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Biomedical subjects

Howard W Francis

Publications and source records attributed to Howard W Francis.

16 recordsLinked to original sources
PubMed2006

Synaptic alterations at inner hair cells precede spiral ganglion cell loss in aging C57BL/6J mice.

Hearing deficits have often been associated with loss of or damage to receptor hair cells and/or degeneration of spiral ganglion cells. There are, however, some physiological abnormalities that are not reliably attributed to loss of these cells. The afferent synapse between radial fibers of spiral ganglion neurons and inner hair cells (IHCs) emerges as another site that could be involved in transmission abnormalities. We tested the hypothesis that the structure of these afferent terminals would differ between young animals and older animals with significant hearing loss. Afferent endings and their synapses were examined by transmission electron microscopy at approximately 45% distance from the basal end of the cochlea in 2-3 month-old and 8-12 month-old C57BL/6J mice. The number of terminals in older animals was reduced by half compared to younger animals. In contrast, there was no difference in the density of SGCs between the age groups. Older animals featured enlarged terminals and mitochondria and enlarged postsynaptic densities and presynaptic bodies. These morphological changes may be a combination of pathologic, adaptive and compensatory responses to sensory dysfunction. Improved knowledge of these processes is necessary to understand the role of afferent connectivity in dysfunction of the aging cochlea.

Aging↗
PubMed2005

Efficient quantification of afferent cochlear ultrastructure using design-based stereology.

The afferent synapse between the auditory nerve fiber and the inner hair cell (IHC) represents a critical junction for hearing. Elucidation of the structure at this site will help establish the substrate for normal sound encoding as well as pathologic processes associated with hearing dysfunction. Previous applications of unbiased (design-based) stereological principles have expanded our knowledge of neuro-morphological changes evident with the light microscope. Applying these principles at the level of the synapse is a promising morphometric approach for the efficient sampling of large reference spaces with electron microscopy. This study tests the accuracy of using ultra-thin sections at a fixed interval, known as disector pairs, to quantify afferent innervation density. We analyzed the total numbers of afferent terminals, synaptic thickenings, and synaptic bodies associated with each IHC in the C57BL/6J mouse cochlea, and confirmed the accuracy of the stereological approach in comparison to three-dimensional reconstructions of serial alternate sections. The higher sampling efficiency of the disector pair method rapidly increases precision while also reducing the largest source of variability, inter-animal differences. We conclude that ultrastructural quantification of afferent innervation can be accomplished in the cochlea using efficient design-based stereology.

Animals↗
PubMed2005

Predictive models for cochlear implantation in elderly candidates.

OBJECTIVE: An aging American population carries a high prevalence of profound sensorineural hearing loss. We examined the performance of multichannel cochlear implant recipients in a large database of adult subjects. DESIGN: Nonconcurrent prospective study of a national cohort with multivariate regression analysis of preoperative and postoperative performance variables in multichannel cochlear implant recipients. We applied models of prediction established in previous studies to the observed results. SETTING: Referral centers with active cochlear implant programs. PATIENTS: Adolescents and adults with profound hearing loss (N = 749; age range, 14-91 years). MAIN OUTCOME MEASURE: Postoperative monosyllabic word recognition. RESULTS: The population 65 years and older demonstrated a clinically insignificant 4.6%-smaller postoperative word score compared with the population younger than 65 years. When duration of deafness exceeded 25 years, elderly recipients demonstrated higher word scores than their younger counterparts. A more significant factor affecting outcomes is the ratio of duration of deafness to age at implantation. CONCLUSIONS: Age at implantation carried relatively little predictive value for postoperative performance in subjects 65 years and older. Although a small decrement in mean speech recognition scores was evident, the clinical significance of this difference is questionable when all of the results observed in elderly patients are considered. A shorter percentage of life spent in severe-to-profound sensorineural hearing loss suggests a foundation of acoustic/auditory processing in the elderly cohort that may mitigate potential physiological effects associated with advanced age. This study confirms and extends previous observations that duration of profound deafness and residual speech recognition carry higher predictive value than the age at which an individual receives an implant.

Adolescent↗
PubMed2005

Cochlear implant outcome is not influenced by the choice of ear.

OBJECTIVES: This study tested the hypothesis that patients with residual hearing in the nonimplanted ear had the same cochlear implant benefit whether the implanted ear had profound or severe hearing loss. DESIGN: A retrospective chart review of adult cochlear implant recipients with postlingual hearing loss. Patients were categorized according to the pure-tone average of the implanted and contralateral ears as (a) bilateral profound, (b) severe-profound, and (c) bilateral severe. The results of a test battery of spoken language measures were compared among patients belonging to these hearing categories at 6, 12, and 24 months after surgery, using a t-test and multivariate regression analyses. RESULTS: The presence of residual hearing in one or both ears was associated with significantly higher postoperative speech perception scores compared with participants with bilateral profound hearing loss. Among participants with similar amounts of residual hearing in the nonimplanted ear, however, there was no difference in speech recognition scores between those with profound and those with severe hearing loss in the implanted ear. CONCLUSIONS: Among participants with asymmetric hearing loss, there is no additional benefit to implanting the better-hearing ear that can be preserved for use with a hearing aid for better speech understanding in noise and sound localization. These results suggest that the additional benefit received by patients with residual hearing is mediated by trophic effects on crossed pathways in the central nervous system and is independent of the preoperative functional status of the implanted ear.

Adult↗
PubMed2005

Inner ear abnormalities in a Kcnq1 (Kvlqt1) knockout mouse: a model of Jervell and Lange-Nielsen syndrome.

HYPOTHESIS: Mice lacking functional KCNQ1 (previously known as KvLQT1) channels exhibit functional and structural abnormalities that indicate disturbed production of endolymph. BACKGROUND: Congenital deafness associated with cardiac conduction abnormalities (Jervell and Lange-Nielsen syndrome) is associated with dysfunctional KCNQ1/KCNE1 channel complex. This potassium channel plays a critical role in the production and homeostasis of endolymph by the stria vascularis. A preliminary report documented severe abnormalities of the scala media and vestibular compartments of a single mouse lacking functional KCNQ1 alleles. METHODS: Hearing thresholds were measured in three Kcnq1 knockout mice, two heterozygous mice, and one wild-type mouse by auditory brainstem response recordings using clicks, after which the temporal bones were removed. After fixation and dehydration, the ears were embedded in araldite, sectioned at 20-microm thickness, stained with toluidine blue on glass slides, and examined with the light microscope. RESULTS: Kcnq1 knockout mice were deaf and demonstrated circling behavior. They exhibited a marked atrophy of the stria vascularis, contraction of the endolymphatic compartments, and collapse and adhesion of surrounding membranes. There was a complete degeneration of the organ of Corti and an associated degeneration of the spiral ganglion. CONCLUSION: Kcnq1 knockout mice exhibit histopathologic findings that are comparable to those reported in human temporal bone cases of Jervell and Lange-Nielsen syndrome, and provide further evidence that KCNQ1 channel dysfunction can lead to congenital deafness in this syndrome.

Animals↗
PubMed2004

Two types of afferent terminals innervate cochlear inner hair cells in C57BL/6J mice.

Afferent synapses on inner hair cells (IHC) transfer auditory information to the central nervous system (CNS). Despite the importance of these synapses for normal hearing, their response to cochlear disease and dysfunction is not well understood. The C57BL/6J mouse is a model for presbycusis and noise-induced hearing loss because of its age-related hearing loss and susceptibility to acoustic over-exposure. In this context, we sought to establish normal synaptic structure in order to better evaluate synaptic changes due to presbycusis and noise exposure. Ultrastructural analysis of IHCs and afferent terminals was performed in a normal hearing 3-month-old C57BL/6J mouse at cochlear sites corresponding to 8, 16 and 32 kHz using semi-serial sections. A stereologic survey of random sections was conducted of IHCs in 11 additional mice. Two morphologically distinct groups of afferent terminals were identified at all 3 frequency locations in 11 out of 12 animals. "Simple" endings demonstrated classic features of bouton terminals, whereas "folded" endings were larger in size and exhibited a novel morphologic feature that consisted of a fully internalized double membrane that partially divided the terminal into two compartments. In many cases, the double membrane was continuous with the outer terminal membrane as if produced by an invagination. We still must determine the generality of these observations with respect to other mouse strains.

Afferent Pathways↗
PubMed2004

Effects of central nervous system residua on cochlear implant results in children deafened by meningitis.

BACKGROUND: This study explored factors associated with speech recognition outcomes in postmeningitic deafness (PMD). The results of cochlear implantation may vary in children with PMD because of sequelae that extend beyond the auditory periphery. OBJECTIVE: To determine which factors might be most determinative of outcome of cochlear implantation in children with PMD. DESIGN: Retrospective chart review. SETTING: A referral center for pediatric cochlear implantation and rehabilitation. SUBJECTS: Thirty children with cochlear implants who were deafened by meningitis were matched with subjects who were deafened by other causes based on the age at diagnosis, age at cochlear implantation, age at which hearing aids were first used, and method of communication used at home or in the classroom. MAIN OUTCOME MEASURE: Speech perception performance within the first 2 years after cochlear implantation and its relationship with presurgical cognitive measures and medical history. RESULTS: There was no difference in the overall cognitive or postoperative speech perception performance between the children with PMD and those deafened by other causes. The presence of postmeningitic hydrocephalus, however, posed greater challenges to the rehabilitation process, as indicated by significantly smaller gains in speech perception and a predilection for behavioral problems. By comparison, cochlear scarring and incomplete electrode insertion had no impact on speech perception results. CONCLUSIONS: Although the results demonstrated no significant delay in cognitive or speech perception performance in the PMD group, central nervous system residua, when present, can impede the acquisition of speech perception with a cochlear implant. Central effects associated with PMD may thus impact language learning potential; cognitive and behavioral therapy should be considered in rehabilitative planning and in establishing expectations of outcome.

Child↗
PubMed2004

Central effects of residual hearing: implications for choice of ear for cochlear implantation.

OBJECTIVES/HYPOTHESIS: The study tested the hypothesis that among patients with similar levels of residual hearing in the nonimplanted ear, speech perception outcome is the same whether or not the implanted ear has profound or severe levels of hearing loss. STUDY DESIGN: Retrospective. METHODS: Levels of hearing loss in postlingually deafened adults who had cochlear implantation at Johns Hopkins University (Baltimore, MD) between 1991 and 2002 were classified according to pure-tone averages as bilateral severe (n = 20), severe-profound (severe in one ear and profound in the other) (n = 23), and bilateral profound (n = 43). There was no significant difference in the age at onset and duration of deafness among the three patient groups. Individuals in the bilateral severe and severe-profound groups had comparable levels of severe hearing loss in their nonimplanted ears, whereas those in severe-profound and bilateral profound groups had comparable levels of profound hearing loss in their implanted ears. Speech perception performance was evaluated using words from the Consonant Nucleus Consonant word list, Hearing in Noise Test sentences in quiet, and Central Institute for the Deaf sentences through recorded presentation at 70 dB sound pressure level (SPL). RESULTS: Despite the profound hearing loss of the implanted ear in the asymmetrical group, there was no significant difference in mean speech perception scores compared with the bilateral severe group within the first year after implant surgery. By comparison, the bilateral profound group had lower speech perception results compared with patients with residual hearing in one or both ears. CONCLUSION: The study results suggest that implantation of the profoundly deafened ear does not diminish the functional advantage conferred by residual hearing in a patient with asymmetrical hearing loss. Therefore, the central auditory pathway may be the site at which persistent auditory function has its most beneficial effects.

Adult↗
PubMed2003

Cochlear implantation update.

Cochlear implantation is recognized as a valuable intervention with important implications for the acquisition of speech perception and verbal language in children with severe to profound hearing impairment. Auditory rehabilitation, language intervention, and close coordination between parents, schools, and the implant center are necessary to maximize efficacy. Early identification of hearing loss, early hearing aid use and language intervention, and cochlear implantation by 2 years of age are positive predictors for language acquisition that can approach the levels of normal-hearing children. There are early indications that increased access to mainstream education and gains in quality of life are long-term benefits that render cochlear implantation a cost-effective intervention.

Auditory Pathways↗
PubMed2003

The functional age of hearing loss in a mouse model of presbycusis. II. Neuroanatomical correlates.

This report relates patterns of age-related outer hair cell (OHC) loss to auditory behavioral deficits in C57BL/6J mice. Hair cell counts were made from serial sections of the cochlear partition in three subject groups representing young (2-3 months), middle (8-9 months), and old ages (12-13 months). The cochlear location of OHC counts was determined from three-dimensional computerized reconstructions of the serial sections. Comparisons of the topographic distribution of surviving OHCs across the subject groups confirmed an orderly base-to-apex progression of cochlear degeneration that is well known in this mouse strain. All mice appeared to follow the same progression of OHC loss, although subjects showed considerable variation in the rate at which they advanced through a uniform sequence of structural changes. Behavioral implications of the magnitude and location of OHC loss were investigated by correlating the histological status of individual mice with sound detection thresholds from the same subjects [Hear. Res. 183 (2003) 44-56]. The analysis revealed regionalized patterns of OHC loss that were correlated with frequency-dependent changes in hearing thresholds, and validates the use of 'functional age' as an indicator of age-related cochlear degeneration and dysfunction. In the absence of physiologically defined cochlear frequency maps for C57BL/6J mice, these structure-function correlation techniques offer an alternative approach for linking anatomical results to hearing abilities.

Age Factors↗
PubMed2003

Task performance in stapedotomy: comparison between surgeons of different experience levels.

OBJECTIVES: Two steps in stapedotomy are particularly challenging: (1) micropick fenestration of the stapes footplate (SF) and (2) crimping of the stapes prosthesis (SP) to the incus. We conducted trials to determine if experience correlates with differences in performance for these tasks. METHODS: In a surgical model of stapedotomy, performance was measured for 3 experienced and 3 novice surgeons. For fenestration, we measured ability to target the fenestration and force applied to the SF. For crimping, we measured crimp quality, movement of the SP during crimping, and force applied to the SF. RESULTS: Experienced surgeons demonstrated significantly better ability to target the fenestration and, during crimping, caused less SP movement and a significantly lower rate of SP dislodgment. CONCLUSIONS: Clear differences in task performance are measurable between more and less experienced surgeons during critical steps of stapedotomy. CLINICAL SIGNIFICANCE: The observed differences in task performance may contribute to an understanding of maneuvers that increase the risk of inadequate prosthesis placement and cochlear trauma-factors likely responsible for variable hearing results with strapedotomy.

Clinical Competence↗
PubMed2002

Protein kinase C mediates potentiation of synaptic transmission by phorbol ester at parallel fibers in the dorsal cochlear nucleus.

Many cells in the outer two layers of the dorsal cochlear nucleus (DCN) express high levels of the phospholipid-activated, calcium dependent kinase, protein kinase C (PKC), an enzyme that can phosphorylate numerous proteins involved in neurotransmission and postsynaptic signaling. We investigated the effects of stimulating PKC with phorbol esters (phorbol 12-13 diacetate; PDAc) on parallel fiber synaptic transmission in brain slices of the guinea pig DCN. Phorbol esters increased the amplitude of the postsynaptic components of the field potential, including the excitatory post-synaptic field potential (fEPSP) and the population spike following electric stimulation of parallel fibers. Phorbol esters simultaneously decreased paired-pulse facilitation, suggesting that transmitter release mechanisms were affected. Potentiation of synaptic transmission and diminished paired-pulse potentiation were also observed in intracellular recordings of DCN neurons. The effects of phorbol esters were antagonized by the specific PKC blockers bisindolylmaleimide and calphostin C. Although modulation of the synaptic potentials appears to be mediated by presynaptic PKC, the differential effects of PDAc on the fEPSP and the population spike also suggest the involvement of postsynaptic PKC and postsynaptic targets. These experiments demonstrate that protein kinase C is capable of profoundly modulating synaptic transmission at parallel fiber synapses in the DCN.

Acoustic Stimulation↗
PubMed2002

Robot-assisted stapedotomy: micropick fenestration of the stapes footplate.

OBJECTIVE: Micropick fenestration of the stapes footplate, a difficult step in stapedotomy, was selected for trials evaluating the potential for robotic assistance (RA) to improve clinical measures of surgical performance. STUDY DESIGN: In a surgical model of stapedotomy, we measured accuracy of fenestration to a desired point location and force applied to the stapes footplate. Performance variables were measured for 3 experienced and 3 less-experienced surgeons. RESULTS: RA significantly reduced the maximum force applied to the stapes footplate. For fenestration targeting, RA significantly improved accuracy for less-experienced surgeons and significantly worsened targeting for more-experienced surgeons. CONCLUSIONS: RA significantly improves performance for micropick fenestration in a surgical model of stapedotomy. For certain tasks, RA differentially affects performance for users of different experience levels. CLINICAL SIGNIFICANCE: These are the first results showing quantitative improvements in performance during simulated ear surgery using RA and differential effects of RA on performance for users of different experience levels.

Clinical Competence↗
PubMed2002

Impact of cochlear implants on the functional health status of older adults.

OBJECTIVES: To assess the impact of cochlear implantation on quality of life changes in older adults aged 50 years and above. STUDY DESIGN: Retrospective study by questionnaire and chart review. METHODS: Forty-seven patients aged 50 to 80 years (mean age, 63.4 y [SD = 8.6 y]), who have multiple-channel cochlear implants received at The Listening Center at Johns Hopkins Hospital, completed the Ontario Health Utilities Index Mark 3 survey and a questionnaire on quality of life changes. Health utility scores before and after cochlear implantation were measured, and audiologic data before implantation and at 6 months and 1 year after implantation were analyzed. RESULTS: Cochlear implantation in older adults is associated with a mean gain in health utility(P <.0001) of 0.24 (SD = 0.33), which corresponds to a favorable cost-utility of $9530 per quality-adjusted life-year. Improvements in hearing and emotional health attributes were primarily responsible for this increase in health-related quality of life measure. There was a significant increase in speech perception scores at 6 months after surgery (P <.0001 for both CID sentence and monosyllabic word tests) and a strong correlation between the magnitude of health utility gains and the postoperative increase in speech perception scores (r = 0.45, P <.05). CONCLUSIONS: Cochlear implants have a significant impact on the quality of life of older deaf patients, and are a cost-effective intervention in this population. Improvements in speech perception are predictive of gains in health-related quality of life and associated emotional benefits after cochlear implantation.

Age Factors↗