| 1. |
- Devarajan, R., et al.
(författare)
-
Targeting collagen XVIII improves the efficiency of ErbB inhibitors in breast cancer models
- 2023
-
Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 133:18
-
Tidskriftsartikel (refereegranskat)abstract
- The tumor extracellular matrix (ECM) critically regulates cancer progression and treatment response. Expression of the basement membrane component collagen XVIII (ColXVIII) is induced in solid tumors, but its involvement in tumorigenesis has remained elusive. We show here that ColXVIII was markedly upregulated in human breast cancer (BC) and was closely associated with a poor prognosis in high-grade BCs. We discovered a role for ColXVIII as a modulator of epidermal growth factor receptor tyrosine kinase (ErbB) signaling and show that it forms a complex with ErbB1 and-2 (also known as EGFR and human epidermal growth factor receptor 2 [HER2]) and alpha 6-integrin to promote cancer cell proliferation in a pathway involving its N-terminal portion and the MAPK/ERK1/2 and PI3K/AKT cascades. Studies using Col18a1 mouse models crossed with the mouse mammary tumor virus-polyoma virus middle T antigen (MMTV-PyMT) mammary carcinogenesis model showed that ColXVIII promoted BC growth and metastasis in a tumor cell-autonomous manner. Moreover, the number of mammary cancer stem cells was significantly reduced in the MMTV-PyMT and human cell models upon ColXVIII inhibition. Finally, ablation of ColXVIII substantially improved the efficacy of ErbB-targeting therapies in both preclinical models. In summary, ColXVIII was found to sustain the stemness properties of BC cells and tumor progression and metastasis through ErbB signaling, suggesting that targeting ColXVIII in the tumor milieu may have important therapeutic potential.
|
|
| 2. |
|
|
| 3. |
- Li, Hao, 1984-, et al.
(författare)
-
Unlocking the human inner ear for therapeutic intervention
- 2022
-
Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 12:1
-
Tidskriftsartikel (refereegranskat)abstract
- The human inner ear contains minute three-dimensional neurosensory structures that are deeply embedded within the skull base, rendering them relatively inaccessible to regenerative therapies for hearing loss. Here we provide a detailed characterisation of the functional architecture of the space that hosts the cell bodies of the auditory nerve to make them safely accessible for the first time for therapeutic intervention. We used synchrotron phase-contrast imaging which offers the required microscopic soft-tissue contrast definition while simultaneously displaying precise bony anatomic detail. Using volume-rendering software we constructed highly accurate 3-dimensional representations of the inner ear. The cell bodies are arranged in a bony helical canal that spirals from the base of the cochlea to its apex; the canal volume is 1.6 mu L but with a diffusion potential of 15 mu L. Modelling data from 10 temporal bones enabled definition of a safe trajectory for therapeutic access while preserving the cochlea's internal architecture. We validated the approach through surgical simulation, anatomical dissection and micro-radiographic analysis. These findings will facilitate future clinical trials of novel therapeutic interventions to restore hearing.
|
|
| 4. |
- Welander, Nike Zoe, et al.
(författare)
-
Migraine, inflammatory bowel disease and celiac disease : A Mendelian randomization study
- 2023
-
Ingår i: Headache. - : John Wiley & Sons. - 0017-8748 .- 1526-4610. ; 63:5, s. 642-651
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To assess whether migraine may be genetically and/or causally associated with inflammatory bowel disease (IBD) or celiac disease.BACKGROUND: Migraine has been linked to IBD and celiac disease in observational studies, but whether this link may be explained by a shared genetic basis or could be causal has not been established. The presence of a causal association could be clinically relevant, as treating one of these medical conditions might mitigate the symptoms of a causally linked condition.METHODS: Linkage disequilibrium score regression and two-sample bidirectional Mendelian randomization analyses were performed using summary statistics from cohort-based genome-wide association studies of migraine (59,674 cases; 316,078 controls), IBD (25,042 cases; 34,915 controls) and celiac disease (11,812 or 4533 cases; 11,837 or 10,750 controls). Migraine with and without aura were analyzed separately, as were the two IBD subtypes Crohn's disease and ulcerative colitis. Positive control analyses and conventional Mendelian randomization sensitivity analyses were performed.RESULTS: Migraine was not genetically correlated with IBD or celiac disease. No evidence was observed for IBD (odds ratio [OR] 1.00, 95% confidence interval [CI] 0.99-1.02, p = 0.703) or celiac disease (OR 1.00, 95% CI 0.99-1.02, p = 0.912) causing migraine or migraine causing either IBD (OR 1.08, 95% CI 0.96-1.22, p = 0.181) or celiac disease (OR 1.08, 95% CI 0.79-1.48, p = 0.614) when all participants with migraine were analyzed jointly. There was some indication of a causal association between celiac disease and migraine with aura (OR 1.04, 95% CI 1.00-1.08, p = 0.045), between celiac disease and migraine without aura (OR 0.95, 95% CI 0.92-0.99, p = 0.006), as well as between migraine without aura and ulcerative colitis (OR 1.15, 95% CI 1.02-1.29, p = 0.025). However, the results were not significant after multiple testing correction.CONCLUSIONS: We found no evidence of a shared genetic basis or of a causal association between migraine and either IBD or celiac disease, although we obtained some indications of causal associations with migraine subtypes.
|
|
| 5. |
- Al-Sabri, Mohamed H., et al.
(författare)
-
Statins Induce Locomotion and Muscular Phenotypes in Drosophila melanogaster That Are Reminiscent of Human Myopathy : Evidence for the Role of the Chloride Channel Inhibition in the Muscular Phenotypes
- 2022
-
Ingår i: Cells. - : MDPI. - 2073-4409. ; 11:22
-
Tidskriftsartikel (refereegranskat)abstract
- The underlying mechanisms for statin-induced myopathy (SIM) are still equivocal. In this study, we employ Drosophila melanogaster to dissect possible underlying mechanisms for SIM. We observe that chronic fluvastatin treatment causes reduced general locomotion activity and climbing ability. In addition, transmission microscopy of dissected skeletal muscles of fluvastatin-treated flies reveals strong myofibrillar damage, including increased sarcomere lengths and Z-line streaming, which are reminiscent of myopathy, along with fragmented mitochondria of larger sizes, most of which are round-like shapes. Furthermore, chronic fluvastatin treatment is associated with impaired lipid metabolism and insulin signalling. Mechanistically, knockdown of the statin-target Hmgcr in the skeletal muscles recapitulates fluvastatin-induced mitochondrial phenotypes and lowered general locomotion activity; however, it was not sufficient to alter sarcomere length or elicit myofibrillar damage compared to controls or fluvastatin treatment. Moreover, we found that fluvastatin treatment was associated with reduced expression of the skeletal muscle chloride channel, C1C-a (Drosophila homolog of CLCN1), while selective knockdown of skeletal muscle C1C-a also recapitulated fluvastatin-induced myofibril damage and increased sarcomere lengths. Surprisingly, exercising fluvastatin-treated flies restored C1C-a expression and normalized sarcomere lengths, suggesting that fluvastatin-induced myofibrillar phenotypes could be linked to lowered C1C-a expression. Taken together, these results may indicate the potential role of C1C-a inhibition in statinassociated muscular phenotypes. This study underlines the importance of Drosophila melanogaster as a powerful model system for elucidating the locomotion and muscular phenotypes, promoting a better understanding of the molecular mechanisms underlying SIM.
|
|
| 6. |
- Al-Sabri, Mohamed H., et al.
(författare)
-
The regulatory role of AP-2 beta in monoaminergic neurotransmitter systems : insights on its signalling pathway, linked disorders and theragnostic potential
- 2022
-
Ingår i: Cell & Bioscience. - : BioMed Central (BMC). - 2045-3701. ; 12:1
-
Forskningsöversikt (refereegranskat)abstract
- Monoaminergic neurotransmitter systems play a central role in neuronal function and behaviour. Dysregulation of these systems gives rise to neuropsychiatric and neurodegenerative disorders with high prevalence and societal burden, collectively termed monoamine neurotransmitter disorders (MNDs). Despite extensive research, the transcriptional regulation of monoaminergic neurotransmitter systems is not fully explored. Interestingly, certain drugs that act on these systems have been shown to modulate central levels of the transcription factor AP-2 beta (AP-2 beta, gene: TFAP2B). AP-2 beta regulates multiple key genes within these systems and thereby its levels correlate with monoamine neurotransmitters measures; yet, its signalling pathways are not well understood. Moreover, although dysregulation of TFAP2B has been associated with MNDs, the underlying mechanisms for these associations remain elusive. In this context, this review addresses AP-2 beta, considering its basic structural aspects, regulation and signalling pathways in the controlling of monoaminergic neurotransmitter systems, and possible mechanisms underpinning associated MNDS. It also underscores the significance of AP-2 beta as a potential diagnostic biomarker and its potential and limitations as a therapeutic target for specific MNDs as well as possible pharmaceutical interventions for targeting it. In essence, this review emphasizes the role of AP-2 beta as a key regulator of the monoaminergic neurotransmitter systems and its importance for understanding the pathogenesis and improving the management of MNDs.
|
|
| 7. |
- Andersson, P, et al.
(författare)
-
Youth with severe mental illness and complex non-somatic motor abnormalities: conflicting conceptualizations and unequal treatment
- 2022
-
Ingår i: Npj mental health research. - : Springer Science and Business Media LLC. - 2731-4251. ; 1:1, s. 13-
-
Tidskriftsartikel (refereegranskat)abstract
- Two emerging diagnostic concepts promote distinct treatments for youth with acute-onset motor abnormalities and severe concurrent psychiatric symptoms: Pediatric acute-onset neuropsychiatric syndrome (PANS) and pediatric catatonia. Both have institutional approval in parts of Europe and in the USA, meriting an unconditional comparison of supporting evidence. Here we report results of qualitative and quantitative analyses of literature and Swedish National Registry Data suggesting that (1) catatonic patients are liable to fulfilling diagnostic criteria for PANS, (2) three conservatively assessed PANS case-reports present with possible unrecognized catatonia, (3) lithium and electroconvulsive therapy usage frequencies in Swedish minors (exclusively recommended for severe mental illness) are strongly intercorrelated and unequally distributed across Swedish counties, (4) established severe mental disorders are rarely overtly considered amongst PANS-specific research and (5) best-available evidence treatments appear markedly superior for pediatric catatonia compared to PANS in both childhood and adolescence. Prioritizing treatments for pediatric catatonia in concerned subjects could markedly improve treatment outcomes.
|
|
| 8. |
- Attwood, Misty M., et al.
(författare)
-
Soluble ligands as drug targets
- 2020
-
Ingår i: Nature reviews. Drug discovery. - : NATURE RESEARCH. - 1474-1776 .- 1474-1784. ; 19:10, s. 695-710
-
Forskningsöversikt (refereegranskat)abstract
- Historically, the main classes of drug targets have been receptors, enzymes, ion channels and transporters. However, owing largely to the rise of antibody-based therapies in the past two decades, soluble protein ligands such as inflammatory cytokines have become an increasingly important class of drug targets. In this Review, we analyse drugs targeting ligands that have reached clinical development at some point since 1992. We identify 291 drugs that target 99 unique ligands, and we discuss trends in the characteristics of the ligands, drugs and indications for which they have been tested. In the last 5 years, the number of ligand-targeting drugs approved by the FDA has doubled to 34, while the number of clinically validated ligand targets has doubled to 22. Cytokines and growth factors are the predominant types of targeted ligands (70%), and inflammation and autoimmune disorders, cancer and ophthalmological diseases are the top therapeutic areas for both approved agents and agents in clinical studies, reflecting the central role of cytokine and/or growth factor pathways in such diseases. With the rise of antibody-based therapies in the past two decades, soluble protein ligands such as inflammatory cytokines have become an increasingly important class of drug targets. This Review analyses drugs targeting ligands that have reached clinical development in the past three decades and discusses strategic issues such as the pros and cons of different ligand-targeting therapeutic modalities.
|
|
| 9. |
- Helpard, Luke, et al.
(författare)
-
An Approach for Individualized Cochlear Frequency Mapping Determined From 3D Synchrotron Radiation Phase-Contrast Imaging
- 2021
-
Ingår i: IEEE Transactions on Biomedical Engineering. - : Institute of Electrical and Electronics Engineers (IEEE). - 0018-9294 .- 1558-2531. ; 68:12, s. 3602-3611
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: Cochlear implants are traditionally programmed to stimulate according to a generalized frequency map, where individual anatomic variability is not considered when selecting the centre frequency of stimulation of each implant electrode. However, high variability in cochlear size and spatial frequency distributions exist among individuals. Generalized cochlear implant frequency maps can result in large pitch perception errors and reduced hearing outcomes for cochlear implant recipients. The objective of this work was to develop an individualized frequency mapping technique for the human cochlea to allow for patient-specific cochlear implant stimulation.Methods: Ten cadaveric human cochleae were scanned using synchrotron radiation phase-contrast imaging (SR-PCI) combined with computed tomography (CT). For each cochlea, ground truth angle-frequency measurements were obtained in three-dimensions using the SR-PCI CT data. Using an approach designed to minimize perceptual error in frequency estimation, an individualized frequency function was determined to relate angular depth to frequency within the cochlea.Results: The individualized frequency mapping function significantly reduced pitch errors in comparison to the current gold standard generalized approach.Conclusion and Significance: This paper presents for the first time a cochlear frequency map which can be individualized using only the angular length of cochleae. This approach can be applied in the clinical setting and has the potential to revolutionize cochlear implant programming for patients worldwide.
|
|
| 10. |
- Helpard, Luke, et al.
(författare)
-
Characterization of the human helicotrema : implications for cochlear duct length and frequency mapping
- 2020
-
Ingår i: Journal of Otolaryngology - Head & Neck Surgery. - : BMC. - 1916-0216. ; 49
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Despite significant anatomical variation amongst patients, cochlear implant frequency-mapping has traditionally followed a patient-independent approach. Basilar membrane (BM) length is required for patient-specific frequency-mapping, however cochlear duct length (CDL) measurements generally extend to the apical tip of the entire cochlea or have no clearly defined end-point. By characterizing the length between the end of the BM and the apical tip of the entire cochlea (helicotrema length), current CDL models can be corrected to obtain the appropriate BM length. Synchrotron radiation phase-contrast imaging has made this analysis possible due to the soft-tissue contrast through the entire cochlear apex.Methods: Helicotrema linear length and helicotrema angular length measurements were performed on synchrotron radiation phase-contrast imaging data of 14 cadaveric human cochleae. On a sub-set of six samples, the CDL to the apical tip of the entire cochlea (CDLTIP) and the BM length (CDLBM) were determined. Regression analysis was performed to assess the relationship between CDLTIP and CDLBM.Results: The mean helicotrema linear length and helicotrema angular length values were 1.6 +/- 0.9 mm and 67.8 +/- 37.9 degrees, respectively. Regression analysis revealed the following relationship between CDLTIP and CDLBM: CDLBM = 0.88(CDLTIP) + 3.71 (R-2 = 0.995).Conclusion: This is the first known study to characterize the length of the helicotrema in the context of CDL measurements. It was determined that the distance between the end of the BM and the tip of the entire cochlea is clinically consequential. A relationship was determined that can predict the BM length of an individual patient based on their respective CDL measured to the apical tip of the cochlea.
|
|
| 11. |
- Helpard, Luke, et al.
(författare)
-
Three-Dimensional Modeling and Measurement of the Human Cochlear Hook Region : Considerations for Tonotopic Mapping
- 2021
-
Ingår i: Otology and Neurotology. - : Lippincott Williams & Wilkins. - 1531-7129 .- 1537-4505. ; 42:6, s. E658-E665
-
Tidskriftsartikel (refereegranskat)abstract
- Hypothesis: Measuring the length of the basilar membrane (BM) in the cochlear hook region will result in improved accuracy of cochlear duct length (CDL) measurements.Background: Cochlear implant pitch mapping is generally performed in a patient independent approach, which has been shown to result in place-pitch mismatches. In order to customize cochlear implant pitch maps, accurate CDL measurements must be obtained. CDL measurements generally begin at the center of the round window (RW) and ignore the basal-most portion of the BM in the hook region. Measuring the size and morphology of the BM in the hook region can improve CDL measurements and our understanding of cochlear tonotopy.Methods: Ten cadaveric human cochleae underwent synchrotron radiation phase-contrast imaging. The length of the BM through the hook region and CDL were measured. Two different CDL measurements were obtained for each sample, with starting points at the center of the RW (CDLRW) and the basal-most tip of the BM (CDLHR). Regression analysis was performed to relate CDLRW to CDLHR. A three-dimensional polynomial model was determined to describe the average BM hook region morphology.Results: The mean CDLRW value was 33.03 ± 1.62 mm, and the mean CDLHR value was 34.68 ± 1.72 mm. The following relationship was determined between CDLRW and CDLHR: CDLHR = 1.06(CDLRW)-0.26 (R2 = 0.99).Conclusion: The length and morphology of the hook region was determined. Current measurements underestimate CDL in the hook region and can be corrected using the results herein.
|
|
| 12. |
- Kämpfe Nordström, Charlotta, et al.
(författare)
-
A Micro-CT and Synchrotron Imaging Study of the Human Endolymphatic Duct with Special Reference to Endolymph Outflow and Meniere's Disease
- 2020
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- Meniere’s disease remains enigmatic, and has no treatment with sufficient evidence. The characteristic histopathological finding is endolymphatic hydrops, suggesting either an overproduction or decreased reabsorption of endolymph in the human inner ear. This study presents the first analysis of the vascular plexus around the human endolymphatic duct using micro computed tomography and coherent synchrotron radiation with phase contrast imaging. Using a software program, data were processed by volume-rendering with scalar opacity mapping to create transparent three-dimensional reconstructions. A rich vascular plexus was discovered around the endolymphatic duct that drained into collecting channels, linked to the vestibular venous outflow system. This network is believed to make up the principal route for endolymph outflow, and its associated malfunction may result in endolymphatic hydrops and Meniere’s disease.
|
|
| 13. |
- Li, Hao, 1984-, et al.
(författare)
-
A Synchrotron and Micro-CT Study of the Human Endolymphatic Duct System : Is Meniere's Disease Caused by an Acute Endolymph Backflow?
- 2021
-
Ingår i: Frontiers in Surgery. - : Frontiers Media S.A.. - 2296-875X. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The etiology of Meniere's disease (MD) and endolymphatic hydrops believed to underlie its symptoms remain unknown. One reason may be the exceptional complexity of the human inner ear, its vulnerability, and surrounding hard bone. The vestibular organ contains an endolymphatic duct system (EDS) bridging the different fluid reservoirs. It may be essential for monitoring hydraulic equilibrium, and a dysregulation may result in distension of the fluid spaces or endolymphatic hydrops. Material and Methods: We studied the EDS using high-resolution synchrotron phase contrast non-invasive imaging (SR-PCI), and micro-computed tomography (micro-CT). Ten fresh human temporal bones underwent SR-PCI. One bone underwent micro-CT after fixation and staining with Lugol's iodine solution (I2KI) to increase tissue resolution. Data were processed using volume-rendering software to create 3D reconstructions allowing orthogonal sectioning, cropping, and tissue segmentation. Results: Combined imaging techniques with segmentation and tissue modeling demonstrated the 3D anatomy of the human saccule, utricle, endolymphatic duct, and sac together with connecting pathways. The utricular duct (UD) and utriculo-endolymphatic valve (UEV or Bast's valve) were demonstrated three-dimensionally for the first time. The reunion duct was displayed with micro-CT. It may serve as a safety valve to maintain cochlear endolymph homeostasis under certain conditions. Discussion: The thin reunion duct seems to play a minor role in the exchange of endolymph between the cochlea and vestibule under normal conditions. The saccule wall appears highly flexible, which may explain occult hydrops occasionally preceding symptoms in MD on magnetic resonance imaging (MRI). The design of the UEV and connecting ducts suggests that there is a reciprocal exchange of fluid among the utricle, semicircular canals, and the EDS. Based on the anatomic framework and previous experimental data, we speculate that precipitous vestibular symptoms in MD arise from a sudden increase in endolymph pressure caused by an uncontrolled endolymphatic sac secretion. A rapid rise in UD pressure, mediated along the fairly wide UEV, may underlie the acute vertigo attack, refuting the rupture/K+-intoxication theory.
|
|
| 14. |
- Li, Hao, 1984-, et al.
(författare)
-
Aeration of the Human Prussak's Space : A 3D Synchrotron Imaging Study
- 2021
-
Ingår i: Otology and Neurotology. - : Lippincott Williams & Wilkins. - 1531-7129 .- 1537-4505. ; 42:7, s. E894-E904
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives: Prussak's space (PS) is an intricate middle ear region which may play an essential role in the development of middle ear disease. The three-dimensional (3D) anatomy of the human PS and its drainage routes remain relatively unknown. Earlier studies have histologically analyzed PS, by micro-dissection and endoscopy. Here, we used synchrotron-radiation phase-contrast imaging (SR-PCI), 3D reconstructions, and modeling to study the framework of the human PS, including aeration pathways. It may lead to increased understanding of development of middle ear pathology.Design: Nine human temporal bone specimens underwent in-line SR-PCI at the Canadian Light Source in Saskatoon, Saskatchewan, Canada. Data were processed with volume-rendering software to create 3D reconstructions using scalar opacity mapping and segmentations to visualize its walls in fixed, undecalcified human temporal bones.Results: The PS was found to be an irregular, variably shaped chamber with different aeration systems. Three different drainage pathways were found: 1) via the posterior malleolar pouch of von Troltsch in seven of nine ears; 2) directly posterior-inferior into the mesotympanum medial to the posterior malleolar pouch in one ear; and 3) anteriorly in another. The posterior-inferior communications depended on the anatomy of the posterior malleolar fold. In one bilateral case, the aeration differed between the ears. Earlier descriptions of upper ventilation routes between the PS and the epitympanic spaces could not be substantiated.Conclusions: The 3D anatomy of the membrane folds organizing the PS in humans was demonstrated for the first time using in-line SR-PCI. The PS was always aerated into the mesotympanum, suggesting its relative independence of attic ventilation. The impact of its various drainage routes on middle ear ventilation and disease were discussed.
|
|
| 15. |
- Li, Hao, 1984-, et al.
(författare)
-
Synchrotron Radiation-Based Reconstruction of the Human Spiral Ganglion : Implications for Cochlear Implantation
- 2020
-
Ingår i: Ear and Hearing. - : LIPPINCOTT WILLIAMS & WILKINS. - 0196-0202 .- 1538-4667. ; 41:1, s. 173-181
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: To three-dimensionally reconstruct Rosenthal's canal (RC) housing the human spiral ganglion (SG) using synchrotron radiation phase-contrast imaging (SR-PCI). Straight cochlear implant electrode arrays were inserted to better comprehend the electro-cochlear interface in cochlear implantation (CI).Design: SR-PCI was used to reconstruct the human cochlea with and without cadaveric CI. Twenty-eight cochleae were volume rendered, of which 12 underwent cadaveric CI with a straight electrode via the round window (RW). Data were input into the 3D Slicer software program and anatomical structures were modeled using a threshold paint tool.Results: The human RC and SG were reproduced three-dimensionally with artefact-free imaging of electrode arrays. The anatomy of the SG and its relationship to the sensory organ (Corti) and soft and bony structures were assessed.Conclusions: SR-PCI and computer-based three-dimensional reconstructions demonstrated the relationships among implanted electrodes, angular insertion depths, and the SG for the first time in intact, unstained, and nondecalcified specimens. This information can be used to assess stimulation strategies and future electrode designs, as well as create place-frequency maps of the SG for optimal stimulation strategies of the human auditory nerve in CI.
|
|
| 16. |
- Li, Hao, 1984-, et al.
(författare)
-
Three-dimensional tonotopic mapping of the human cochlea based on synchrotron radiation phase-contrast imaging
- 2021
-
Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- The human cochlea transforms sound waves into electrical signals in the acoustic nerve fibers with high acuity. This transformation occurs via vibrating anisotropic membranes (basilar and tectorial membranes) and frequency-specific hair cell receptors. Frequency-positions can be mapped within the cochlea to create a tonotopic chart which fits an almost-exponential function with lowest frequencies positioned apically and highest frequencies positioned at the cochlear base (Bekesy 1960, Greenwood 1961). To date, models of frequency positions have been based on a two-dimensional analysis with inaccurate representations of the cochlear hook region. In the present study, the first three-dimensional frequency analysis of the cochlea using dendritic mapping to obtain accurate tonotopic maps of the human basilar membrane/organ of Corti and the spiral ganglion was performed. A novel imaging technique, synchrotron radiation phase-contrast imaging, was used and a spiral ganglion frequency function was estimated by nonlinear least squares fitting a Greenwood-like function (F=A (10(ax) - K)) to the data. The three-dimensional tonotopic data presented herein has large implications for validating electrode position and creating customized frequency maps for cochlear implant recipients.
|
|
| 17. |
- Li, Hao, 1984-, et al.
(författare)
-
Vestibular Organ and Cochlear Implantation-A Synchrotron and Micro-CT Study
- 2021
-
Ingår i: Frontiers in Neurology. - : Frontiers Media S.A.. - 1664-2295. ; 12
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Reports vary on the incidence of vestibular dysfunction and dizziness in patients following cochlear implantation (CI). Disequilibrium may be caused by surgery at the cochlear base, leading to functional disturbances of the vestibular receptors and endolymphatic duct system (EDS) which are located nearby. Here, we analyzed the three-dimensional (3D) anatomy of this region, aiming to optimize surgical approaches to limit damage to the vestibular organ.Material and Methods: A total of 22 fresh-frozen human temporal bones underwent synchrotron radiation phase-contrast imaging (SR-PCI). One temporal bone underwent micro-computed tomography (micro-CT) after fixation and staining with Lugol's iodine solution (I2KI) to increase tissue contrast. We used volume-rendering software to create 3D reconstructions and tissue segmentation that allowed precise assessment of anatomical relationships and topography. Macerated human ears belonging to the Uppsala collection were also used. Drilling and insertion of CI electrodes was performed with metric analyses of different trajectories.Results and Conclusions: SR-PCI and micro-CT imaging demonstrated the complex 3D anatomy of the basal region of the human cochlea, vestibular apparatus, and EDS. Drilling of a cochleostomy may disturb vestibular organ function by injuring the endolymphatic space and disrupting fluid barriers. The saccule is at particular risk due to its proximity to the surgical area and may explain immediate and long-term post-operative vertigo. Round window insertion may be less traumatic to the inner ear, however it may affect the vestibular receptors.
|
|
| 18. |
- Liu, Wei, et al.
(författare)
-
Immuno-surveillance and protection of the human cochlea
- 2024
-
Ingår i: Frontiers in Neurology. - : Frontiers Media S.A.. - 1664-2295. ; 15
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Despite its location near infection-prone areas, the human inner ear demonstrates remarkable resilience. This suggests that there are inherent instruments deterring the invasion and spread of pathogens into the inner ear. Here, we combined high-resolution light microscopy, super-resolution immunohistochemistry (SR-SIM) and synchrotron phase contrast imaging (SR-PCI) to identify the protection and barrier systems in the various parts of the human inner ear, focusing on the lateral wall, spiral ganglion, and endolymphatic sac.Materials and methods: Light microscopy was conducted on mid-modiolar, semi-thin sections, after direct glutaraldehyde/osmium tetroxide fixation. The tonotopic locations were estimated using SR-PCI and 3D reconstruction in cadaveric specimens. The sections were analyzed for leucocyte and macrophage activity, and the results were correlated with immunohistochemistry using confocal microscopy and SR-SIM.Results: Light microscopy revealed unprecedented preservation of cell anatomy and several macrophage-like cells that were localized in the cochlea. Immunohistochemistry demonstrated IBA1 cells frequently co-expressing MHC II in the spiral ganglion, nerve fibers, lateral wall, spiral limbus, and tympanic covering layer at all cochlear turns as well as in the endolymphatic sac. RNAscope assays revealed extensive expression of fractalkine gene transcripts in type I spiral ganglion cells. CD4 and CD8 cells occasionally surrounded blood vessels in the modiolus and lateral wall. TMEM119 and P2Y12 were not expressed, indicating that the cells labeled with IBA1 were not microglia. The round window niche, compact basilar membrane, and secondary spiral lamina may form protective shields in the cochlear base.Discussion: The results suggest that the human cochlea is surveilled by dwelling and circulating immune cells. Resident and blood-borne macrophages may initiate protective immune responses via chemokine signaling in the lateral wall, spiral lamina, and spiral ganglion at different frequency locations. Synchrotron imaging revealed intriguing protective barriers in the base of the cochlea. The role of the endolymphatic sac in human inner ear innate and adaptive immunity is discussed.
|
|
| 19. |
- Mei, Xueshuang, et al.
(författare)
-
Vascular Supply of the Human Spiral Ganglion : Novel Three-Dimensional Analysis Using Synchrotron Phase-Contrast Imaging and Histology
- 2020
-
Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- Human spiral ganglion (HSG) cell bodies located in the bony cochlea depend on a rich vascular supply to maintain excitability. These neurons are targeted by cochlear implantation (CI) to treat deafness, and their viability is critical to ensure successful clinical outcomes. The blood supply of the HSG is difficult to study due to its helical structure and encasement in hard bone. The objective of this study was to present the first three-dimensional (3D) reconstruction and analysis of the HSG blood supply using synchrotron radiation phase-contrast imaging (SR-PCI) in combination with histological analyses of archival human cochlear sections. Twenty-six human temporal bones underwent SR-PCI. Data were processed using volume-rendering software, and a representative three-dimensional (3D) model was created to allow visualization of the vascular anatomy. Histologic analysis was used to verify the segmentations. Results revealed that the HSG is supplied by radial vascular twigs which are separate from the rest of the inner ear and encased in bone. Unlike with most organs, the arteries and veins in the human cochlea do not follow the same conduits. There is a dual venous outflow and a modiolar arterial supply. This organization may explain why the HSG may endure even in cases of advanced cochlear pathology.
|
|
| 20. |
- Steinacher, Claudia, et al.
(författare)
-
Visualization of macrophage subsets in the development of the fetal human inner ear
- 2022
-
Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 13
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Human inner ear contains macrophages whose functional role in early development is yet unclear. Recent studies describe inner ear macrophages act as effector cells of the innate immune system and are often activated following acoustic trauma or exposure to ototoxic drugs. Few or limited literature describing the role of macrophages during inner ear development and organogenesis. Material and Methods: We performed a study combining immunohistochemistry and immunofluorescence using antibodies against IBA1, CX3CL1, CD168, CD68, CD45 and CollagenIV. Immune staining and quantification was performed on human embryonic inner ear sections from gestational week 09 to 17. Results: The study showed IBA1 and CD45 positive cells in the mesenchymal tissue at GW 09 to GW17. No IBA1 positive macrophages were detected in the sensory epithelium of the cochlea and vestibulum. Fractalkine (CX3CL1) signalling was initiated GW10 and parallel chemotactic attraction and migration of macrophages into the inner ear. Macrophages also migrated into the spiral ganglion, cochlear nerve, and peripheral nerve fibers and tissue-expressing CX3CL1. The mesenchymal tissue at all gestational weeks expressed CD163 and CD68. Conclusion: Expressions of markers for resident and non-resident macrophages (IBA1, CD45, CD68, and CD163) were identified in the human fetal inner ear. We speculate that these cells play a role for the development of human inner ear tissue including shaping of the gracile structures.
|
|
| 21. |
- Wendin, Karin, 1963-, et al.
(författare)
-
Introducing mealworm as an ingredient in crisps and pâtés – sensory characterization and consumer liking
- 2021
-
Ingår i: Future Foods. - : Elsevier. - 2666-8335. ; 4, s. 1-8
-
Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to evaluate sensory perception and consumers’ attitude and liking of products with different textures, crisps and pâtés, with added mealworm ingredient in different amounts. By addition of mealworm ( Tenebrio molitor L. ) in the crisps, the brittleness increased. However, an increase in mealworm also increased the darkness. Adding mealworms to pâté reduced the odour and flavour of vegetable and increased the flavour of cinnamon and pepper as well as the oily texture. There was no significant difference in total liking between 10 and 30% addition of mealworm, nor between 0 and 10% addition, in any of the two products. The crisps received higher liking score than the pâtés. Thus, there is also a much higher probability that a customer would buy insect crisps than insect pâté. Environmental sustainability and sensory properties were shown to be the main reasons for buying foods with added insect ingredients.
|
|
