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Various drugs are discussed and many references are mentioned. It was concluded that the development of methods of pharmacological prevention of the harmful effect of drugs on the auditory analyzor is a necessity.
Many genes share sequence similarity between species, but their properties often change significantly during evolution. For example, the Drosophila genes engrailed and orthodenticle and the onychophoran gene Ultrabithorax only partially substitute for their mouse or Drosophila homologs. We have been analyzing the relationship between atonal (ato) in the fruit fly and its mouse homolog, Math1. In flies, ato acts as a proneural gene that governs the development of chordotonal organs (CHOs), which serve as stretch receptors in the body wall and joints and as auditory organs in the antennae. In the fly CNS, ato is important not for specification but for axonal arborization. Math1, in contrast, is required for the specification of cells in both the CNS and the PNS. Furthermore, Math1 serves a role in the development of secretory lineage cells in the gut, a function that does not parallel any known to be served by ato. We wondered whether ato and Math1 might be more functionally homologous than they appear, so we expressed Math1 in ato mutant flies and ato in Math1 null mice. To our surprise, the two proteins are functionally interchangeable.
Hearing is a fundamental sense of many animals, including all mammals, birds, some reptiles, amphibians, fish, and arthropods. The auditory organs of these animals are extremely diverse in anatomy after hundreds of millions of years of evolution, yet all are made up of cellular tissue and are morphologically part of the bodies of animals. Here, we show that hearing in the orb-weaving spider Larinioides sclopetarius is not constrained by the organism’s body but is extended through outsourcing hearing to its extended phenotype, the proteinaceous, self-manufactured orb web. We find that the wispy, wheel-shaped orb web acts as a hyperacute acoustic antenna to capture the sound-induced air particle movements that approach the maximum physical efficiency better than the acoustic responsivity of all previously known eardrums. By sensing the motion of web threads, the spider remotely detects and localizes the source of an incoming airborne acoustic wave, such as those emitted by approaching prey or predators. By outsourcing its acoustic sensors to its web, the spider is released from body size constraints and permits the araneid spider to increase its sound-sensitive surface area enormously, up to 10,000 times greater than the spider itself. The spider also enables the flexibility to functionally adjust and regularly regenerate its external "eardrum" according to its needs. The outsourcing and supersizing of auditory function in spiders provides unique features for studying extended and regenerative sensing and designing novel acoustic flow detectors for precise fluid dynamic measurement and manipulation.
The individual exposure integral noise load on workers before the beginning of hearing impairment was determined for a group of 20 male miners who had worked with drilling equipment and harvesters for 8 to 20 years before the onset of the disability. Results show that the total exposure energy load of about 4 kw x h sq m, obtained by miners in the examined group, resulted in occupational injury to the auditory organ (cochlear neuritis) in 75% of the cases. The equivalent energy level of noise computed according to the date of total energy load is roughly 99 db A, which significantly exceeds the permissible amount of 85 db A. There is a correlation (r = 0.77) between the integral exposure energy noise on the aural analyzer in the degree of increase in the total threshold for the mean speech range.
Cats were exposed to tones of 125, 1000, 2000, and 4000 Hz at sound pressure levels in the range 120 to 157.5 db, and for durations of one hour (1000, 2000, 4000 Hz) or four hours (125 Hz). Pure tone audiograms were obtained for each animal before and after exposure. Cochleas of animals were examined by phase-contrast microscopy. Extent of inner ear damage and range of frequencies for which hearing loss occurred increased as exposure tone was decreased in frequency. For example, exposure to 4000 Hz produced damage in a restricted region of the cochlea and hearing loss for a relatively narrow range of frequencies; exposure to 125 Hz produced wide-spread inner ear damage and hearing loss throughout the frequency range 125 to 6000 Hz.
Purpose: The aim of the current study was to (a) calculate the organ equivalent dose (OED) and (b) estimate the associated second cancer risk to partially in-field critical structures from adjuvant radiotherapy for stage I seminoma of the testis on the basis of three different nonlinear risk models. Methods: Three-dimensional plans were created for twelve patients who underwent a treatment planning computed tomography of the abdomen. The plans for irradiation of seminoma consisted of para-aortic anteroposterior and posteroanterior fields giving 20 Gy to the target site with 6 MV photons. The OED of stomach, colon, liver, pancreas, and kidneys, that were partially included in the treatment volume, was calculated using differential dose–volume histograms. The mechanistic, bell-shaped, and plateau models were employed for these calculations provided that organ-specific parameters were available for the subsequent assessment of the excess absolute risk (EAR) for second cancer development. The estimated organ-specific lifetime risks were compared with the respective nominal intrinsic probabilities for cancer induction. Results: The mean OED, which was calculated from the patients’ treatment plans, varied from 0.54 to 6.61 Gy by the partially in-field organ of interest and the model used for dosimetric calculations. The difference between the OED of liver derived from the mechanistic model with those from the bell-shaped and plateau models was less than 1.8%. An even smaller deviation of 1.0% was observed for colon. For the rest organs of interest, the differences between the OED values obtained by the examined models varied from 8.6% to 50.0%. The EAR for stomach, colon, liver, pancreas, and kidney cancer induction at an age of 70 yr because of treatment of a typical 39-yr-old individual was up to 4.24, 11.39, 0.91, 3.04, and 0.14 per 10 000 persons-yr, respectively. Patient’s irradiation was found to elevate the lifetime intrinsic risks by 8.3%–63.0% depending upon the organ of interest and the model employed for risk analysis. Conclusions: Radiotherapy for stage I seminoma of the testis may result in an excess risk for the appearance of secondary malignancies in partially in-field organs. The organ- and model-dependent second cancer risk assessments of this study may be of value for patient counseling and follow-up.
A prospective clinical trial, Radiation Therapy Oncology Group (RTOG) 0933, has demonstrated that whole brain radiotherapy (WBRT) using conformal radiation delivery technique with hippocampal avoidance is associated with less memory complications. Further sparing of other organs at risk (OARs) including the scalp, ear canals, cochleae, and parotid glands could be associated with reductions in additional toxicities for patients treated with WBRT. We investigated the feasibility of WBRT using volumetric-modulated arc therapy (VMAT) to spare the hippocampi and the aforementioned OARs. Ten patients previously treated with nonconformal WBRT (NC-WBRT) using opposed lateral beams were retrospectively re-planned using VMAT with hippocampal sparing according to the RTOG 0933 protocol. The OARs (scalp, auditory canals, cochleae, and parotid glands) were considered as dose-constrained structures. VMAT plans were generated for a prescription dose of 30 Gy in 10 fractions. Comparison of the dosimetric parameters achieved by VMAT and NC-WBRT plans was performed using paired t-tests using upper bound p-value of 100% ) of 8.4 ± 0.3 Gy and maximum dose of 15.6 ± 0.4 Gy, respectively. A statistically significant dose reduction (p < 0.001) to all OARs was achieved. The mean and maximum scalp doses were reduced by an average of 9 Gy (32%) and 2 Gy (6%), respectively. The mean and maximum doses to the auditory canals were reduced from 29.5 ± 0.5 Gy and 31.0 ± 0.4 Gy with NC-WBRT, to 21.8 ± 1.6 Gy (26%) and 27.4 ± 1.4 Gy (12%) with VMAT. VMAT also reduced mean and maximum doses to the cochlea by an average of 4 Gy (13%) and 2 Gy (6%), respectively. The parotid glands mean and maximum doses with VMAT were 4.4 ± 1.9 Gy and 15.7 ± 5.0 Gy, compared to 12.8 ± 4.9 Gy and 30.6 ± 0.5 Gy with NC-WBRT, respectively. The average dose reduction of mean and maximum of parotid glands from VMAT were 65% and 50%, respectively. The average beam on time and MUs were 2.3minutes and 719 on VMAT, and 0.7 minutes and 350 on NC-WBRT. This study demonstrated the feasibility of WBRT using VMAT to not only spare the hippocampi, but also significantly reduce dose to OARs. These advantages of VMAT could potentially decrease the toxicities associated with NC-WBRT and improve patients' quality of life, especially for patients with favorable prognosis receiving WBRT or patients receiving prophylactic cranial irradiation (PCI).
In this study, we have developed a phase-sensitive Fourier-domain optical coherence tomography system to simultaneously measure the in vivo inner ear vibrations in the hook area and second turn of the mouse cochlea. This technical development will enable measurement of intra-cochlear distortion products at ideal locations such as the distortion product generation site and reflection site. This information is necessary to un-mix the complex mixture of intra-cochlear waves comprising the DPOAE and thus leads to the non-invasive identification of the local region of cochlear damage.
Purpose: To compare the difference in robustness of single-field optimized (SFO) and robust multifield optimized (rMFO) proton plans for oropharynx carcinoma patients by an improved robustness analysis. Methods and Materials: We generated rMFO proton plans for 11 patients with oropharynx carcinoma treated with SFO intensity modulated proton therapy with simultaneous integrated boost prescription. Doses from both planning approaches were compared for the initial plans and the worst cases from 20 optimization scenarios of setup errors and range uncertainties. Expected average dose distributions per range uncertainty were obtained by weighting the contributions from the respective scenarios with their expected setup error probability, and the spread of dose parameters for different range uncertainties were quantified. Using boundary dose distributions created from 56 combined setup error and range uncertainty scenarios and considering the vanishing influence of setup errors after 30 fractions, we approximated realistic worst-case values for the total treatment course. Error bar metrics derived from these boundary doses are reported for the clinical target volumes (CTVs) and organs at risk (OARs). Results: The rMFO plans showed improved CTV coverage and homogeneity while simultaneously reducing the average mean dose to the constrictor muscles, larynx, and ipsilateral middle ear by 5.6 Gy, 2.0 Gy, and 3.9 Gy, respectively. We observed slightly larger differences during robustness evaluation, as well as a significantly higher average brainstem maximum and ipsilateral parotid mean dose for SFO plans. For rMFO plans, the range uncertainty-related spread in OAR dose parameters and many error bar metrics were found to be superior. The SFO plans showed a lower global maximum dose for single-scenario worst cases and a slightly lower mean oral cavity dose throughout. Conclusions: An enhanced robustness analysis has been proposed and implemented into clinical systems. The benefit of better CTV coverage and OAR dose sparing in oropharynx carcinoma patients by rMFO compared with SFO proton plans is preserved in a robustness analysis with consideration of setup error and range uncertainty.
Objectives/Hypothesis: To establish comprehensive transcriptomic profiles of cholesteatoma perimatrix tissue and granulation tissue from chronic otitis media (COM) that did not develop cholesteatoma, which can indicate molecular pathways involved in the cholesteatoma perimatrix pathology and invasiveness. Study Design: Retrospective Case Series. Methods: Transcriptome data were obtained from cholesteatoma perimatrix tissue and COM granulation tissue by an Illumina iScan microarray. Differentially expressed genes (DEGs) were subsequently analyzed using both bioinformatical functional annotation and network analysis. Expression of candidate genes (MMP9 and LCN2) was validated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) on a larger group of samples. Results: Analysis of the transcriptome led to the identification of 169 differentially expressed genes between investigated tissues. Bioinformatic analysis suggested that most significant biological processes involving DEGs were previously described in cholesteatoma pathology. Network analysis identified ERBB2, TFAP2A, and TP63 as major hubs of the DEGs molecular network. Furthermore, it was observed that the cellular component most significantly enriched in DEGs was extracellular space containing 47 DEGs. Using qRT-PCR, it was confirmed that mRNA levels of the major extracellular hub (MMP9) are increased, whereas its interacting molecule (LCN2) mRNA levels were decreased in cholesteatoma perimatrix tissue compared to COM granulation tissue. Conclusions: The current study approach offers an overall look at molecular mechanisms that describe the cholesteatoma entity by focusing exclusively on the perimatrix processes in comparison to COM granulation tissue. The observed differences in gene expression between cholesteatoma perimatrix and COM granulation tissue could suggest novel markers potentially influenced by the perimatrix–matrix molecular interplay, which is not present in COM without cholesteatoma. Level of Evidence: NA. Laryngoscope, 130:E220–E227, 2020. © 2019 The American Laryngological, Rhinological and Otological Society, Inc.
Crouzon’s syndrome is the commonest variety of syndromic craniosynostosis. Life-threatening ear bleed due to ruptured jugular venous diverticulum in Crouzon’s syndrome has not been described previously. In patients with syndromic craniosynostosis, definitive repair of jugular diverticulum by open surgery is fraught with high risk of bleeding, poor functional outcomes, and even death. A 24-year-old woman with Crouzon’s syndrome presented with conductive hearing loss and recurrent episodes of torrential bleeding from her left ear. On computed tomography, a defect in the roof of jugular fossa containing jugular venous diverticulum immediately inferior to the bony external auditory canal was seen. The clinical presentation, imaging features, and endovascular management of Crouzon’s syndrome due to a ruptured jugular venous diverticulum is described.
The planar anisotropy (PA) and tension–compression asymmetry (TCA) of the CP-Ti were investigated via uniaxial tension and compression tests at room temperature. The formability and the earing behavior of the CP-Ti sheet were studied via deep drawing experiment. The deep drawing simulations using the uniaxial tensile and the compressive curves as the hardening rules were compared with each other and with the experimental results. The CP-Ti sheet showed PA and TCA in yielding and strain hardening. The PA was characterized by the plastic strain ratio r{sub 0}, r{sub 45}, and r{sub 90} of 1.47, 2.06, and 2.05. The TCA showed PA, which showed tension–compression yield strength ratios of 1.12, 1.08, and 1.04 in 0°, 45°, and 90° in the rolling direction, and tensile and compressive hardening exponent ratios of 0.86, 0.8, and 0.62. The orientation distribution functions (ODFs) analysis demonstrated that the tensile and the compressive deformation textures were different and showed PA. The simulative results, including the simulated forming force and the earing profiles using the uniaxial tensile and compressive curves as the hardening rules, were not in agreement with each other. The results were not in good agreement with the experimental results, implying that the TCA had an important effect on the formability of the sheet. The TCA tended to reduce the thickness of the deep drawing parts, increase the earing ratio, and affect the drawing force.
The influence of alloying elements and processing technology on the microstructure, crystallographic texture and earing propensity has been investigated in two kinds of DR tinplate differing in Ti content: steel A, no Ti addition, and steel B 0.015% added. The cementite distribution, second-phase particles and the content of dissolved carbon and nitrogen atoms were obtained by SEM, TEM and XPS, respectively. Since the two steels develop both a partial 〈110〉//RD fiber and a {111}//ND fiber, the relative intensities of the several vital texture components seem to differ visibly. There are three types of strengthening mechanisms involved here: strengthening by grain size reduction, solution strengthening and strain hardening. That the tensile strength of steel B is greater than A implies the third mode plays a dominant role in the strength increasing for the DR tinplate. The crystallographic texture of materials not only results in a “preferential orientation” of the mechanical property, but also takes the primary responsibility for ears forming during drawing. Increasing the second cold-rolled reduction is not favorable to reduce the ear height, but this situation seems to be ameliorable. The average ears height of steel B is smaller than that of A, which demonstrated a low level of solute atoms and an ideal texture characteristic before deformation could alleviate the adverse effect caused by an elevated second cold reduction.
Highlights: • PolySia expressed on neurons primarily during early stages of neuronal development. • PolySia–NCAM is expressed on neural stem cells from adult guinea pig spiral ganglion. • PolySia is a biomarker that modulates neuronal differentiation in inner ear stem cells. - Abstract: During brain development, polysialylated (polySia) neural cell adhesion molecules (polySia–NCAMs) modulate cell–cell adhesive interactions involved in synaptogenesis, neural plasticity, myelination, and neural stem cell (NSC) proliferation and differentiation. Our findings show that polySia–NCAM is expressed on NSC isolated from adult guinea pig spiral ganglion (GPSG), and in neurons and Schwann cells after differentiation of the NSC with epidermal, glia, fibroblast growth factors (GFs) and neurotrophins. These differentiated cells were immunoreactive with mAb’s to polySia, NCAM, β-III tubulin, nestin, S-100 and stained with BrdU. NSC could regenerate and be differentiated into neurons and Schwann cells. We conclude: (1) polySia is expressed on NSC isolated from adult GPSG and on neurons and Schwann cells differentiated from these NSC; (2) polySia is expressed on neurons primarily during the early stage of neuronal development and is expressed on Schwann cells at points of cell–cell contact; (3) polySia is a functional biomarker that modulates neuronal differentiation in inner ear stem cells. These new findings suggest that replacement of defective cells in the inner ear of hearing impaired patients using adult spiral ganglion neurons may offer potential hope to improve the quality of life for patients with auditory dysfunction and impaired hearing disorders.
Mitochondrial diabetes (MD) is a heterogeneous disorder characterized by a chronic hyperglycemia, maternal transmission and its association with a bilateral hearing impairment. Several studies reported mutations in mitochondrial genes as potentially pathogenic for diabetes, since mitochondrial oxidative phosphorylation plays an important role in glucose-stimulated insulin secretion from beta cells. In the present report, we studied a Tunisian family with mitochondrial diabetes (MD) and deafness associated with nephropathy. The mutational analysis screening revealed the presence of a novel heteroplasmic mutation m.9276G>C in the mitochondrial COIII gene, detected in mtDNA extracted from leukocytes of a mother and her two daughters indicating that this mutation is maternally transmitted and suggest its implication in the observed phenotype. Bioinformatic tools showed that m.9267G>C mutation (p.A21P) is « deleterious » and it can modify the function and the stability of the MT-COIII protein by affecting the assembly of mitochondrial COX subunits and the translocation of protons then reducing the activity of the respective OXPHOS complexes of ATP synthesis. The nonsynonymous mutation (p.A21P) has not been reported before, it is the first mutation described in the COXIII gene which is related to insulin dependent mitochondrial diabetes and deafness and could be specific to the Tunisian population. The m.9267G>C mutation was present with a nonsynonymous inherited mitochondrial homoplasmic variation MT-COI m.5913 G>A (D4N) responsible of high blood pressure, a clinical feature detected in all explored patients. - Highlights: • MT-COX3 m.9267G>C (p.A21P), heteroplasmic substitution, is not reported in any database. • m.9267G>C can be responsible of the MIDD associated with nephropaty. • This substitution can modify the function and the stability of the MT-CO3 protein. • This substitution can modify MT-CO3 structure (2D and 3D). • MT-COX3 m.9267G>C is associated with MT-CO1 m.5913G>A a homoplasmic substitution.
The biological actions of vitamin D are largely mediated through binding to the vitamin D receptor (VDR), a member of the nuclear hormone receptor family, which regulates gene expression in a wide variety of tissues and cells. Mutations in VDR gene have been implicated in ear disorders (hearing loss and balance disorder) but the mechanisms are not well established. In this study, to investigate the role of VDR in inner ear development, morpholino-mediated gene knockdown approaches were used in zebrafish model system. Two paralogs for VDR, vdra and vdrb, have been identified in zebrafish. Knockdown of vdra had no effect on ear development, whereas knockdown of vdrb displayed morphological ear defects including smaller otic vesicles with malformed semicircular canals and abnormal otoliths. Loss-of-vdrb resulted in down-regulation of pre-otic markers, pax8 and pax2a, indicating impairment of otic induction. Furthermore, zebrafish embryos lacking vdrb produced fewer sensory hair cells in the ears and showed disruption of balance and motor coordination. These data reveal that VDR signaling plays an important role in ear development. - Highlights: • VDR signaling is involved in ear development. • Knockdown of vdrb causes inner ear malformations during embryogenesis. • Knockdown of vdrb affects otic placode induction. • Knockdown of vdrb reduces the number of sensory hair cells in the inner ear. • Knockdown of vdrb disrupts balance and motor coordination.
Hypertrophic scarring (HS) is an overcompensation of wound healing that increases the risk of cosmetic disfigurement and functional impairment. No gold standard has been established for the treatment or prevention of HS. Our study aims to elucidate the expression and function of lumican in the pathogenesis of HS as well as the underlying mechanism involved in this procedure. An animal model of HS (rabbit ear) was established, and the Ad-lumican vectors were locally injected. Primary fibroblasts isolated from patients with hypertrophic burn scars were used in vitro. Histological and molecular changes in HS pathogenesis were evaluated. The results showed that lumican is significantly reduced in HS tissues and fibroblasts from HS patients as compared to normal skin or cells. Lumican levels were further suppressed in response to TGF-β stimulation. However, lumican upregulation effectively thinned the scar area and inhibited fibroblast proliferation and the cell cycle. Meanwhile, Ad-lumican administration suppressed the deposition of extracellular matrix, such as collagen and CTGF. Ad-lumican injected animals or fibroblasts presented comparable integrin α{sub 2}β{sub 1} expression while greatly reduced phosphorylation of FAK compared to the negative control. Moreover, Ad-lumican administration largely enhanced the binding of lumican to integrin α{sub 2}β{sub 1} and may thus inhibit the signaling propagation of collagen-integrin α{sub 2}β{sub 1}. Overall, the restoration of lumican levels contributed to suppressing the HS progression by inhibiting collagen-integrin α{sub 2}β{sub 1}-FAK signaling. - Highlights: • Lumican is downregulated during hypertrophic scar formation. • Lumican inhibits fibroblast proliferation. • Lumican inhibits extracellular matrix deposition. • Lumican suppresses collagen-integrin-FAK signaling.
Contact allergy is a T cell-mediated, delayed-type hypersensitivity generated by contact exposure of an allergen to the skin and mucosal surface. The clinical manifestations of allergic responses between the skin and oral mucosa vary and the differences in immunopathology have not been clarified. We generated hapten-induced contact hypersensitivity (CH) of the buccal mucosa (BM) in parallel studies with ear skin (ES) CH, and observed several characteristic findings of BM CH. The BM challenge induced more rapid and more severe inflammation than the ES challenge, with abundant granulocyte and CD8{sup +} T cell infiltration. However, these inflammatory responses diminished quickly. Recruiting CD8{sup +} T cells in the BM had higher ratios of CD62L{sup −}CD44{sup low-hi} memory-type cells, and showed impaired IFN-γ, greater PD-1, and comparable Ki-67 expression, suggesting that the recruiting-proliferating CD8{sup +} T cells were unable to differentiate into effector T cells and converted into exhausted T cells at the local site. This finding may explain the rapid recovery of the BM from severe inflammation. Preferentially greater expression of PD-1 ligand (B7-H1), was observed in the BM epithelium under the peak inflammation, and the absence of B7-H1 further accelerated CH responses, suggesting the occurrence of PD-1:B7-H1-mediated immune regulation at the local site. Our results may facilitate the understanding of the unique features of contact allergies in the oral mucosa, and guide the development of new strategies for control of contact allergy. - Highlights: • Contact allergy in the oral mucosa shows severe responses, but quick recovery. • Oral mucosa-infiltrating CD8{sup +} T cells have unique activatory and regulatory status. • PD-1:B7-H1-mediated pathway is involved in the site-specific regulation.