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Bagger-Sjoback, D., Stromback, K., Hakizimana, P., Plue, J., Larsson, C., Hultcrantz, M., . . . Fridberger, A. (2015). A Randomised, Double Blind Trial of N-Acetylcysteine for Hearing Protection during Stapes Surgery. PLoS ONE, 10(3), e0115657
Open this publication in new window or tab >>A Randomised, Double Blind Trial of N-Acetylcysteine for Hearing Protection during Stapes Surgery
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 3, p. e0115657-Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Public Library of Science, 2015
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-117231 (URN)10.1371/journal.pone.0115657 (DOI)000351276300003 ()25763866 (PubMedID)
Note

Funding Agencies|AFA Forsakrings AB; Swedish Research Council [K2011-63X-14061-11-3]; Research Council for Working Life and Social Research [2006-1526]; Swedish National Association for Hard of Hearing People; Tysta Skolan foundation

Available from: 2015-04-22 Created: 2015-04-21 Last updated: 2017-12-04
Hakizimana, P. & Fridberger, A. (2015). Effects of salicylate on sound-evoked outer hair cell stereocilia deflections. Pflügers Archiv: European Journal of Physiology, 467(9), 2021-2029
Open this publication in new window or tab >>Effects of salicylate on sound-evoked outer hair cell stereocilia deflections
2015 (English)In: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 467, no 9, p. 2021-2029Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Springer Berlin/Heidelberg, 2015
Keywords
Outer hair cells, Hearing, Salicylate, Tributyltin, Mechanotransduction, sound-evoked stereocilia movements
National Category
Health Sciences
Identifiers
urn:nbn:se:liu:diva-112088 (URN)10.1007/s00424-014-1646-4 (DOI)000359812600013 ()25392240 (PubMedID)
Funder
Swedish Research CouncilWenner-Gren Foundations
Note

Funders. Swedish Research Council [K2011-63X-14061-11-3]; Swedish Council for Working Life and Social Research [2006-1526]; Wallenberg foundations; Torsten Soderberg foundation; Tysta Skolan Foundation; Horselskadades Riksforbund; Wenner-Gren foundations

Available from: 2014-11-13 Created: 2014-11-13 Last updated: 2017-12-05
Bagger-Sjoback, D., Stromback, K., Hultcrantz, M., Papatziamos, G., Smeds, H., Danckwardt-Lilliestrom, N., . . . Fridberger, A. (2015). High-frequency hearing, tinnitus, and patient satisfaction with stapedotomy: A randomized prospective study. Scientific Reports, 5(13341)
Open this publication in new window or tab >>High-frequency hearing, tinnitus, and patient satisfaction with stapedotomy: A randomized prospective study
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2015 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, no 13341Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Nature Publishing Group: Open Access Journals - Option C / Nature Publishing Group, 2015
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-121105 (URN)10.1038/srep13341 (DOI)000359839200001 ()26293121 (PubMedID)
Note

Funding Agencies|AFA Forsakrings AB; Swedish Research Council [K2014-63X-14061-14-5]; Stockholm County Council; Tysta Skolan foundation; Horselskadades Riksforbund; Swedish Research Council for Health, Working Life and Welfare [2006-1526]

Available from: 2015-09-07 Created: 2015-09-07 Last updated: 2017-12-04
Yamashita, T., Hakizimana, P., Wu, S., Hassan, A., Jacob, S., Temirov, J., . . . Zuo, J. (2015). Outer Hair Cell Lateral Wall Structure Constrains the Mobility of Plasma Membrane Proteins. PLOS Genetics, 11(9), Article ID e1005500.
Open this publication in new window or tab >>Outer Hair Cell Lateral Wall Structure Constrains the Mobility of Plasma Membrane Proteins
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2015 (English)In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 9, article id e1005500Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Public Library of Science, 2015
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-121278 (URN)10.1371/journal.pgen.1005500 (DOI)000362269000022 ()26352669 (PubMedID)
Note

Funding text: National Institutes of Health [DC006471, P30CA21765, DC00354, DC02775, P01GM051487]; Office of Naval Research [N000140911014, N000141210191, N000141210775]; Swedish Research Council [K2014-63X-14061-14-5]; Research Council for Working Life and Social Rese

Available from: 2015-09-11 Created: 2015-09-11 Last updated: 2018-02-23
Hakizimana, P., Brownell, W. E., Jacob, S. & Fridberger, A. (2012). Sound-induced length changes in outer hair cell stereocilia. Nature Communications, 3
Open this publication in new window or tab >>Sound-induced length changes in outer hair cell stereocilia
2012 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 3Article in journal (Refereed) Published
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.

National Category
Neurosciences
Identifiers
urn:nbn:se:liu:diva-101049 (URN)10.1038/ncomms2100 (DOI)23033070 (PubMedID)
Available from: 2013-11-19 Created: 2013-11-19 Last updated: 2018-01-11
Brownell, W. E., Jacob, S., Hakizimana, P., Ulfendahl, M. & Fridberger, A. (2011). Decreasing Outer Hair Cell Membrane Cholesterol Increases Cochlear Electromechanics. In: Shera, CA; Olson, ES (Ed.), WHAT FIRE IS IN MINE EARS: PROGRESS IN AUDITORY BIOMECHANICS: PROCEEDINGS OF THE 11TH INTERNATIONAL MECHANICS OF HEARING WORKSHOP: . Paper presented at AIP Conf. 2011. Williamstown, Massachusetts (USA). American Institute of Physics (AIP), 1403
Open this publication in new window or tab >>Decreasing Outer Hair Cell Membrane Cholesterol Increases Cochlear Electromechanics
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2011 (English)In: 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. 1403Conference paper, Published paper (Refereed)
Place, publisher, year, edition, pages
American Institute of Physics (AIP), 2011
Series
AIP Conference Proceedings, ISSN 0094-243X ; 1403
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-107589 (URN)10.1063/1.3658076 (DOI)000301945200025 ()978-0-7354-0975-0 (ISBN)
Conference
AIP Conf. 2011. Williamstown, Massachusetts (USA)
Note

The effect of decreasing membrane cholesterol on the mechanical response of the cochlea to acoustic and/or electrical stimulation was monitored using laser interferometry. In contrast to pharmacological interventions that typically decrease cochlear electromechanics, reducing membrane cholesterol increased the response. The electromechanical response in untreated preparations was asymmetric with greater displacements in response to positive currents and cholesterol depletion increased the asymmetry. The results confirm that outer hair cell electromotility is enhanced by low membrane cholesterol. The asymmetry of the response indicates the outer hair cell resting membrane potential is hyperpolarized relative to the voltage of maximum gain for the outer hair cell voltage‐displacement function. The magnitude of the response increase suggests a non‐uniform distribution of cholesterol along the lateral wall of normal adult outer hair cells.

Available from: 2014-06-17 Created: 2014-06-17 Last updated: 2017-01-18
Brownell, W. E., Jacob, S., Hakizimana, P., Ulfendahl, M. & Fridberger, A. (2011). Membrane cholesterol modulates cochlear electromechanics. Pflügers Archiv: European Journal of Physiology, 461(6), 677-686
Open this publication in new window or tab >>Membrane cholesterol modulates cochlear electromechanics
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2011 (English)In: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 461, no 6, p. 677-686Article in journal (Refereed) Published
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.

National Category
Neurosciences
Identifiers
urn:nbn:se:liu:diva-101057 (URN)10.1007/s00424-011-0942-5 (DOI)21373862 (PubMedID)
Available from: 2013-11-19 Created: 2013-11-19 Last updated: 2018-01-11
Hakizimana, P., Brownell, W. E., Jacob, S. & Fridberger, A. (2011). Sound‐Evoked Length Changes of the Outer Hair Cell Stereocilia Bundle are Modulated by Endocochlear Currents. In: Christopher A. Shera and Elizabeth S. Olson (Ed.), WHAT FIRE IS IN MINE EARS: PROGRESS IN AUDITORY BIOMECHANICS: Proceedings of the 11th International Mechanics of Hearing Workshop: . Paper presented at AIP Conf. Williamstown, 2011. Massachusetts (USA). American Institute of Physics (AIP), 1403
Open this publication in new window or tab >>Sound‐Evoked Length Changes of the Outer Hair Cell Stereocilia Bundle are Modulated by Endocochlear Currents
2011 (English)In: 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. 1403Conference paper, Published paper (Refereed)
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.

Place, publisher, year, edition, pages
American Institute of Physics (AIP), 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-107585 (URN)10.1063/1.3658056 (DOI)000301945200005 ()
Conference
AIP Conf. Williamstown, 2011. Massachusetts (USA)
Available from: 2014-06-17 Created: 2014-06-17 Last updated: 2017-01-19
Hakizimana, P. (2009). Interactions between membrane transporters and phospholipids: Phosphatidylethanolamine regulates the function and the structure of LmrP, a bacterial ... associated to antibiotic resistance. VDM Verlag Dr. Müller Aktiengesellschaft & Co. KG
Open this publication in new window or tab >>Interactions between membrane transporters and phospholipids: Phosphatidylethanolamine regulates the function and the structure of LmrP, a bacterial ... associated to antibiotic resistance
2009 (English)Book (Other academic)
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.

Place, publisher, year, edition, pages
VDM Verlag Dr. Müller Aktiengesellschaft & Co. KG, 2009. p. 92
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-107188 (URN)978-3639136708 (ISBN)
Available from: 2014-06-09 Created: 2014-06-09 Last updated: 2015-02-09Bibliographically approved
Hakizimana, P., Masureel, M., Gbaguidi, B., Ruysschaert, J.-M. & Govaerts, C. (2008). Interactions between phosphatidylethanolamine headgroup and LmrP, a multidrug transporter: a conserved mechanism for proton gradient sensing?. Journal of Biological Chemistry, 283(14), 9369-9376
Open this publication in new window or tab >>Interactions between phosphatidylethanolamine headgroup and LmrP, a multidrug transporter: a conserved mechanism for proton gradient sensing?
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2008 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 283, no 14, p. 9369-9376Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
American Society for Biochemistry and Molecular Biology, 2008
National Category
Biomedical Laboratory Science/Technology
Identifiers
urn:nbn:se:liu:diva-107020 (URN)10.1074/jbc.M708427200 (DOI)18234676 (PubMedID)
Available from: 2014-06-03 Created: 2014-06-03 Last updated: 2017-12-05Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-9615-3885

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