss was assessed 96 hours later. The total amount of platinum in cochlear tissue was determined using mass spectrometry. ResultsOrganic cation transporter 2 was found in the supporting cells and in type I spiral ganglion cells in the cochlea of all species studied. Pretreatment with phenformin did not reduce the ototoxic side effect of cisplatin. Furthermore, the concentration of platinum in the cochlea was not affected by phenformin. ConclusionsThe localization of OCT2 in the supporting cells and type I spiral ganglion cells suggests that this transport protein is not primarily involved in cisplatin uptake from the systemic circulation. We hypothesize that OCT2 transport intensifies cisplatin ototoxicity via transport mechanisms in alternate compartments of the cochlea. Level of EvidenceN/A. Laryngoscope, 125:E320-E325, 2015

  • 13. Hirt, B.
    et al.
    Penkova, Z. H.
    Eckhard, A.
    Liu, Wei
    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.
    Müller, M.
    Löwenheim, H.
    The subcellular distribution of aquaporin 5 in the cochlea reveals a water shunt at the perilymph-endolymph barrier2010In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 168, no 4, p. 957-970Article in journal (Refereed)
    Abstract [en]

    Aquaporins are membrane water channel proteins that have also been identified in the cochlea. Auditory function critically depends on the homeostasis of the cochlear fluids perilymph and endolymph. In particular, the ion and water regulation of the endolymph is essential for sensory transduction. Within the cochlear duct the lateral wall epithelium has been proposed to secrete endolymph by an aquaporin-mediated flow of water across its epithelial tight junction barrier. This study identifies interspecies differences in the cellular distribution of aquaporin 5 (AQP5) in the cochlear lateral wall of mice, rats, gerbils and guinea pigs. In addition the cellular expression pattern of AQP5 is described in the human cochlea. Developmental changes in rats demonstrate longitudinal and radial gradients along the cochlear duct. During early postnatal development a pancochlear expression is detected. However a regression to the apical quadrant and limitation to outer sulcus cells (OSCs) is observed in the adult. This developmental loss of AQP5 expression in the basal cochlear segments coincides with a morphological loss of contact between OSCs and the endolymph. At the subcellular level, AQP5 exhibits polarized expression in the apical plasma membrane of the OSCs. Complementary, the basolateral membrane in the root processes of the OSCs exhibits AQP4 expression. This differential localization of AQP5 and AQP4 in the apical and basolateral membranes of the same epithelial cell type suggests a direct aquaporin-mediated transcellular water shunt between the perilymph and endolymph in the OSCs of the cochlear lateral wall. In the human cochlea these findings may have pathophysiological implications attributed to a dysfunctional water regulation by AQP5 such as endolymphatic hydrops (i.e. in Meniere's disease) or sensorineural hearing loss (i.e. in Sjögren's syndrome).

  • 14.
    Liu, Wei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Atturo, Francesca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Aldaya, Robair
    Santi, Peter
    Cureoglu, Sebahattin
    Obwegeser, Sabrina
    Glueckert, Rudolf
    Pfaller, Kristian
    Schrott-Fischer, Annelies
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Macromolecular organization and fine structure of the human basilar membrane - RELEVANCE for cochlear implantation2015In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 360, no 2, p. 245-262Article in journal (Refereed)
    Abstract [en]

    Introduction Cochlear micromechanics and frequency tuning depend on the macromolecular organization of the basilar membrane (BM), which is still unclear in man. Novel techniques in cochlear implantation (CI) motivate further analyses of the BM. Materials and methods Normal cochleae from patients undergoing removal of life-threatening petro-clival meningioma and an autopsy specimen from a normal human were used. Laser-confocal microscopy, high resolution scanning (SEM) and transmission electronmicroscopy (TEM) were carried out in combination. In addition, one human temporal bone was decellularized and investigated by SEM. Results The human BM consisted in four separate layers: (1) epithelial basement membrane positive for laminin-beta 2 andcollagen IV, (2) BM Bproper boolean AND composed of radial fibers expressing collagen II and XI, (3) layer of collagen IV and (4) tympanic covering layer (TCL) expressing collagen IV, fibronectin and integrin. BM thickness varied both radially and longitudinally (mean 0.55-1.16 mu m). BM was thinnest near the OHC region and laterally. Conclusions There are several important similarities and differences between the morphology of the BM in humans and animals. Unlike in animals, it does not contain a distinct pars tecta (arcuate) and pectinata. Its width increases and thickness decreases as it travels apically in the cochlea. Findings show that the human BM is thinnest and probably most vibration-sensitive at the outer pillar feet/Deiter cells at the OHCs. The inner pillar and IHCs seem situated on a fairly rigid part of the BM. The gradient design of the BM suggests that its vulnerability increases apical wards when performing hearing preservation CI surgery.

  • 15.
    Liu, Wei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Boström, Marja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Kinnefors, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Linthicum, Fred
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Expression of myelin basic protein in the human auditory nerve: an immunohistochemical and comparative study2012In: Auris, nasus, larynx, ISSN 0385-8146, E-ISSN 1879-1476, Vol. 39, no 1, p. 18-24Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The aim of this study is to analyse the expression and distribution of myelin basic protein (MBP or Myelin A1 protein) in the human spiral ganglion and auditory nerve.

    MATERIALS AND METHODS: Cryostat sections were made from freshly fixed human cochlear specimens removed at surgery in patients with life-threatening petro-clival meningiomas compressing the brain stem. The sections were subjected to immunohistochemistry using antibodies against MBP, S-100 and Tubulin. The immunoreaction was documented using laser confocal microscopy.

    RESULTS: Type I spiral ganglion nerve somata (SGN) were surrounded by so-called "satellite glial cells" (SGCs) that lacked expression of MBP consistent with earlier light and electron microscopic findings indicating that these cells are non-myelinating. S-100 labeling showed that the SGCs form a continuous network in the apical region.

    CONCLUSIONS: The pattern of myelination in human spiral ganglion is different from that in other species' spiral ganglion. The striking differences in myelin outline should be investigated further in combination with its influence on signal coding and preservation properties in man.

  • 16.
    Liu, Wei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Boström, Marja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Kinnefors, Anders
    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.
    Unique expression of connexins in the human cochlea2009In: Hearing Research, ISSN 0378-5955, E-ISSN 1878-5891, Vol. 250, no 1-2, p. 55-62Article in journal (Refereed)
    Abstract [en]

    Mutations in the genes GJB2 and GJB6, which encode the proteins Connexin 26 (Cx26) and Connexin 30 (Cx30), have been linked to nonsyndromic prelingual deafness in humans. These proteins may form so-called gap junctions (GJ) or transcellular pathways between cells. The pathogenesis of deafness due to GJ Connexin mutations remains unclear partly because examinations performed in the human ear are infrequent. Here we analysed the expression and distribution of Cx26 and Cx30 in five fresh normal human cochleae taken out at occasional surgery. Immunohistochemistry including confocal microscopy in decalcified specimen showed that these proteins are widely expressed in the human cochlea. In the lateral wall there was strong antibody co-labeling for Cx26 and Cx30 that support the existence of channels comprising heteromeric Cx26/Cx30 connexons. In the organ of Corti there were some co-labeling in the supporting cell area including mainly the Claudius cells and Deiter cells of these two Cxs, apart from isolated Cx26 and Cx30 labeling in the same area, suggestive of both homomeric/homotypic pattern and hybrid pattern (heteromeric or heterotypic). Cx30, Cx26 and Connexin 36 (Cx36) immunoreactivity was also associated with spiral ganglion type I neurons, the latter being a gap junction protein specific to neurons. Gap-junction-based electrical synapses are not known to occur in mammalian auditory system other than in bats where they may play a role for fast electrical nerve transmission useful for echolocation. Their potential role in the processing of human auditory nerve signaling as well as non-GJ roles of the connexins in human cochlea is discussed.

  • 17.
    Liu, Wei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Boström, Marja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic 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.
    Expression of peripherin in the pig spiral ganglion: aspects of nerve injury and regeneration2009In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 129, no 6, p. 608-14Article in journal (Refereed)
    Abstract [en]

    CONCLUSION: Peripherin protein may be important not only for developing neurons but also for the maintenance and regeneration of axonal processes in the mature cochlea. More knowledge about its expression and function could improve our understanding with reference to axonal regrowth and nerve restoration in the damaged cochlea. OBJECTIVE: To investigate the existence of peripherin protein in adult pig spiral ganglion and cultured spiral ganglion neurons of the guinea pig. MATERIALS AND METHODS: Immunohistochemistry with anti-peripherin antibodies was performed on sections of adult pig spiral ganglion and guinea pig spiral ganglion cell (SGC) culture. RESULTS: In pig auditory neurons, both type I and type II SGCs showed expression of the protein peripherin. These cells were not preferentially located near the intraganglionic spiral bundle (IGSB). The IGSB consisted of thin calibre fibres showing intense peripherin and thicker fibres that were TUJ-1 positive. Only a few fibres within the IGSB co-expressed both peripherin and TUJ-1. Cultured guinea pig neurons displayed a rich expression of peripherin, including the nuclei. This protein was expressed in regions such as the perikaryon and axons but there was also a segmental expression of peripherin in some regions. Peripherin was more expressed in areas of axon branching and in the centre of the active growth cones and lammelipodia.

  • 18.
    Liu, Wei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Edin, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Atturo, Francesca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Rieger, G.
    Lowenheim, H.
    Senn, P.
    Blumer, M.
    Schrott-Fischer, A.
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Glueckert, R.
    The Pre- and Post-Somatic Segments of the Human Type I Spiral Ganglion Neurons - Structural and Functional Considerations Related to Cochlear Implantation2015In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 284, p. 470-482Article in journal (Refereed)
    Abstract [en]

    Human auditory nerve afferents consist of two separate systems; one is represented by the large type I cells innervating the inner hair cells and the other one by the small type II cells innervating the outer hair cells. Type I spiral ganglion neurons (SGNs) constitute 96% of the afferent nerve population and, in contrast to other mammals, their soma and pre- and post-somatic segments are unmyelinated. Type II nerve soma and fibers are unmyelinated. Histopathology and clinical experience imply that human SGNs can persist electrically excitable without dendrites, thus lacking connection to the organ of Corti. The biological background to this phenomenon remains elusive. We analyzed the pre- and post-somatic segments of the type I human SGNs using immunohistochemistry and transmission electron microscopy (TEM) in normal and pathological conditions. These segments were found surrounded by non-myelinated Schwann cells (NMSCs) showing strong intracellular expression of laminin-beta 2/collagen IV. These cells also bordered the perikaryal entry zone and disclosed surface rugosities outlined by a folded basement membrane (BM) expressing laminin-beta 2 and collagen IV. It is presumed that human large SGNs are demarcated by three cell categories: (a) myelinated Schwann cells, (b) NMSCs and (c) satellite glial cells (SGCs). Their BMs express laminin-beta 2/collagen IV and reaches the BM of the sensory epithelium at the habenula perforata. We speculate that the NMSCs protect SGNs from further degeneration following dendrite loss. It may give further explanation why SGNs can persist as electrically excitable monopolar cells even after long-time deafness, a blessing for the deaf treated with cochlear implantation. (C) 2014 The Authors. Published by Elsevier Ltd. on behalf of IBRO. This is an open access article under the CC BY-NC-ND license.

  • 19.
    Liu, Wei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Edin, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Blom, Hans
    Royal Inst Technol, Dept Appl Phys, Sci Life Lab, Tomtebodavagen 23A, S-17121 Solna, Sweden..
    Magnusson, Peetra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Schrott-Fischer, Annelies
    Med Univ Innsbruck, Dept Otolaryngol, Anichstr 35, A-6020 Innsbruck, Austria..
    Glueckert, Rudolf
    Med Univ Innsbruck, Dept Otolaryngol, Anichstr 35, A-6020 Innsbruck, Austria..
    Santi, Peter A.
    Univ Minnesota, Dept Otolaryngol, 121 Lions Res Bldg,2001 Sixth St SE, Minneapolis, MN 55455 USA..
    Li, Hao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Laurell, Göran
    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.
    Super-resolution structured illumination fluorescence microscopy of the lateral wall of the cochlea: the Connexin26/30 proteins are separately expressed in man2016In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 365, no 1, p. 13-27Article in journal (Refereed)
    Abstract [en]

    Globally 360 million people have disabling hearing loss and, of these, 32 million are children. Human hearing relies on 15,000 hair cells that transduce mechanical vibrations to electrical signals in the auditory nerve. The process is powered by the endo-cochlear potential, which is produced by a vascularized epithelium that actively transports ions in conjunction with a gap junction (GJ) system. This "battery" is located "off-site" in the lateral wall of the cochlea. The GJ syncytium contains the GJ protein genes beta 2 (GJB2/connexin26 (Cx26)) and 6 (GJB6/connexin30 (Cx30)), which are commonly involved in hereditary deafness. Because the molecular arrangement of these proteins is obscure, we analyze GJ protein expression (Cx26/30) in human cochleae by using super-resolution structured illumination microscopy. At this resolution, the Cx26 and Cx30 proteins were visible as separate plaques, rather than being co-localized in heterotypic channels, as previously suggested. The Cx26 and Cx30 proteins thus seem not to be co-expressed but to form closely associated assemblies of GJ plaques. These results could assist in the development of strategies to treat genetic hearing loss in the future.

  • 20.
    Liu, Wei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Glueckert, Rudolf
    Kinnefors, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Schrott-Fischer, Annelies
    Bitsche, Mario
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Distribution of P75 neurotrophin receptor in adult human cochlea: an immunohistochemical study2012In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 348, no 3, p. 407-415Article in journal (Refereed)
    Abstract [en]

    Mechanisms underlying the unique survival property of human spiral neurons are yet to be explored. P75 (p75(NTR)) is a low affinity receptor for neurotrophins and is known to interact with Trk receptors to modulate ligand binding and signaling. Up-regulation of this receptor was found to be associated with apoptosis as well as with cell proliferation. Its distribution and injury-induced change in expression pattern in the cochlea have been mainly studied in rodents. There is still no report concerning p75(NTR) in post-natal human inner ear. We analyzed, for the first time, p75(NTR) expression in five freshly fixed human cochleae by using immunohistochemistry techniques, including myelin basic protein (MBP) as a myelin sheath marker and TrkB as the human spiral neuron marker, and by using thin optical sectioning of laser confocal microscopy. The inner ear specimens were obtained from adult patients who had normal pure tone thresholds before the surgical procedures, via a trans-cochlear approach for removal of giant posterior cranial fossa meningioma. The expression of p75(NTR) was investigated and localized in the glial cells, including Schwann cells and satellite glial cells in the Rosenthal canal, in the central nerve bundles within the modiolus, and in the osseous spiral lamina of the human cochleae. The biological significance of p75(NTR) in human cochlea is discussed.

  • 21.
    Liu, Wei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Glueckert, Rudolf
    Linthicum, Fred H
    Rieger, Gunde
    Blumer, Michael
    Bitsche, Mario
    Pechriggl, Elisabeth
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Schrott-Fischer, Annelies
    Possible role of gap junction intercellular channels and connexin 43 in satellite glial cells (SGCs) for preservation of human spiral ganglion neurons: A comparative study with clinical implications2014In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 355, no 2, p. 267-278Article in journal (Refereed)
    Abstract [en]

    Human spiral ganglion (SG) neurons show remarkable survival properties and maintain electric excitability for a long time after complete deafness and even separation from the organ of Corti, features essential for cochlear implantation. Here, we analyze and compare the localization and distribution of gap junction (GJ) intercellular channels and connexin 43 (Cx43) in cells surrounding SG cell bodies in man and guinea pig by using transmission electron microscopy and confocal immunohistochemistry. GJs and Cx43 expression has been recognized in satellite glial cells (SGCs) in non-myelinating sensory ganglia including the human SG. In man, SG neurons can survive as mono-polar or "amputated" cells with unbroken central projections following dendrite degeneration and consolidation of the dendrite pole. Cx43-mediated GJ signaling between SGCs is believed to play a key role in this "healing" process and could explain the unique preservation of human SG neurons and the persistence of cochlear implant function.

  • 22.
    Liu, Wei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Kinnefors, Anders
    Boström, Marja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Edin, Fredrik
    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.
    Distribution of pejvakin in human spiral ganglion: an immunohistochemical study2013In: Cochlear Implants International, ISSN 1467-0100, E-ISSN 1754-7628, Vol. 14, no 4, p. 225-231Article in journal (Refereed)
    Abstract [en]

    Up to 10% of permanent hearing impairments in children originate from lesions in the neuronal auditory pathway. This form of auditory neuron injury called auditory neuropathy features a preservation of outer hair cell integrity but an impaired inner hair cell function and/or neuronal transmission. DFNB59 gene encodes the protein pejvakin (PJVK) and its mutations cause autosomal recessive auditory neuropathy as well as other forms of sensorineural hearing loss. The finding of distinct forms of hearing anomalies was based on studies of consanguineous families from different ethnic groups as well as studies in mice with PJVK gene mutations. In the present immunohistochemical study, the distribution of pejvakin protein in surgically obtained human cochleae was for the first time investigated. The human cochleae had normal hearing thresholds before the operation. The expression of pejvakin was located in the cell bodies of all spiral ganglion neurons rather than the nerve fibers that were labeled with Tuj 1 antibody. As Tuj 1 antibody stained the cytoplasm of Type 1 cells, pejvakin antibody labeled both type 1 and type 2 cells. The nuclei of the neurons were also PJVK-positive. No labeling was seen in the structures within the organ of Corti and the stria vascularis. In the previous study, PJVK had been detected in the hair cells, the spiral ganglion, the cochlear nuclei, the superior olivary nucleus, and the inferior colliculus in mouse. Our study demonstrated for the first time the expression of PJVK in human spiral ganglion neurons. Its functional role in neural signal propagation and synchrony needs further elucidation.

  • 23.
    Liu, Wei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Kinnefors, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Boström, Marja
    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.
    Expression of peripherin in human cochlea2010In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 342, no 3, p. 345-351Article in journal (Refereed)
    Abstract [en]

    The organ of Corti contains two different types of auditory receptors; the inner (IHCs) and outer (OHCs) hair cells. This dualism is further represented in their innervation, IHCs being innervated by type I neurons, and OHCs by type II neurons (in man, named small ganglion cells). Two efferent systems are also present. Here, we have analyzed the expression of the 57-kDa neuron-specific intermediate filament protein peripherin (PP) in human cochlea. In the human organ of Corti, PP seems to be specifically expressed in OHC afferents. Small or type II spiral ganglion cell bodies also intensely express PP. Thus, PP can be used as a marker for the characterization of the innervation of the OHC system in man.

  • 24.
    Liu, Wei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Kinnefors, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Boström, Marja
    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.
    Expression of TrkB and BDNF in human cochlea: an immunohistochemical study2011In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 345, no 2, p. 213-221Article in journal (Refereed)
    Abstract [en]

    Surgical human cochlear specimens were obtained during the removal of large posterior cranial fossa meningioma by a transcochlear approach in which the cochlea was removed for maximal exposure of the tumor and protection of important structures, such as the brainstem, cranial nerves, and pivotal blood vessels. The cochlear tissue was fixed and cryo-sectioned for tyrosine kinase receptor B (TrkB) and brain-derived neurotrophic factor (BDNF) immunohistochemistry. TrkB receptor protein was expressed in both neuronal somata and the processes of human spiral ganglion neurons (SGNs). In the human organ of Corti, TrkB immunoreactivity was mainly present in nerve fibers underneath outer hair cells. BDNF expression was found neither in the organ of Corti nor in the spiral ganglion of human cochlea. For antibody specificity and for control and comparative purposes, TrkB immunocytochemistry was performed in primary cultures of cochlear neuron/glia from adult guinea pig. Confocal laser scanning microscopy showed that TrkB was homogeneously distributed in the cytoplasm of both neuronal somata and axons. Knowledge of the expression of TrkB receptor in human cochlea should help to determine the target structures for neuron preservation in hearing-impaired patients. Our results indicate that the regeneration of SGNs under pathological conditions can be enhanced with BDNF/TrkB-based pharmaceutical or genetic strategies.

  • 25.
    Liu, Wei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Li, Hao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Edin, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Brännström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Glueckert, Rudolf
    Med Univ Innsbruck, Innsbruck, Austria.
    Schrott-Fischer, Annelies
    Med Univ Innsbruck, Innsbruck, Austria.
    Molnar, Matyas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pacholsky, Dirk
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pfaller, Kristian
    Med Univ Innsbruck, Innsbruck, Austria.
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Molecular composition and distribution of gap junctions in the sensory epithelium of the human cochlea a super-resolution structured illumination microscopy (SR-SIM) study2017In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 3, p. 160-170Article in journal (Refereed)
    Abstract [en]

    Background: Mutations in the GJB2 gene, which encodes the Connexin26 (Cx26) protein, are the most common cause of childhood hearing loss in American and European populations. The cochlea contains a gap junction (GJ) network in the sensory epithelium and two connective tissue networks in the lateral wall and spiral limbus. The syncytia contain the GJ proteins beta 2 (GJB2/Cx26) and beta 6 (GJB6/Cx30). Our knowledge of their expression in humans is insufficient due to the limited availability of tissue. Here, we sought to establish the molecular arrangement of GJs in the epithelial network of the human cochlea using surgically obtained samples. Methods: We analyzed Cx26 and Cx30 expression in GJ networks in well-preserved adult human auditory sensory epithelium using confocal, electron, and super -resolution structured illumination microscopy (SR-SIM). Results: Cx30 plaques (<5 mu m) dominated, while Cx26 plaques were subtle and appeared as 'mini junctions' (2-300 nm). 3-D volume rendering of Z-stacks and orthogonal projections from single optical sections suggested that the GJs are homomeric/homotypic and consist of assemblies of identical GJs composed of either Cx26 or Cx30. Occasionally, the two protein types were co-expressed, suggesting functional cooperation. Conclusions: Establishing the molecular composition and distribution of the GJ networks in the human cochlea may increase our understanding of the pathophysiology of Cx-related hearing loss. This information may also assist in developing future strategies to treat genetic hearing loss.

  • 26.
    Liu, Wei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Loewenheim, Hubert
    Eberhard Karls Univ Tubingen, Tubingen Hearing Res Ctr, Dept Otolaryngol Head & Neck Surg, D-72076 Tubingen, Germany.
    Santi, Peter A.
    Univ Minnesota, Dept Otolaryngol, 121 Lions Res Bldg,2001 Sixth St SE, Minneapolis, MN 55455 USA.
    Glueckert, Rudolf
    Med Univ Innsbruck, Dept Otolaryngol, Anichstr 35, A-6020 Innsbruck, Austria.
    Schrott-Fischer, Annelies
    Med Univ Innsbruck, Dept Otolaryngol, Anichstr 35, A-6020 Innsbruck, Austria.
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Expression of trans-membrane serine protease 3 (TMPRSS3) in the human organ of Corti2018In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 372, no 3, p. 445-456Article in journal (Refereed)
    Abstract [en]

    TMPRSS3 (Trans-membrane Serine Protease 3) is a type II trans-membrane serine protease that has proteolytic activity essential for hearing. Mutations in the gene cause non-syndromic autosomal recessive deafness (DFNB8/10) in humans. Knowledge about its cellular distribution in the human inner ear may increase our understanding of its physiological role and involvement in deafness, ultimately leading to therapeutic interventions. In this study, we used super-resolution structured illumination microscopy for the first time together with transmission electron microscopy to localize the TMPRSS3 protein in the human organ of Corti. Archival human cochleae were dissected out during petroclival meningioma surgery. Microscopy with Zeiss LSM710 microscope achieved a lateral resolution of approximately 80 nm. TMPRSS3 was found to be associated with actin in both inner and outer hair cells. TMPRSS3 was located in cell surface-associated cytoskeletal bodies (surfoskelosomes) in inner and outer pillar cells and Deiters cells and in subcuticular organelles in outer hair cells. Our results suggest that TMPRSS3 proteolysis is linked to hair cell sterociliary mechanics and to the actin/microtubule networks that support cell motility and integrity.

  • 27.
    Liu, Wei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Molnar, Matyas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Garnham, Carolyn
    MED EL Med Elect, Innsbruck, Austria..
    Benav, Heval
    R&D MED EL GmbH, Innsbruck, Austria..
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Macrophages in the Human Cochlea: Saviors or Predators-A Study Using Super-Resolution Immunohistochemistry2018In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 223Article in journal (Refereed)
    Abstract [en]

    The human inner ear, which is segregated by a blood/labyrinth barrier, contains resident macrophages [CD163, ionized calcium-binding adaptor molecule 1 (IBA1)-, and CD68-positive cells] within the connective tissue, neurons, and supporting cells. In the lateral wall of the cochlea, these cells frequently lie close to blood vessels as perivascular macrophages. Macrophages are also shown to be recruited from blood-borne monocytes to damaged and dying hair cells induced by noise, ototoxic drugs, aging, and diphtheria toxin-induced hair cell degeneration. Precise monitoring may be crucial to avoid self-targeting. Macrophage biology has recently shown that populations of resident tissue macrophages may be fundamentally different from circulating macrophages. We removed uniquely preserved human cochleae during surgery for treating petroclival meningioma compressing the brain stem, after ethical consent. Molecular and cellular characterization using immunofluorescence with antibodies against IBA1, TUJ1, CX3CL1, and type IV collagen, and super-resolution structured illumination microscopy (SR-SIM) were made together with transmission electron microscopy. The super-resolution microscopy disclosed remarkable phenotypic variants of IBA1 cells closely associated with the spiral ganglion cells. Monitoring cells adhered to neurons with "synapse-like" specializations and protrusions. Active macrophages migrated occasionally nearby damaged hair cells. Results suggest that the human auditory nerve is under the surveillance and possible neurotrophic stimulation of a well-developed resident macrophage system. It may be alleviated by the non-myelinated nerve soma partly explaining why, in contrary to most mammals, the human's auditory nerve is conserved following deafferentiation. It makes cochlear implantation possible, for the advantage of the profoundly deaf. The IBA1 cells may serve additional purposes such as immune modulation, waste disposal, and nerve regeneration. Their role in future stem cell-based therapy needs further exploration.

  • 28.
    Liu, Wei
    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.
    Immunohistological analysis of neurturin and its receptors in human cochlea2014In: Auris, nasus, larynx, ISSN 0385-8146, E-ISSN 1879-1476, Vol. 41, no 2, p. 172-178Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Difficulties in obtaining properly preserved human cochlea have been a major obstacle to in vitro study of this deeply located and hard bone-fortressed hearing organ. Our study aimed at investigating GDNF family ligands (GFLs) and their receptors in the human cochleae that were surgically obtained during a transcochlear approach dealing with life-threatening, intra-cranial meningiomas.

    METHODS: The specimens were properly fixed with 4% paraformaldehyde in the operating room. By using immunohistochemical techniques, distribution of GDNF, Neurturin (NTN, one member of GFLs), as well as cRet, GFRα-1 and GFRα-2 receptors in the human cochleae was investigated. Five cochleae from five adult patients were processed for the study. The patients had normal hearing threshold before operation.

    RESULTS: cRet receptor immunoreactivity was seen in the spiral ganglion neurons, mainly inside the cell bodies but rarely in the nerve fibers and not in the organ of Corti. Immunolabeling for GFRα-1 and GFRα-2 receptors was identified mainly in the cell bodies of the spiral neurons than in the nerve fibers. In the organ of Corti, GFRα-1 immunostaining could be demonstrated in the Deiters' cells, Hensen cells, inner pillar cells, and weakly in the inner hair cells but not in the outer hair cells; no structures in the organ of Corti were labeled with GFRα-2 receptor antibody. NTN immunostaining was found in the supporting cells of organ of Corti, including Deiters' cells, Hensen cells as well as Claudius' cells. In the spiral ganglia, NTN immunostaining was seen in both the cell bodies and the nerve fibers of neurons. GDNF immunoreactivity was not revealed in human cochlea.

    CONCLUSION: Surgically obtained human cochleae were properly fixed and underwent immunohistochemical investigation of neurotrophic elements. NTN and its receptors discovered in current study can be responsible for the unique neuronal survival properties in human spiral ganglion (hSG); a prerequisite for the function of cochlear implants.

  • 29.
    Liu, Wei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Schrott-Fischer, Annelies
    Med Univ Innsbruck, Dept Otolaryngol, Innsbruck, Austria..
    Glueckert, Rudolf
    Med Univ Innsbruck, Dept Otolaryngol, Innsbruck, Austria..
    Benav, Heval
    MED EL GmbH, R&D, Innsbruck, Austria..
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    The Human "Cochlear Battery" - Claudin-11 Barrier and Ion Transport Proteins in the Lateral Wall of the Cochlea2017In: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 10, article id 239Article in journal (Refereed)
    Abstract [en]

    Background: The cochlea produces an electric field potential essential for hair cell transduction and hearing. This biological "battery" is situated in the lateral wall of the cochlea and contains molecular machinery that secretes and recycles K+ ions. Its functioning depends on junctional proteins that restrict the para-cellular escape of ions. The tight junction protein Claudin-11 has been found to be one of the major constituents of this barrier that maintains ion gradients (Gow et al., 2004; Kitajiri et al., 2004a). We are the first to elucidate the human Claudin-11 framework and the associated ion transport machinery using super-resolution fluorescence illumination microscopy (SR-SIM). Methods: Archival cochleae obtained during meningioma surgery were used for SR-SIM together with transmission electron microscopy after ethical consent. Results: Claudin-11-expressing cells formed parallel tight junction lamellae that insulated the epithelial syncytium of the stria vascularis and extended to the suprastrial region. Intercellular gap junctions were found between the barrier cells and fibrocytes. Conclusion: Transmission electron microscopy, confocal microscopy and SR-SIM revealed exclusive cell specialization in the various subdomains of the lateral wall of the human cochlea. The Claudin-11-expressing cells exhibited both conductor and isolator characteristics, and these micro-porous separators may selectively mediate the movement of charged units to the intrastrial space in a manner that is analogous to a conventional electrochemical "battery." The function and relevance of this battery for the development of inner ear disease are discussed.

  • 30.
    Rask-Andersen, Helge
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Erixon, Elsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Kinnefors, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Löwenheim, Hubert
    Schrott-Fischer, Anneliese
    Liu, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Anatomy of the human cochlea: implications for cochlear implantation2011In: Cochlear Implants International, ISSN 1467-0100, E-ISSN 1754-7628, Vol. 12, no Suppl 1, p. S8-S13Article in journal (Refereed)
    Abstract [en]

    Since the classical description by Retzius in 1884, many extensive studies of the micro-anatomy of the human cochlea have been presented. The human cochlea is one of the most difficult tissues to study due to the bony capsule and its delicate contents. Most preparations suffer from post-mortem changes caused by the delay between demise and fixation. For over a decade, we have analyzed human inner-ear tissue obtained at surgery using transmission electron microscopy, scanning electron microscopy, in vitro culture, and immunohistochemistry. These studies show the value of these techniques for fine structural and molecular analyses. Modern cochlear implant surgery requires that ear surgeons are familiar with the intricate anatomy of the human cochlea and its variations. The classical technique to insert electrode arrays through a drilled cochleostomy has been abandoned by some surgeons today. Instead a round-window approach can be used as originally implemented by William House for short electrodes. This so-called 'hook' region of the cochlea presents extensive anatomical variations that can be difficult to foresee on pre-operative computed tomography. CI depends on the functional status of remaining spiral ganglion neurons. These cells are more or less preserved in CI patients but how the conservation influences the outcome of CI is debatable. Notwithstanding their preservation is crucial and more information should be attained about their deterioration and how it can be prevented. Better understanding of structure, function, and regenerative capability is needed to comprehend the nature of electrical stimulation of the peripheral and central nervous system to improve the design of future implant systems.

  • 31.
    Rask-Andersen, Helge
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Liu, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Auditory nerve preservation and regeneration in man: relevance for cochlear implantation2015In: Neural Regeneration Research, ISSN 1673-5374, E-ISSN 1876-7958, Vol. 10, no 5, p. 710-712Article in journal (Other academic)
  • 32.
    Rask-Andersen, Helge
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Liu, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Boström, Marja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Pfaller, K
    Kinnefors, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Glueckert, R
    Schrott-Fischer, A
    Immunolocalization of prestin in human Cochlea2010In: Audiological Medicine, ISSN 1651-386X, E-ISSN 1651-3835, Vol. 8, no 2, p. 56-62Article in journal (Refereed)
    Abstract [en]

     

     

     

     

     

     

    Objective:

     

    Prestin is an anion-transporter-related protein highly expressed in mammalian outer hair cells (OHCs). It is associated

    with the OHC basolateral plasma membrane and responsible for cell body contraction, increasing cochlear sensitivity

    and frequency resolution. Here, we analysed the expression and distribution of prestin in the human cochlea.

     

    Study Design:

    Immunohistochemistry including confocal microscopy and SEM were performed on EDTA-decalcifi ed human cochlea

    removed during petro-clival meningioma surgery.

     

    Results:

    Prestin was found to be expressed solely in OHCs. No staining

    was seen in IHCs. Prestin immunolabelling framed the OHCs along the sensory region of the human cochlea. Staining was

    most prominent in the lateral cell membrane with less expression in the sub- and peri-nuclear part of the cell. Prestin immunostaining

    was also detected in the OHC cytosol, presumably refl ecting intracellular molecular traffi cking.

     

    Conclusion:

    This

    study describes for the fi rst time the localization and distribution of prestin in the well preserved human organ of Corti.

  • 33.
    Rask-Andersen, Helge
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Liu, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Erixon, Elsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Kinnefors, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Pfaller, K.
    Schrott-Fischer, A.
    Glueckert, R.
    Human cochlea: Anatomical characteristics and their relevance for cochlear implantation2012In: Anatomical Record, ISSN 1932-8486, Vol. 295, no 11, p. 1791-1811Article in journal (Refereed)
    Abstract [en]

    This is a review of the anatomical characteristics of human cochlea and the importance of variations in this anatomy to the process of cochlear implantation (CI). Studies of the human cochlea are essential to better comprehend the physiology and pathology of man's hearing. The human cochlea is difficult to explore due to its vulnerability and bordering capsule. Inner ear tissue undergoes quick autolytic changes making investigations of autopsy material difficult, even though excellent results have been presented over time. Important issues today are novel inner ear therapies including CI and new approaches for inner ear pharmacological treatments. Inner ear surgery is now a reality, and technical advancements in the design of electrode arrays and surgical approaches allow preservation of remaining structure/function in most cases. Surgeons should aim to conserve cochlear structures for future potential stem cell and gene therapies. Renewal interest of round window approaches necessitates further acquaintance of this complex anatomy and its variations. Rough cochleostomy drilling at the intricate "hook" region can generate intracochlear bone-dust-inducing fibrosis and new bone formation, which could negatively influence auditory nerve responses at a later time point. Here, we present macro- and microanatomic investigations of the human cochlea viewing the extensive anatomic variations that influence electrode insertion. In addition, electron microscopic (TEM and SEM) and immunohistochemical results, based on specimens removed at surgeries for life-threatening petroclival meningioma and some well-preserved postmortal tissues, are displayed. These give us new information about structure as well as protein and molecular expression in man. Our aim was not to formulate a complete description of the complex human anatomy but to focus on aspects clinically relevant for electric stimulation, predominantly, the sensory targets, and how surgical atraumaticity best could be reached.

  • 34.
    Rask-Andersen, Helge
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Liu, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Linthicum, Fred
    Ganglion and dendritic population in EAS ears2010In: Cochlear Implants and Hearing Preservation / [ed] Paul Van de Heyning & Andrea Kleine Punte, Basel: Karger , 2010, p. 14-27Chapter in book (Other (popular science, discussion, etc.))
  • 35.
    Rask-Andersen, Helge
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Liu, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Linthicum, Fred
    Ganglion Cell and 'Dendrite' Populations in Electric Acoustic Stimulation Ears2010In: Advances in Oto-Rhino-Laryngology, ISSN 0065-3071, E-ISSN 1662-2847, Vol. 67, p. 14-27Article in journal (Refereed)
    Abstract [en]

    Background/Aims: The electric acoustic stimulation (EAS) technique combines electric and acoustic stimulation in the same ear and utilizes both low-frequency acoustic hearing and electric stimulation of preserved neurons. We present data of ganglion cell and dendrite populations in ears from normal individuals and those suffering from adult-onset hereditary progressive hearing loss with various degrees of residual low-frequency hearing. Some of these were potential candidates for EAS surgery. The data may give us information about the neuroanatomic situation in EAS ears. Methods: Dendrites and ganglion cells were calculated and audiocytocochleograms constructed. The temporal bones were from the collection at the House Ear Institute in Los Angeles, Calif., USA. Normal human anatomy, based on surgical specimens, is presented. Results: Inner and outer hair cells, supporting cells, ganglion cells and dendrites were preserved in the apical region. In the mid-frequency region, around 1 kHz, the organ of Corti with inner and outer hair cells was often conserved while in the lower basal turn, representing frequencies above 3 kHz, the organ of Corti was atrophic and replaced by thin cells. Despite loss of hair cells and lamina fibers ganglion cells were present even after 28 years of deafness. Conclusions: Conditions with profound sensorineural hearing loss and preserved low-frequency hearing may have several causes and the pathology may vary accordingly. In our patients with progressive adult-onset sensorineural hearing loss (amalgamated into 'presbyacusis'), neurons were conserved even after long duration of deafness. These spiral ganglion cells may be excellent targets for electric stimulationusing the EAS technique.

  • 36.
    Rask-Andersen, Helge
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Wei, Liu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Bostrom, Marja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Linthicum, Fred
    Hearing preservation and nanotechnology-based targted drug delivry future in cochlear implantation?2009In: Otology Japan, ISSN 1884-1457, Vol. 19, no 5, p. 687-697Article in journal (Refereed)
    Abstract [en]

    Cochlear Implantation (CI) remains as one of the greatest medical achievements in modern medicine. New and innovative strategies continue to be developed to optimize and improve the functional results of CI surgery. Preservation of residual hearing through a-traumatic surgical techniques and electrode arrays may alter indications. Conditions with profound SNHL with preserved low tone hearing may have several causes and pathology may vary accordingly. In patients with progressive adult-onset SNHL neurons may be conserved even after long duration of deafness. IHCs and OHCs, supporting cells, ganglion cells and dendrites may be preserved in the apical region while in the lower turn despite atrophic organ of Corti and loss of lamina fibers ganglion cells can be present even after 28 years duration of deafness. These spiral ganglion cells may be excellent targets for electric stimulation using EAS technique that combines electric and acoustic stimulation in the same ear and utilizes both low frequency acoustic hearing and electric stimulation of preserved neurons. At the moment we are trying to elucidate the mechanism responsible for this preservation in humans and to use this knowledge for future therapy. Nano-technology may offer new possibilities for focused release of drugs and possibly genes to the inner ear. European project“NanoEar”is a concerted action to develop 3rd generation of nanoparticles (NP) for treatment of inner ear deafness. One goal is to target drugs and genes to specific inner ear cells through so-called multifunctional NP which are degradable, non-toxic, traceable and can be released in a controlled and biocompatible way. The small size of the NP may give new properties for technical advancement but risks must also be thoroughly evaluated. Uppsala is a Swedish partner to evaluate NP uptake in vitro in both human and animal spiral ganglion neurons. In my presentation I will show the system of culture spiral ganglion cells and demonstrate their locomotive behaviour and NP intracellular uptake using time lapse video recording and combined immunofluorescence and confocal microscopy.

  • 37.
    Rask-Andersen, Helge
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Wei, Liu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Kinnefors, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Pfaller, Kristian
    Glueckert, Rudolf
    Schrott-Fischer, Anneliese
    Boström, Marja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Studies of the human cochlea with aspects of future hearing rehabilitation2010In: Otology Japan, ISSN 1884-1457, Vol. 20, no 2, p. 119-129Article in journal (Refereed)
    Abstract [en]

    More than 600 million people suffer from neurosensory diseases, with hearing loss being one of the dominant causes of all ages. Deafness affects 2-3 children in 1000 born, over 10% of adults and 30% of elderly individuals above 65 years of age. Most patients with a hearing problem are diagnosed with sensorineural hearing loss primarily caused by hair cell dysfunction. Auditory neuropathies may be more frequent than earlier understood and studies of human ear may suggest additional filtering and synchronous activity in the first neuron important for speech coding. Cochlear implantation and prospects of treating inner ear disorders by application of substances into the middle ear necessitate further exploration of the human labyrinth. Still our knowledge of the structure/function of the human spiral ganglion (SGC) relative to electric stimulation is limited. In our study specimens were obtained at surgery for large life-threatening petro-clival meningioma after patient and ethical committee consent. Excellently preserved human tissue could be obtained after decalcification and observation in a TEM (JEOL 100 SX) and Field Emission Scanning Electron Microscope (ZEISS DSM 982 Gemini Field Emission Electron Microscope), and laser confocal microscopy (Nikon TE2000, DEclipse C1). The fine structure of the human cochlear nerve and hair cells could be analysed. This presentation is a short “round trip” in the human cochlea presenting some anatomical characteristics that may be useful to recognize during surgery and future inner ear research. New research in molecular medicine, gene therapy, stem cell inducement and nano-technology may lead to further breakthroughs in diagnostic, with new causative treatments of diseases of the auditory systems. We may anticipate a challenging future in regenerative medicine with new techniques to induce cell repair even in patients suffering from neural deafness. However, it is also imperative not to furnish unrealistic promises but give reasonable prospects for future progress. This presentation will focus on some results obtained recently in these fields and try to foresee strategies and advances for further progress of hearing rehabilitation.

  • 38.
    Senn, Pascal
    et al.
    Univ Bern, Inselspital, Univ Dept ORL Head & Neck Surg, Bern, Switzerland.;Univ Bern, Dept Clin Res, Bern, Switzerland.;Univ Hosp Geneva, Dept Clin Neurosci, Serv ORL & HNS, HUG, Geneva, Switzerland..
    Roccio, Marta
    Univ Bern, Inselspital, Univ Dept ORL Head & Neck Surg, Bern, Switzerland.;Univ Bern, Dept Clin Res, Bern, Switzerland..
    Hahnewald, Stefan
    Univ Bern, Inselspital, Univ Dept ORL Head & Neck Surg, Bern, Switzerland.;Univ Bern, Dept Clin Res, Bern, Switzerland..
    Frick, Claudia
    Univ Tubingen, Dept Otorhinolaryngol Head & Neck Surg, Tubingen, Germany..
    Kwiatkowska, Monika
    Univ Tubingen, Dept Otorhinolaryngol Head & Neck Surg, Tubingen, Germany..
    Ishikawa, Masaaki
    Univ Tubingen, Dept Otorhinolaryngol Head & Neck Surg, Tubingen, Germany..
    Bako, Peter
    Univ Tubingen, Dept Otorhinolaryngol Head & Neck Surg, Tubingen, Germany..
    Li, Hao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Edin, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Liu, Wei
    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.
    Pyykko, Ilmari
    Univ Tampere, Hearing & Balance Res Unit, Dept Otorhinolaryngol, Tampere, Finland.;Univ Tampere, Finnish Ctr Alternat Methods, Tampere, Finland..
    Zou, Jing
    Univ Tampere, Hearing & Balance Res Unit, Dept Otorhinolaryngol, Tampere, Finland.;Univ Tampere, Finnish Ctr Alternat Methods, Tampere, Finland..
    Mannerstrom, Marika
    Univ Tampere, Hearing & Balance Res Unit, Dept Otorhinolaryngol, Tampere, Finland.;Univ Tampere, Finnish Ctr Alternat Methods, Tampere, Finland..
    Keppner, Herbert
    HES SO Univ Appl Sci Western Switzerland, Haute Ecole Arc Ingn, La Chaux De Fonds, Switzerland..
    Homsy, Alexandra
    HES SO Univ Appl Sci Western Switzerland, Haute Ecole Arc Ingn, La Chaux De Fonds, Switzerland..
    Laux, Edith
    HES SO Univ Appl Sci Western Switzerland, Haute Ecole Arc Ingn, La Chaux De Fonds, Switzerland..
    Llera, Miguel
    HES SO Univ Appl Sci Western Switzerland, Haute Ecole Arc Ingn, La Chaux De Fonds, Switzerland..
    Lellouche, Jean-Paul
    Bar Ilan Univ, Dept Chem, Ctr Adv Mat & Nanotechnol, Ramat Gan, Israel.;Bar Ilan Univ, Dept Chem, Mina & Everard Goodman Fac Life Sci, Ramat Gan, Israel..
    Ostrovsky, Stella
    Bar Ilan Univ, Dept Chem, Ctr Adv Mat & Nanotechnol, Ramat Gan, Israel.;Bar Ilan Univ, Dept Chem, Mina & Everard Goodman Fac Life Sci, Ramat Gan, Israel..
    Banin, Ehud
    Bar Ilan Univ, Dept Chem, Ctr Adv Mat & Nanotechnol, Ramat Gan, Israel.;Bar Ilan Univ, Dept Chem, Mina & Everard Goodman Fac Life Sci, Ramat Gan, Israel..
    Gedanken, Aharon
    Bar Ilan Univ, Dept Chem, Ctr Adv Mat & Nanotechnol, Ramat Gan, Israel.;Bar Ilan Univ, Dept Chem, Mina & Everard Goodman Fac Life Sci, Ramat Gan, Israel..
    Perkas, Nina
    Bar Ilan Univ, Dept Chem, Ctr Adv Mat & Nanotechnol, Ramat Gan, Israel.;Bar Ilan Univ, Dept Chem, Mina & Everard Goodman Fac Life Sci, Ramat Gan, Israel..
    Wank, Ute
    EMC Microcollect GmbH, Tubingen, Germany..
    Wiesmueller, Karl-Heinz
    EMC Microcollect GmbH, Tubingen, Germany..
    Mistrik, Pavel
    MED EL GmbH, Worldwide Headquarters, Innsbruck, Austria..
    Benav, Heval
    MED EL GmbH, Worldwide Headquarters, Innsbruck, Austria..
    Garnham, Carolyn
    MED EL GmbH, Worldwide Headquarters, Innsbruck, Austria..
    Jolly, Claude
    MED EL GmbH, Worldwide Headquarters, Innsbruck, Austria..
    Gander, Filippo
    SCIPROM Sarl, Rue Ctr 70, St Sulpice, Switzerland..
    Ulrich, Peter
    SCIPROM Sarl, Rue Ctr 70, St Sulpice, Switzerland..
    Mueller, Marcus
    Univ Tubingen, Dept Otorhinolaryngol Head & Neck Surg, Tubingen, Germany..
    Loewenheim, Hubert
    Univ Tubingen, Dept Otorhinolaryngol Head & Neck Surg, Tubingen, Germany..
    NANOCI-Nanotechnology Based Cochlear Implant With Gapless Interface to Auditory Neurons2017In: Otology and Neurotology, ISSN 1531-7129, E-ISSN 1537-4505, Vol. 38, no 8, p. E224-E231Article in journal (Refereed)
    Abstract [en]

    Cochlear implants (CI) restore functional hearing in the majority of deaf patients. Despite the tremendous success of these devices, some limitations remain. The bottleneck for optimal electrical stimulation with CI is caused by the anatomical gap between the electrode array and the auditory neurons in the inner ear. As a consequence, current devices are limited through 1) low frequency resolution, hence suboptimal sound quality and 2), large stimulation currents, hence high energy consumption (responsible for significant battery costs and for impeding the development of fully implantable systems). A recently completed, multinational and interdisciplinary project called NANOCI aimed at overcoming current limitations by creating a gapless interface between auditory nerve fibers and the cochlear implant electrode array. This ambitious goal was achieved in vivo by neurotrophin-induced attraction of neurites through an intra-cochlear gel-nanomatrix onto a modified nanoCI electrode array located in the scala tympani of deafened guinea pigs. Functionally, the gapless interface led to lower stimulation thresholds and a larger dynamic range in vivo, and to reduced stimulation energy requirement (up to fivefold) in an in vitro model using auditory neurons cultured on multi-electrode arrays. In conclusion, the NANOCI project yielded proof of concept that a gapless interface between auditory neurons and cochlear implant electrode arrays is feasible. These findings may be of relevance for the development of future CI systems with better sound quality and performance and lower energy consumption. The present overview/review paper summarizes the NANOCI project history and highlights achievements of the individual work packages.

1 - 38 of 38
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Output format
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  • asciidoc
  • rtf