| 1. |
- Aabel, Peder, et al.
(author)
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Transcription and microRNA Profiling of Cultured Human Tympanic Membrane Epidermal Keratinocytes
- 2018
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In: Journal of the Association for Research in Otolaryngology. - : SPRINGER. - 1525-3961 .- 1438-7573. ; 19:3, s. 243-260
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Journal article (peer-reviewed)abstract
- The human tympanic membrane (TM) has a thin outer epidermal layer which plays an important role in TM homeostasis and ear health. The specialised cells of the TM epidermis have a different physiology compared to normal skin epidermal keratinocytes, displaying a dynamic and constitutive migration that maintains a clear TM surface and assists in regeneration. Here, we characterise and compare molecular phenotypes in keratinocyte cultures from TM and normal skin. TM keratinocytes were isolated by enzymatic digestion and cultured in vitro. We compared global mRNA and microRNA expression of the cultured cells with that of human epidermal keratinocyte cultures. Genes with either relatively higher or lower expression were analysed further using the biostatistical tools g:Profiler and Ingenuity Pathway Analysis. Approximately 500 genes were found differentially expressed. Gene ontology enrichment and Ingenuity analyses identified cellular migration and closely related biological processes to be the most significant functions of the genes highly expressed in the TM keratinocytes. The genes of low expression showed a marked difference in homeobox (HOX) genes of clusters A and C, giving the TM keratinocytes a strikingly low HOX gene expression profile. An in vitro scratch wound assay showed a more individualised cell movement in cells from the tympanic membrane than normal epidermal keratinocytes. We identified 10 microRNAs with differential expression, several of which can also be linked to regulation of cell migration and expression of HOX genes. Our data provides clues to understanding the specific physiological properties of TM keratinocytes, including candidate genes for constitutive migration, and may thus help focus further research.
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| 2. |
- Cederroth, Christopher R., et al.
(author)
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Screening for Circulating Inflammatory Proteins Does Not Reveal Plasma Biomarkers of Constant Tinnitus
- 2023
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In: Journal of the Association for Research in Otolaryngology. - 1525-3961 .- 1438-7573. ; 24:6, s. 593-606
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Journal article (peer-reviewed)abstract
- Background and Objective Tinnitus would benefit from an objective biomarker. The goal of this study is to identify plasma biomarkers of constant and chronic tinnitus among selected circulating inflammatory proteins.Methods A case–control retrospective study on 548 cases with constant tinnitus and 548 matched controls from the Swedish Tinnitus Outreach Project (STOP), whose plasma samples were examined using Olink’s Inflammatory panel. Replication and meta-analysis were performed using the same method on samples from the TwinsUK cohort. Participants from LifeGene, whose blood was collected in Stockholm and Umeå, were recruited to STOP for a tinnitus subtyping study. An age and sex matching was performed at the individual level. TwinsUK participants (n = 928) were selected based on self-reported tinnitus status over 2 to 10 years. Primary outcomes include normalized levels for 96 circulating proteins, which were used as an index test. No reference standard was available in this study.Results After adjustment for age, sex, BMI, smoking, hearing loss, and laboratory site, the top proteins identified were FGF-21, MCP4, GDNF, CXCL9, and MCP-1; however, these were no longer statistically significant after correction for multiple testing. Stratification by sex did not yield any significant associations. Similarly, associations with hearing loss or other tinnitus-related comorbidities such as stress, anxiety, depression, hyperacusis, temporomandibular joint disorders, and headache did not yield any significant associations. Analysis in the TwinsUK failed in replicating the top candidates. Meta-analysis of STOP and TwinsUK did not reveal any significant association. Using elastic net regularization, models exhibited poor predictive capacity tinnitus based on inflammatory markers [sensitivity = 0.52 (95% CI 0.47–0.57), specificity = 0.53 (0.48–0.58), positive predictive value = 0.52 (0.47–0.56), negative predictive values = 0.53 (0.49–0.58), and AUC = 0.53 (0.49–0.56)].Discussion Our results did not identify significant associations of the selected inflammatory proteins with constant tinnitus. Future studies examining longitudinal relations among those with more severe tinnitus and using more recent expanded proteomics platforms and sampling of cerebrospinal fluid could increase the likelihood of identifying relevant molecular biomarkers.
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| 3. |
- Cederroth, Christopher R., et al.
(author)
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Screening for Circulating Inflammatory Proteins Does Not Reveal Plasma Biomarkers of Constant Tinnitus
- 2023
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In: Journal of the Association for Research in Otolaryngology. - : Springer Nature. - 1525-3961 .- 1438-7573. ; 24:6, s. 593-606
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Journal article (peer-reviewed)abstract
- Background and Objective: Tinnitus would benefit from an objective biomarker. The goal of this study is to identify plasma biomarkers of constant and chronic tinnitus among selected circulating inflammatory proteins. Methods: A case–control retrospective study on 548 cases with constant tinnitus and 548 matched controls from the Swedish Tinnitus Outreach Project (STOP), whose plasma samples were examined using Olink’s Inflammatory panel. Replication and meta-analysis were performed using the same method on samples from the TwinsUK cohort. Participants from LifeGene, whose blood was collected in Stockholm and Umeå, were recruited to STOP for a tinnitus subtyping study. An age and sex matching was performed at the individual level. TwinsUK participants (n = 928) were selected based on self-reported tinnitus status over 2 to 10 years. Primary outcomes include normalized levels for 96 circulating proteins, which were used as an index test. No reference standard was available in this study. Results: After adjustment for age, sex, BMI, smoking, hearing loss, and laboratory site, the top proteins identified were FGF-21, MCP4, GDNF, CXCL9, and MCP-1; however, these were no longer statistically significant after correction for multiple testing. Stratification by sex did not yield any significant associations. Similarly, associations with hearing loss or other tinnitus-related comorbidities such as stress, anxiety, depression, hyperacusis, temporomandibular joint disorders, and headache did not yield any significant associations. Analysis in the TwinsUK failed in replicating the top candidates. Meta-analysis of STOP and TwinsUK did not reveal any significant association. Using elastic net regularization, models exhibited poor predictive capacity tinnitus based on inflammatory markers [sensitivity = 0.52 (95% CI 0.47–0.57), specificity = 0.53 (0.48–0.58), positive predictive value = 0.52 (0.47–0.56), negative predictive values = 0.53 (0.49–0.58), and AUC = 0.53 (0.49–0.56)]. Discussion: Our results did not identify significant associations of the selected inflammatory proteins with constant tinnitus. Future studies examining longitudinal relations among those with more severe tinnitus and using more recent expanded proteomics platforms and sampling of cerebrospinal fluid could increase the likelihood of identifying relevant molecular biomarkers.
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| 4. |
- Cederroth, CR
(author)
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Reporting and Sharing Matters
- 2023
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In: Journal of the Association for Research in Otolaryngology : JARO. - 1438-7573. ; 24:5, s. 463-
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Journal article (other academic/artistic)
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| 5. |
- Fransen, Erik, et al.
(author)
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Occupational Noise, Smoking, and a High Body Mass Index are Risk Factors for Age-related Hearing Impairment and Moderate Alcohol Consumption is Protective : A European Population-based Multicenter Study
- 2008
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In: Journal of the Association for Research in Otolaryngology. - : Springer. - 1525-3961 .- 1438-7573. ; 9:3, s. 264-276
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Journal article (peer-reviewed)abstract
- A multicenter study was set up to elucidate the environmental and medical risk factors contributing to age-related hearing impairment (ARHI). Nine subsamples, collected by nine audiological centers across Europe, added up to a total of 4,083 subjects between 53 and 67 years. Audiometric data (pure-tone average [PTA]) were collected and the participants filled out a questionnaire on environmental risk factors and medical history. People with a history of disease that could affect hearing were excluded. PTAs were adjusted for age and sex and tested for association with exposure to risk factors. Noise exposure was associated with a significant loss of hearing at high sound frequencies (>1 kHz). Smoking significantly increased high-frequency hearing loss, and the effect was dose-dependent. The effect of smoking remained significant when accounting for cardiovascular disease events. Taller people had better hearing on average with a more pronounced effect at low sound frequencies (<2 kHz). A high body mass index (BMI) correlated with hearing loss across the frequency range tested. Moderate alcohol consumption was inversely correlated with hearing loss. Significant associations were found in the high
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| 6. |
- Hultgård-Ekwall, Anna-Karin, et al.
(author)
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An interstitial network of podoplanin-expressing cells in the human endolymphatic duct
- 2006
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In: Journal of the Association for Research in Otolaryngology. - : Springer Science and Business Media LLC. - 1525-3961 .- 1438-7573. ; 7:1, s. 38-47
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Journal article (peer-reviewed)abstract
- The human endolymphatic duct (ED) with encompassing interstitial connective tissue (CT) is believed to be important for endolymph resorption and fluid pressure regulation of the inner ear. The periductal CT cells are interconnected via numerous cellular extensions, but do not form vessel structures. Here we report that the periductal CT is populated by two distinct cell phenotypes; one expressing podoplanin, a protein otherwise found on lymph endothelia and on epithelia involved in fluid fluxes, and a second expressing a fibroblast marker. A majority of the interstitial cells expressed podoplanin but not the lymphatic endothelial cell markers hyaluronan receptor (LYVE-1) or vascular endothelial growth factor receptor-3 (VEGFR-3). The fibroblast marker positive cells were found close to the ED epithelium. In the mid- and distal parts of the ED, these cells were enriched under folded epithelia. Furthermore, subepithelial CT cells were found to express activated platelet derived growth factor (PDGF)-beta receptors. Cultured CT cells from human inner ear periductal and perisaccular explant tissues were identified as fibroblasts. These cells compacted a three-dimensional collagen lattice by a process that could be promoted by PDGF-BB, a factor involved in interstitial fluid pressure regulation. Our results are compatible with the notion that the periductal CT cells are involved in the regulation of inner ear fluid pressure. By active compaction of the periductal CT and by the formation of villous structures, the CT cells could modulate fluid fluxes over the ED epithelium as well as the longitudinal flow of endolymph in the ED.
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| 7. |
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| 8. |
- Raufer, Stefan, et al.
(author)
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Anatomy of the Human Osseous Spiral Lamina and Cochlear Partition Bridge: Relevance for Cochlear Partition Motion
- 2020
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In: Journal of the Association for Research in Otolaryngology. - : SPRINGER. - 1525-3961 .- 1438-7573. ; 21:2, s. 171-182
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Journal article (peer-reviewed)abstract
- The classic view of cochlear partition (CP) motion, generalized to be for all mammals, was derived from basal-turn measurements in laboratory animals. Recently, we reported motion of the human CP in the cochlear base that differs substantially from the classic view. We described a human soft tissue "bridge" (non-existent in the classic view) between the osseous spiral lamina (OSL) and basilar membrane (BM), and showed how OSL and bridge move in response to sound. Here, we detail relevant human anatomy to better understand the relationship between form and function. The bridge and BM have similar widths that increase linearly from base to apex, whereas the OSL width decreases from base to apex, leading to an approximately constant total CP width throughout the cochlea. The bony three-dimensional OSL microstructure, reconstructed from unconventionally thin, 2-mu m histological sections, revealed thin, radially wide OSL plates with pores that vary in size, extent, and distribution with cochlear location. Polarized light microscopy revealed collagen fibers in the BM that spread out medially through the bridge to connect to the OSL. The long width and porosity of the OSL may explain its considerable bending flexibility. The similarity of BM and bridge widths along the cochlea, both containing continuous collagen fibers, may make them a functional unit and allow maximum CP motion near the bridge-BM boundary, as recently described. These anatomical findings may help us better understand the motion of the structures surrounding the organ of Corti and how they shape the input to the cochlear sensory mechanism.
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| 9. |
- Santi, Peter A., et al.
(author)
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Scanning Electron Microscopic Examination of the Extracellular Matrix in the Decellularized Mouse and Human Cochlea
- 2016
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In: Journal of the Association for Research in Otolaryngology. - : Springer Science and Business Media LLC. - 1525-3961 .- 1438-7573. ; 17:3, s. 159-171
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Journal article (peer-reviewed)abstract
- Decellularized tissues have been used to investigate the extracellular matrix (ECM) in a number of different tissues and species. Santi and Johnson JARO 14: 3-15 (2013) first described the decellularized inner ear in the mouse, rat, and human using scanning thin-sheet laser imaging microscopy (sTSLIM). The purpose of the present investigation is to examine decellularized cochleas in the mouse and human at higher resolution using scanning electron microscopy (SEM). Fresh cochleas were harvested and decellularized using detergent extraction methods. Following decellularization, the ECM of the bone, basilar membrane, spiral limbus, and ligament remained, and all of the cells were removed from the cochlea. A number of similarities and differences in the ECM of the mouse and human were observed. A novel, spirally directed structure was present on the basilar membrane and is located at the border between Hensen and Boettcher cells. These septa-like structures formed a single row in the mouse and multiple rows in the human. The basal lamina of the stria vascularis capillaries was present and appeared thicker in the human compared with the mouse. In the mouse, numerous openings beneath the spiral prominence that previously housed the root processes of the external sulcus cells were observed but in the human there was only a single row of openings. These and other anatomical differences in the ECM between the mouse and human may reflect functional differences and/or be due to aging; however, decellularized cochleas provide a new way to examine the cochlear ECM and reveal new observations.
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| 10. |
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