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  • 1.
    Bagger-Sjoback, Dan
    et al.
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Stromback, Karin
    Academic Hospital, Sweden.
    Hakizimana, Pierre
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Karolinska Institute, Sweden.
    Plue, Jan
    Stockholm University, Sweden.
    Larsson, Christina
    Karolinska University Hospital, Sweden.
    Hultcrantz, Malou
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Papatziamos, Georgios
    Karolinska University Hospital, Sweden.
    Smeds, Henrik
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Danckwardt-Lilliestrom, Niklas
    Academic Hospital, Sweden.
    Hellstrom, Sten
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Johansson, Ann
    Karolinska University Hospital, Sweden.
    Tideholm, Bo
    Karolinska University Hospital, Sweden.
    Fridberger, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Karolinska Institute, Sweden.
    A Randomised, Double Blind Trial of N-Acetylcysteine for Hearing Protection during Stapes Surgery2015Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 3, s. e0115657-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background Otosclerosis is a disorder that impairs middle ear function, leading to conductive hearing loss. Surgical treatment results in large improvement of hearing at low sound frequencies, but high-frequency hearing often suffers. A likely reason for this is that inner ear sensory cells are damaged by surgical trauma and loud sounds generated during the operation. Animal studies have shown that antioxidants such as N-Acetylcysteine can protect the inner ear from noise, surgical trauma, and some ototoxic substances, but it is not known if this works in humans. This trial was performed to determine whether antioxidants improve surgical results at high frequencies. Methods We performed a randomized, double-blind and placebo-controlled parallel group clinical trial at three Swedish university clinics. Using block-stratified randomization, 156 adult patients undergoing stapedotomy were assigned to intravenous N-Acetylcysteine (150 mg/kg body weight) or matching placebo (1:1 ratio), starting one hour before surgery. The primary outcome was the hearing threshold at 6 and 8 kHz; secondary outcomes included the severity of tinnitus and vertigo. Findings One year after surgery, high-frequency hearing had improved 2.7 +/- 3.8 dB in the placebo group (67 patients analysed) and 2.4 +/- 3.7 dB in the treated group (72 patients; means +/- 95% confidence interval, p = 0.54; linear mixed model). Surgery improved tinnitus, but there was no significant intergroup difference. Post-operative balance disturbance was common but improved during the first year, without significant difference between groups. Four patients receiving N-Acetylcysteine experienced mild side effects such as nausea and vomiting. Conclusions N-Acetylcysteine has no effect on hearing thresholds, tinnitus, or balance disturbance after stapedotomy.

  • 2.
    Bagger-Sjoback, Dan
    et al.
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Stromback, Karin
    Uppsala University, Sweden.
    Hultcrantz, Malou
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Papatziamos, Georgios
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Smeds, Henrik
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Danckwardt-Lilliestrom, Niklas
    Uppsala University, Sweden.
    Tideholm, Bo
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Johansson, Ann
    Karolinska University Hospital, Sweden.
    Hellstrom, Sten
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Hakizimana, Pierre
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Fridberger, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    High-frequency hearing, tinnitus, and patient satisfaction with stapedotomy: A randomized prospective study2015Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, nr 13341Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Otosclerosis is a common disorder that leads to conductive hearing loss. Most patients with otosclerosis also have tinnitus, and surgical treatment is known to improve hearing as well as tinnitus. Some patients however experience worsening of tinnitus after the operation, but there are no known factors that allow surgeons to predict who will be at risk. In this prospective observational study on 133 patients undergoing stapedotomy, we show that postoperative air conduction thresholds at very high stimulus frequencies predict improvement of tinnitus, as assessed with proportional odds logistic regression models. Young patients were significantly more likely to experience reduction of tinnitus and patients whose tinnitus became better were also more satisfied with the outcome of the operation. These findings have practical importance for patients and their surgeons. Young patients can be advised that surgery is likely to be beneficial for their tinnitus, but a less positive message should be conveyed to older patients.

  • 3.
    Brownell, William E
    et al.
    Otolaryngology—H&N Surgery, Baylor College of Medicine, USA.
    Jacob, Stefan
    Center for Hearing and Communication Research, Karolinska Institutet.
    Hakizimana, Pierre
    Center for Hearing and Communication Research, Karolinska Institutet.
    Ulfendahl, Mats
    Center for Hearing and Communication Research, Karolinska Institutet.
    Fridberger, Anders
    Center for Hearing and Communication Research, Karolinska Institutet.
    Decreasing Outer Hair Cell Membrane Cholesterol Increases Cochlear Electromechanics2011Inngår i: WHAT FIRE IS IN MINE EARS: PROGRESS IN AUDITORY BIOMECHANICS: PROCEEDINGS OF THE 11TH INTERNATIONAL MECHANICS OF HEARING WORKSHOP / [ed] Shera, CA; Olson, ES, American Institute of Physics (AIP), 2011, Vol. 1403Konferansepaper (Fagfellevurdert)
  • 4. Brownell, William E
    et al.
    Jacob, Stefan
    Hakizimana, Pierre
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Ulfendahl, Mats
    Fridberger, Anders
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Membrane cholesterol modulates cochlear electromechanics2011Inngår i: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 461, nr 6, s. 677-686Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Changing the concentration of cholesterol in the plasma membrane of isolated outer hair cells modulates electromotility and prestin-associated charge movement, suggesting that a similar manipulation would alter cochlear mechanics. We examined cochlear function before and after depletion of membrane cholesterol with methyl-β-cyclodextrin (MβCD) in an excised guinea pig temporal bone preparation. The mechanical response of the cochlear partition to acoustic and/or electrical stimulation was monitored using laser interferometry and time-resolved confocal microscopy. The electromechanical response in untreated preparations was asymmetric with greater displacements in response to positive currents. Exposure to MβCD increased the magnitude and asymmetry of the response, without changing the frequency tuning of sound-evoked mechanical responses or cochlear microphonic potentials. Sodium salicylate reversibly blocked the enhanced electromechanical response in cholesterol depleted preparations. The increase of sound-evoked vibrations during positive current injection was enhanced following MβCD in some preparations. Imaging was used to assess cellular integrity which remained unchanged after several hours of exposure to MβCD in several preparations. The enhanced electromechanical response reflects an increase in outer hair cell electromotility and may reveal features of cholesterol distribution and trafficking in outer hair cells.

  • 5.
    Gbaguidi, Bénédicte
    et al.
    Free University of Brussels, Belgium .
    Hakizimana, Pierre
    Free University of Brussels, Belgium .
    Vandenbussche, G
    Free University of Brussels, Belgium .
    Ruysschaert, Jean-Marie
    Free University of Brussels, Belgium .
    Conformational changes in a bacterial multidrug transporter are phosphatidylethanolamine-dependent2007Inngår i: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 64, nr 12, s. 1571-1582Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    LmrP is an electrogenic H(+)/drug antiporter that extrudes a broad spectrum of antibiotics. Five carboxylic residues are implicated in drug binding (Asp142 and Glu327) and proton motive force-mediated restructuring (Asp68, Asp128 and Asp235). ATR-FTIR (Attenuated Total Reflection - Fourier Transform Infrared) and tryptophan quenching experiments revealed that phosphatidylethanolamine (PE) is required to generate the structural intermediates induced by ionization of carboxylic residues. Surprisingly, no ionization-induced conformational changes were detectable in the absence of PE, suggesting either that carboxylic acid residues do not ionize or that ionization does not lead to any conformational change. The mean pKa of carboxylic residues evaluated by ATR-FTIR spectroscopy was 6.5 for LmrP reconstituted in PE liposomes, whereas the pKa calculated in the absence of PE was 4.6. Considering that 16 of the 19 carboxylic residues are located in the extramembrane loops, the pKa values obtained in the absence and in the presence of PE suggest that the interaction of the loop acid residues with the membrane interface depends on the lipid composition.

  • 6.
    Hakizimana, Pierre
    Université Libre de Bruxelles, Belgium.
    Interactions between membrane transporters and phospholipids: Phosphatidylethanolamine regulates the function and the structure of LmrP, a bacterial ... associated to antibiotic resistance2009Bok (Annet vitenskapelig)
    Abstract [en]

    Highly solved crystal structures and a wealth of biochemical data are now available for an increasing number of membrane proteins. However, the question of how lipid molecules interact with integral membrane proteins and regulate their structure and function in biological membranes remains unsatisfactorily addressed. This book discusses the functional mechanisms of membrane proteins in general and the effect of the surrounding lipidic environment, in the context of recent developments in the field. Recent experimental investigations on the proton gradient-driven multidrug transporter LmrP are also discussed. Using this membrane protein as a model, we demonstrated that the protein structure and function was depending on the phosphatidylethanolamine (PE) headgroup. We then showed that a negatively charged residue, Asp68, could participate in the interaction with PE and that such interaction is required for proper activity and structure of the protein. Because Asp-68 belongs to a highly conserved motif of the Major Facilitator Superfamily (MFS) , this interaction might be a general feature of these transporters that is involved in proton gradient sensing and lipid dependence.

  • 7.
    Hakizimana, Pierre
    et al.
    Center for Hearing and Communication Research, Karolinska Institutet, Sweden.
    Brownell, William E
    Otolaryngology–H&N Surgery, Baylor College of Medicine, USA.
    Jacob, Stefan
    Center for Hearing and Communication Research, Karolinska Institutet, Sweden.
    Fridberger, Anders
    Center for Hearing and Communication Research, Karolinska Institutet, Sweden.
    Sound‐Evoked Length Changes of the Outer Hair Cell Stereocilia Bundle are Modulated by Endocochlear Currents2011Inngår i: WHAT FIRE IS IN MINE EARS: PROGRESS IN AUDITORY BIOMECHANICS: Proceedings of the 11th International Mechanics of Hearing Workshop / [ed] Christopher A. Shera and Elizabeth S. Olson, American Institute of Physics (AIP), 2011, Vol. 1403Konferansepaper (Fagfellevurdert)
    Abstract [en]

    The apical surface of vertebrate inner ear sensory cells is characterized by a bundle of giant microvilli commonly known as stereocilia. Stereocilia bend about a neck‐like thinning near their base and more than three decades of research has established that the direction and magnitude of sideways bundle deflection is the basis of the mechanoelectrical signalling that initiates sound perception. Aside from its ability to bend at the neck, the stereocilium is usually considered as a stiff inelastic rod. Here we show that the length of OHC stereocilia changes during sound transduction, demonstrating their axial compliance, and that the magnitude of the length change is modulated by currents that mimic in vivo endocochlear currents. A reciprocal relation between length change and bundle deflection is evident: the smaller the length changes, the larger the bundle deflection.

  • 8.
    Hakizimana, Pierre
    et al.
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Brownell, William E
    Jacob, Stefan
    Fridberger, Anders
    Karolinska Institutet / Karolinska University Hospital, Stockholm, Sweden.
    Sound-induced length changes in outer hair cell stereocilia2012Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 3Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hearing relies on mechanical stimulation of stereocilia bundles on the sensory cells of the inner ear. When sound hits the ear, each stereocilium pivots about a neck-like taper near their base. More than three decades of research have established that sideways deflection of stereocilia is essential for converting mechanical stimuli into electrical signals. Here we show that mammalian outer hair cell stereocilia not only move sideways but also change length during sound stimulation. Currents that enter stereocilia through mechanically sensitive ion channels control the magnitude of both length changes and bundle deflections in a reciprocal manner: the smaller the length change, the larger is the bundle deflection. Thus, the transduction current is important for maintaining the resting mechanical properties of stereocilia. Hair cell stimulation is most effective when bundles are in a state that ensures minimal length change.

  • 9.
    Hakizimana, Pierre
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Fridberger, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Effects of salicylate on sound-evoked outer hair cell stereocilia deflections2015Inngår i: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 467, nr 9, s. 2021-2029Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hearing depends on sound-evoked deflections of the stereocilia that protrude from the sensory hair cells in the inner ear. Although sound provides an important force driving stereocilia, forces generated through mechanically sensitive ion channels and through the motor protein prestin have been shown to influence stereocilia motion in solitary hair cells. While a possible influence of prestin on mechanically sensitive ion channels has not been systematically investigated, a decrease in transducer currents is evident in solitary hair cells when prestin is blocked with salicylate, raising the question of whether a reduced prestin activity or salicylate itself affected the mechanotransduction apparatus. We used two- and three-dimensional time-resolved confocal imaging to visualize outer hair cell stereocilia during sound stimulation in the apical turn of cochlear explant preparations from the guinea pig. Surprisingly, following application of salicylate, outer hair cell stereocilia deflections increased, while cochlear microphonic potentials decreased. However, when prestin activity was altered with the chloride ionophore tributyltin, both the cochlear microphonic potential and the stereocilia deflection amplitude decreased. Neither positive nor negative current stimulation abolished the bundle movements in the presence of salicylate, indicating that the observed effects did not depend on the endocochlear potential. These data suggest that salicylate may alter the mechanical properties of stereocilia, decreasing their bending stiffness.

  • 10.
    Hakizimana, Pierre
    et al.
    Université Libre de Bruxelles, Belgium.
    Masureel, Matthieu
    Université Libre de Bruxelles, Belgium.
    Gbaguidi, Bénédicte
    Université Libre de Bruxelles, Belgium.
    Ruysschaert, Jean-Marie
    Université Libre de Bruxelles, Belgium.
    Govaerts, Cédric
    Université Libre de Bruxelles, Belgium.
    Interactions between phosphatidylethanolamine headgroup and LmrP, a multidrug transporter: a conserved mechanism for proton gradient sensing?2008Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 283, nr 14, s. 9369-9376Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In a number of cases, the function of membrane proteins appears to require the presence of specific lipid species in the bilayer. We have shown that the secondary multidrug transporter LmrP requires the presence of phosphatidylethanolamine (PE), as its replacement by phosphatidylcholine (PC) inhibits transport activity and directly affects its structure, although the underlying mechanism was unknown. Here, we show that the effect of PE on the structure and the function of LmrP is mediated by interactions between the lipid headgroup and the protein. We used methyl-PE and dimethyl-PE analogs of PE to show that only replacement of the three hydrogens by methyl moieties leads to changes in the biochemical and biophysical properties of the reconstituted protein. This suggests that LmrP does not depend on the bulk properties of the phospholipids tested but solely on the hydrogen bonding ability of the headgroup. We then show that a single point mutation in LmrP, D68C, is sufficient to recapitulate precisely every biochemical and biophysical effect observed when PE is replaced by PC, including energy transfer between the protein tryptophan residues and the lipid headgroups. We conclude that the negatively charged Asp-68 is likely to participate in the interaction with PE and that such interaction is required for proton gradient sensing, substrate binding, and transport. Because Asp-68 belongs to a highly conserved motif in the Major Facilitator Superfamily (which includes LacY and EmrD), this interaction might be a general feature of these transporters that is involved in proton gradient sensing and lipid dependence.

  • 11.
    Strimbu, Clark Elliott
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten. Columbia Univ, NY 10032 USA.
    Prasad, Sonal
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Hakizimana, Pierre
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Fridberger, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Control of hearing sensitivity by tectorial membrane calcium2019Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, nr 12, s. 5756-5764Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    When sound stimulates the stereocilia on the sensory cells in the hearing organ, Ca2+ ions flow through mechanically gated ion channels. This Ca2+ influx is thought to be important for ensuring that the mechanically gated channels operate within their most sensitive response region, setting the fraction of channels open at rest, and possibly for the continued maintenance of stereocilia. Since the extracellular Ca2+ concentration will affect the amount of Ca2+ entering during stimulation, it is important to determine the level of the ion close to the sensory cells. Using fluorescence imaging and fluorescence correlation spectroscopy, we measured the Ca2+ concentration near guinea pig stereocilia in situ. Surprisingly, we found that an acellular accessory structure close to the stereocilia, the tectorial membrane, had much higher Ca2+ than the surrounding fluid. Loud sounds depleted Ca2+ from the tectorial membrane, and Ca2+ manipulations had large effects on hair cell function. Hence, the tectorial membrane contributes to control of hearing sensitivity by influencing the ionic environment around the stereocilia.

  • 12.
    Yamashita, Tetsuji
    et al.
    St. Jude Children’s Research Hospital, Memphis, Tennessee, United States of America.
    Hakizimana, Pierre
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Karolinska Institutet, Stockholm, Sweden; Karolinska University Hospital, Stockholm, Sweden.
    Wu, Siva
    Lawrence Berkeley National Laboratory, Berkeley, California, United States of America.
    Hassan, Ahmed
    Lawrence Berkeley National Laboratory, Berkeley, California, United States of America.
    Jacob, Stefan
    Karolinska Institutet, Stockholm, Sweden.
    Temirov, Jamshid
    St. Jude Children’s Research Hospital, Memphis, Tennessee, United States of America.
    Fang, Jie
    St. Jude Children’s Research Hospital, Memphis, Tennessee, United States of America.
    Mellado-Lagarde, Marcia
    St. Jude Children’s Research Hospital, Memphis, Tennessee, United States of America; University of Brigthon, Brighton, United Kingdom.
    Gursky, Richard
    St. Jude Children’s Research Hospital, Memphis, Tennessee, United States of America.
    Horner, Linda
    St. Jude Children’s Research Hospital, Memphis, Tennessee, United States of America.
    Leibiger, Barbara
    Karolinska Institutet, Stockholm, Sweden.
    Leijon, Sara
    Karolinska Institutet, Stockholm, Sweden.
    Centonze, Victoria E
    St. Jude Children’s Research Hospital, Memphis, Tennessee, United States of America.
    Berggren, Per-Olof
    Karolinska Institutet, Stockholm, Sweden.
    Frase, Sharon
    St. Jude Children’s Research Hospital, Memphis, Tennessee, United States of America.
    Auer, Manfred
    Lawrence Berkeley National Laboratory, Berkeley, California,United States of America.
    Brownell, William E
    Baylor College of Medicine, Houston, Texas, United States of America.
    Fridberger, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Karolinska Institutet, Stockholm, Sweden; Karolinska University Hospital, Stockholm, Sweden.
    Zuo, Jian
    St. Jude Children’s Research Hospital, Memphis, Tennessee, United States of America.
    Outer Hair Cell Lateral Wall Structure Constrains the Mobility of Plasma Membrane Proteins2015Inngår i: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, nr 9, artikkel-id e1005500Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Nature's fastest motors are the cochlear outer hair cells (OHCs). These sensory cells use a membrane protein, Slc26a5 (prestin), to generate mechanical force at high frequencies, which is essential for explaining the exquisite hearing sensitivity of mammalian ears. Previous studies suggest that Slc26a5 continuously diffuses within the membrane, but how can a freely moving motor protein effectively convey forces critical for hearing? To provide direct evidence in OHCs for freely moving Slc26a5 molecules, we created a knockin mouse where Slc26a5 is fused with YFP. These mice and four other strains expressing fluorescently labeled membrane proteins were used to examine their lateral diffusion in the OHC lateral wall. All five proteins showed minimal diffusion, but did move after pharmacological disruption of membrane-associated structures with a cholesterol-depleting agent and salicylate. Thus, our results demonstrate that OHC lateral wall structure constrains the mobility of plasma membrane proteins and that the integrity of such membrane-associated structures are critical for Slc26a5's active and structural roles. The structural constraint of membrane proteins may exemplify convergent evolution of cellular motors across species. Our findings also suggest a possible mechanism for disorders of cholesterol metabolism with hearing loss such as Niemann-Pick Type C diseases.

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