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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.
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.
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.
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.
Highlights: • IL-36α was detected in the skin of psoriatic dermatitis, but not contact dermatitis. • IL-36α is not essential for dendritic cell migration. • IL-36α is involved in hapten-specific T-cell induction and activation. • IL-36α is not essential for induction of the inflammation of contact dermatitis. Levels of IL36α are known to be increased in specimens from patients with atopic dermatitis and psoriasis. In addition, it has been reported that IL-36α is crucial for development of imiquimod-induced psoriatic dermatitis in mice. On the other hand, the role of IL-36α in induction of allergic contact dermatitis/contact hypersensitivity (ACD/CHS) is poorly understood. We found that IL-36α was produced in keratinocytes of mice during imiquimod-induced psoriatic dermatitis, but it was hardly detectable in the skin of mice during either fluorescein isothiocyanate (FITC)- or 1-fluoro-2, 4-dinitrobenzene (DNFB)-induced CHS. Although IL-36α can enhance activation of dendritic cells (DCs) and T cells, in CHS, IL-36α was not essential for DC migration from the skin to draining LNs, but it was required for induction or activation of hapten-specific T cells such as Th/Tc1 or Th17 cells. However, local inflammation, assessed by measurement of ear skin thickness, was comparable between wild-type and IL-36α-deficient mice during both FITC- and DNFB-induced CHS. These observations indicate that IL-36α is involved in induction and/or activation of hapten-specific T-cell subsets in the sensitization phase of CHS, but not essential for induction of local inflammation in the elicitation phase.
Highlights: • More cell phone radiation is absorbed by children's inner brain tissues than adults’. • Children's radiofrequency radiation exposure should be reduced. • Further research to evaluate the risks to the eye from use of VR is urgently needed. • It is biologically relevant and feasible to reduce the standards’ averaging volume. • Current methods to determine wireless device compliance should be revised. Children's brains are more susceptible to hazardous exposures, and are thought to absorb higher doses of radiation from cell phones in some regions of the brain. Globally the numbers and applications of wireless devices are increasing rapidly, but since 1997 safety testing has relied on a large, homogenous, adult male head phantom to simulate exposures; the “Standard Anthropomorphic Mannequin” (SAM) is used to estimate only whether tissue temperature will be increased by more than 1 Celsius degree in the periphery. The present work employs anatomically based modeling currently used to set standards for surgical and medical devices, that incorporates heterogeneous characteristics of age and anatomy. Modeling of a cell phone held to the ear, or of virtual reality devices in front of the eyes, reveals that young eyes and brains absorb substantially higher local radiation doses than adults’. Age-specific simulations indicate the need to apply refined methods for regulatory compliance testing; and for public education regarding manufacturers' advice to keep phones off the body, and prudent use to limit exposures, particularly to protect the young.
Warm summer episodes have a significant effect on the overall health and well-being of young cattle; however, it is not known which temperature measure should be used for estimating heat stress in dairy calves. In this study, generalized linear mixed-effects models were used to estimate the relationships between thermal comfort indices and animal-based heat stress indicators in sixteen Holstein bull calves that were housed in individual calf hutches. Data were collected under continental weather characteristics over a 5-day period: day 1 (lower-temperature day), days 2 and 3 (heat stress days), and a 2-day post-stress period. Relative humidity, ambient temperature, the heat index, the humidex and five different temperature–humidity indices (THI) were used as thermal indices. Physiological variables monitored included respiratory rate, rectal temperature, ear skin temperature and heart rate. The heat index and the humidex measuring human thermal comfort were more closely associated with physiological measures than were the ambient temperature or the THIs (in case of heat index: R{sup 2} = 0.87 for respiratory rate, R{sup 2} = 0.63 for rectal temperature, R{sup 2} = 0.70 for ear skin temperature, and R{sup 2} = 0.78 for heart rate, respectively; in case of humidex: R{sup 2} = 0.85 for respiratory rate, R{sup 2} = 0.60 for rectal temperature, R{sup 2} = 0.68 for ear skin temperature, and R{sup 2} = 0.75 for heart rate, respectively). Based on our results, parameters of human outdoor comfort seem better to estimate heat stress in dairy calves in a continental region than those of THIs or ambient temperature.
Highlights: • Baseline urinary tungsten levels were not associated with cardiovascular disease incidence. • Elevated urinary tungsten was associated with cardiovascular disease in the presence of low urinary molybdenum. • The association between tungsten and cardiovascular disease was inverse at higher molybdenum levels. • Molybdenum may modify the association between tungsten and incident cardiovascular disease. Tungsten (W) interferes with molybdenum (Mo) binding sites and has been associated with prevalent cardiovascular disease (CVD). We evaluated if (1) W exposure is prospectively associated with incident CVD and (2) the association between urinary W levels and incident CVD is modified by urinary Mo levels.