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News Article | February 24, 2017
Site: www.eurekalert.org

Study to be published in Journal of Cystic Fibrosis for the first time measures cumulative dosage over a patient's lifetime A powerful class of antibiotics provides life-saving relief for people with cystic fibrosis; however, a new study for the first time reveals the levels at which high cumulative dosages over time significantly increases the risk of permanent hearing loss in these patients. Cystic fibrosis, or CF, is an inherited chronic disease that affects the lungs and digestive system. Approximately 30,000 people in the United States and 70,000 worldwide are living with the disease. The study, to be published Feb. 23 in the Journal of Cystic Fibrosis, suggests physicians who treat patients with cystic fibrosis may be able to consider alternative strategies for treating the symptoms of respiratory infections associated with CF, especially if patients are responsive to different classes of antibiotics. New medications are emerging that have shown a reduced toxic effect on both the kidneys and ears of these patients, while effectively treating infections. "Preventing or ameliorating the effects of permanent [hearing loss] is crucial for patients with CF who already have a significantly compromised quality of life due to the disease," the authors concluded. The study examined the medical records of 81 CF patients, aged 15 to 63 years, grouping them into four quartiles based on the cumulative dosage of aminoglycoside antibiotics administered intravenously. Researchers found that the two highest dosage groups were 4.79 times more likely to experience permanent hearing loss than the two quartiles with the lowest cumulative dosage exposure. "This is an early step toward developing a model for predicting hearing loss in these patients," said lead author Angela Garinis, Ph.D., a senior research associate in the Oregon Hearing Research Center at OHSU and research audiologist with the VA Portland Health Care System. Aminoglycosides inhibit bacterial protein synthesis, and they are often necessary to clear life-threatening respiratory infections. However, these medications can degrade auditory function in the inner ear as well as kidney function. Previous research had demonstrated a greater risk of hearing loss from aminoglycoside antibiotics, but the new study is the first to factor in cumulative exposure over a patient's lifetime while also weighting the daily dosing schedule used by patients. The findings suggest it is imperative for physicians to routinely monitor hearing in any patient receiving aminoglycosides intravenously. "This information will allow both the patient and the physician to discuss possible modifications to the treatment regimen, particularly if an alternative approach is or becomes available," according to the study. Patients with cystic fibrosis are living longer, raising the importance of maintaining their quality of life over a longer period of time. "People don't realize the trauma of hearing loss until after they've lost it," said senior author Peter Steyger, Ph.D., a professor of otolaryngology/head and neck surgery in the OHSU School of Medicine who lost hearing as a child after being treated with antibiotics for a case of meningitis at age 14 months. "Helen Keller said, 'Blindness separates people from things; deafness separates people from people.' It can lead to isolation, depression and cognitive decline." In addition to Garinis and Steyger, authors include Campbell P. Cross, Priya Srikanth, Kelly Carroll, M. Patrick Feeney, Ph.D., Daniel B. Putterman, Au.D., David M. Cohen, M.D., and Jeffrey A. Gold, M.D., of OHSU; Douglas H. Keefe, Ph.D., of Boys Town National Research Hospital in Omaha, Nebraska; and Lisa L. Hunter, Ph.D., of Cincinnati Children's Hospital. Garinis, Feeney and Putterman have joint appointments at the National Center for Rehabilitative Auditory Research at the VA Portland Health Care System in Portland. The research was supported by the National Institutes of Health CTSA grant (UL1TR000128) to the Oregon Clinical and Translational Research Institute and NIH-NIDCD Grant Awards: R01 DC004555, R01 DC012588, and R01 DC10202.


Lewis J.D.,Boys Town National Research Hospital | Goodman S.S.,University of Iowa
JARO - Journal of the Association for Research in Otolaryngology | Year: 2015

The presence of short-latency (SL), less compressive-growing components in bandpass-filtered transient-evoked otoacoustic emission (TEOAE) waveforms may implicate contributions from cochlear regions basal to the tonotopic place. Recent empirical work suggests a region of SL generation between ∼1/5 and 1/10-octave basal to the TEOAE frequency’s tonotopic place. However, this estimate may be biased to regions closer to the tonotopic place as the TEOAE extraction technique precluded measurement of components with latencies shorter than ∼5 ms. Using a variant of the non-linear, double-evoked extraction paradigm that permitted extraction of components with latencies as early as 1 ms, the current study empirically estimated the spatial-extent of the cochlear region contributing to 2 kHz SL TEOAE components. TEOAEs were evoked during simultaneous presentation of a suppressor stimulus, in order to suppress contributions to the TEOAE from different places along the cochlear partition. Three or four different-latency components of similar frequency content (∼2 kHz) were identified for most subjects. Component latencies ranged from 1.4 to 9.6 ms; latency was predictive of the component’s growth rate and the suppressor frequency to which the component’s magnitude was most sensitive to change. As component latency decreased, growth became less compressive and suppressor-frequency sensitivity shifted to higher frequencies. The shortest-latency components were most sensitive to suppressors approximately 3/5-octave higher than their nominal frequency of 2 kHz. These results are consistent with a distributed region of generation extending to approximately 3/5-octave basal to the TEOAE frequency’s tonotopic place. The empirical estimates of TEOAE generation are similar to model-based estimates where generation of the different-latency components occurs through linear reflection from impedance discontinuities distributed across the cochlear partition. © 2014, Association for Research in Otolaryngology.


Moeller M.P.,Boys Town National Research Hospital | Tomblin J.B.,University of Iowa
Ear and Hearing | Year: 2015

The landscape of service provision for young children with hearing loss has shifted in recent years as a result of newborn hearing screening and the early provision of interventions, including hearing technologies. It is expected that early service provision will minimize or prevent linguistic delays that typically accompany untreated permanent childhood hearing loss. The post-newborn hearing screening era has seen a resurgence of interest in empirically examining the outcomes of children with hearing loss to determine if service innovations have resulted in expected improvements in children's functioning. The Outcomes of Children with Hearing Loss (OCHL) project was among these recent research efforts, and this introductory article provides background in the form of literature review and theoretical discussion to support the goals of the study. The Outcomes of Children with Hearing Loss project was designed to examine the language and auditory outcomes of infants and preschool-age children with permanent, bilateral, mild-to-severe hearing loss, and to identify factors that moderate the relationship between hearing loss and longitudinal outcomes. The authors propose that children who are hard of hearing experience limitations in access to linguistic input, which lead to a decrease in uptake of language exposure and an overall reduction in linguistic experience. The authors explore this hypothesis in relation to three primary factors that are proposed to influence children's access to linguistic input: aided audibility, duration and consistency of hearing aid use, and characteristics of caregiver input. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.


Rasetshwane D.M.,Boys Town National Research Hospital | Neely S.T.,Boys Town National Research Hospital
JARO - Journal of the Association for Research in Otolaryngology | Year: 2012

The total sound pressure measured in the ear canal may be decomposed into a forward- and a reversepropagating component. Most of the reverse-propagating component is due to reflection at the eardrum. However, a measurable contribution to the reversepropagating component comes from the cochlea. Otoacoustic emissions (OAEs) are associated with this component and have been shown to be important noninvasive probes of cochlear function. Total earcanal reflectance (ECR) is the transfer function between forward and reverse propagating components measured in the ear canal. Cochlear reflectance (CR) is the inner-ear contribution to the total ECR, which is the measured OAE normalized by the stimulus. Methods are described for measuring CR with a wide-band noise stimulus. These measurements offer wider bandwidth and minimize the influence of the measurement system while still maintaining features of other OAEs (i.e., frequency- and level-dependent latency). CR magnitude decreases as stimulus level increases. Envelopes of individual band-limited components of the time-domain CR have multiple peaks with latencies that persist across stimulus level, despite a shift in group delay. CR has the potential to infer cochlear function and status, similar to other OAE measurements. © 2012 Association for Research in Otolaryngology.


Kelley P.M.,Boys Town National Research Hospital | Connor A.L.,Boys Town National Research Hospital | Tempero R.M.,Boys Town National Research Hospital
American Journal of Pathology | Year: 2013

Inflammation stimulates new lymphatic vessel growth (inflammatory lymphangiogenesis). One key question is how recurrent inflammation, a common clinical condition, regulates lymphatic vessel remodeling. We show here that recurrent inflammation accelerated the development a functional lymphatic vessel network. This observation suggests a novel program of lymphangiogenesis and identifies a property of lymphatic vessel memory in response to recurrent inflammation. A brief episode of initial inflammation regressed lymphatic vessels, and a significant increase in CD11b+ macrophages were associated with the development of lymphatic vessel memory. These vessels had major differences in the structure and the spatial distribution of specialized lymphatic vessel features. Surprisingly, we found that the lymphatic vessel memory response did not depend on the vascular endothelial growth factor C or A pathway, indicating that different molecular pathways regulate inflammatory lymphangiogenesis and lymphatic vessel memory. These findings uncover a priming mechanism to facilitate a rapid lymphatic vessel memory response: a potential important component of peripheral host defense. Copyright © 2013 American Society for Investigative Pathology.


Cosgrove D.,Boys Town National Research Hospital
Pediatric Nephrology | Year: 2012

We have known for some time that mutations in the genes encoding 3 of the 6 type IV collagen chains are the underlying defect responsible for both X-linked (where the COL4A5 gene is involved) and autosomal (where either COL4A3 or COL4A4 genes are involved) Alport syndrome. The result of these mutations is the absence of the sub-epithelial network of all three chains in the glomerular basement membrane (GBM), resulting, at maturity, in a type IV collagen GBM network comprising only α1(IV) and α2(IV) chains. The altered GBM functions adequately in early life. Eventually, there is onset of proteinuria associated with the classic and progressive irregular thickening, thinning, and splitting of the GBM, which culminates in end-stage renal failure. We have learned much about the molecular events associated with disease onset and progression through the study of animal models for Alport syndrome, and have identified some potential therapeutic approaches that may serve to delay the onset or slow the progression of the disease. This review focuses on where we are in our understanding of the disease, where we need to go to understand the molecular triggers that set the process in motion, and what emergent therapeutic approaches show promise for ameliorating disease progression in the clinic. © IPNA 2011.


Keefe D.H.,Boys Town National Research Hospital
Journal of the Acoustical Society of America | Year: 2015

An acoustical transmission line model of the middle-ear cavities and mastoid air cell system (MACS) was constructed for the adult human middle ear with normal function. The air-filled cavities comprised the tympanic cavity, aditus, antrum, and MACS. A binary symmetrical airway branching model of the MACS was constructed using an optimization procedure to match the average total volume and surface area of human temporal bones. The acoustical input impedance of the MACS was calculated using a recursive procedure, and used to predict the input impedance of the middle-ear cavities at the location of the tympanic membrane. The model also calculated the ratio of the acoustical pressure in the antrum to the pressure in the middle-ear cavities at the location of the tympanic membrane. The predicted responses were sensitive to the magnitude of the viscothermal losses within the MACS. These predicted input impedance and pressure ratio functions explained the presence of multiple resonances reported in published data, which were not explained by existing MACS models. © 2015 Acoustical Society of America.


Gunda V.,Boys Town National Research Hospital
Investigative ophthalmology & visual science | Year: 2013

The inhibitory effects and mechanism(s) of type IV collagen α-6 chain-derived noncollagenous domain (α6[IV]NC1 or hexastatin) on elastin-derived peptide (EDP)-activated choroidal endothelial cell migration, kinase signaling, and membrane type 1 metalloproteinase (MT1-MMP) activation are explored. Mouse choroidal endothelial cells (MCECs) were incubated in media with soluble EDPs (kappa elastin, mouse elastin, and Val-Gly-Val-Ala-Pro-Gly [VGVAPG] hexapeptide) for different time intervals with or without α6(IV)NC1. The MCECs proliferation, migration, tube formation, MT1-MMP expression, and angiogenic signaling were analyzed in cells subjected to EDP and α6(IV)NC1 treatments. The MCECs also were subjected to EDPs, and specific inhibitors for evaluation of focal adhesion kinase (FAK) and protein kinase B (Akt) phosphorylation. Kappa elastin, mouse elastin, and VGVAPG enhanced the migration, without affecting the proliferation of MCECs. The α6(IV)NC1 inhibited survival and EDP-activated migration of MCECs. The EDP-activated MCEC tube formation on matrigel also was inhibited by α6(IV)NC1. Further, EDP-activated MT1-MMP expression and FAK/phosphoinositide-3-kinase (PI-3K)/mammalian target of rapamycin (mToR)/Akt phosphorylation in MCECs, were reduced by α6(IV)NC1. The EDP-induced FAK and Akt phosphorylation was blocked by FAK- and Akt-specific inhibitors. The EDPs and α6(IV)NC1 are identified to exhibit opposing effects on MCEC angiogenic behavior and signaling. The α6(IV)NC1 inhibited cell survival, EDP-mediated migration, MT1-MMP expression and, FAK/PI-3K/mToR/Akt phosphorylation in MCECs. This work demonstrates α6(IV)NC1 as a prospective endogenous molecule for the treatment of diseases involving choroidal neovascularization in the eye.


Cosgrove D.,Boys Town National Research Hospital | Zallocchi M.,Boys Town National Research Hospital
International Journal of Biochemistry and Cell Biology | Year: 2014

The 10 different genes associated with the deaf/blind disorder, Usher syndrome, encode a number of structurally and functionally distinct proteins, most expressed as multiple isoforms/protein variants. Functional characterization of these proteins suggests a role in stereocilia development in cochlear hair cells, likely owing to adhesive interactions in hair bundles. In mature hair cells, homodimers of the Usher cadherins, cadherin 23 and protocadherin 15, interact to form a structural fiber, the tip link, and the linkages that anchor the taller stereocilia's actin cytoskeleton core to the shorter adjacent stereocilia and the elusive mechanotransduction channels, explaining the deafness phenotype when these molecular interactions are perturbed. The conundrum is that photoreceptors lack a synonymous mechanotransduction apparatus, and so a common theory for Usher protein function in the two neurosensory cell types affected in Usher syndrome is lacking. Recent evidence linking photoreceptor cell dysfunction in the shaker 1 mouse model for Usher syndrome to light-induced protein translocation defects, combined with localization of an Usher protein interactome at the periciliary region of the photoreceptors suggests Usher proteins might regulate protein trafficking between the inner and outer segments of photoreceptors. A distinct Usher protein complex is trafficked to the ribbon synapses of hair cells, and synaptic defects have been reported in Usher mutants in both hair cells and photoreceptors. This review aims to clarify what is known about Usher protein function at the synaptic and apical poles of hair cells and photoreceptors and the prospects for identifying a unifying pathobiological mechanism to explain deaf/blindness in Usher syndrome.© 2013 Elsevier Ltd. All rights reserved.


Keefe D.H.,Boys Town National Research Hospital
Journal of the Acoustical Society of America | Year: 2012

A click-evoked otoacoustic emission (CEOAE) has group delay and spread as first- and second-order temporal moments varying over frequency, and instantaneous frequency and bandwidth as first- and second-order spectral moments varying over time. Energy-smoothed moments were calculated from a CEOAE database over 0.5-15 kHz bandwidth and 0.25-20 ms duration. Group delay and instantaneous frequency were calculated without phase unwrapping using a coherence synchrony measure that accurately classified ears with hearing loss. CEOAE moment measurements were repeatable in individual ears. Group delays were similar for CEOAEs and stimulus-frequency OAEs. Group spread is a frequency-specific measure of temporal spread in an emission, related to spatial spread across tonotopic generation sites along the cochlea. In normal ears, group delay and spread increased with frequency and decreased with level. A direct measure of cochlear tuning above 4 kHz was analyzed using instantaneous frequency and bandwidth. Synchronized spontaneous OAEs were present in most ears below 4 kHz, and confounded interpretation of moments. In ears with sensorineural hearing loss, group delay and spread varied with audiometric classification and amount of hearing loss; group delay differed between older males and females. CEOAE moments reveal clinically relevant information on cochlear tuning in ears with normal and impaired hearing. © 2012 Acoustical Society of America.

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