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Biomedical subjects

E M Keithley

Publications and source records attributed to E M Keithley.

53 records · Page 3Linked to original sources
PubMed1990

Effects of cyclophosphamide on the pathogenesis of cytomegalovirus-induced labyrinthitis.

Cyclophosphamide was used in this study to define the contribution of the inflammatory response relative to direct cytopathic effects of guinea pig cytomegalovirus (GPCMV) in inducing sensorineural hearing loss in the guinea pig. The eighth nerve compound action potential (CAP) threshold on day 7 after inoculation of GPCMV into the scala tympani was an average of 35 dB greater for control animals than for those that were immunosuppressed with daily intraperitoneal injections of cyclophosphamide (20 mg/kg body weight). The amount of GPCMV antigen in the cochlea, detected immunohistochemically did not correlate with the CAP threshold. However, the greater the inflammatory response to GPCMV in the cochlea, the higher the CAP threshold and thus the greater the hearing loss. This study demonstrates that the inflammatory response to GPCMV may be more important than direct cytopathic effects of the virus in producing sensorineural hearing loss in GPCMV-induced labyrinthitis.

Action Potentials↗
PubMed1989

Spiral ganglion cell density in young and old gerbils.

The Mongolian gerbil, like other mammalian species, has a decreased number of spiral ganglion cells as a function of age. This loss of cells was first seen in 24- to 30-month old animals in the basal end of the ganglion. In the oldest individuals the apical end of the ganglion was also affected. There were approximately 15-25% fewer cells in the affected areas in the 36- to 42-month old animals. In the oldest animals degeneration of the stria vascularis was seen in the apical turn and some degenerative changes in the organ of Corti were seen throughout the length of the cochlear duct. The aging pattern in the gerbil cochlea, is similar to that described for other species. Vacuoles, previously described in the gerbil cochlear nucleus, were also seen in the auditory nerve within the modiolus, but central to the Schwann-glial border in all animals. Vacuoles were not present within the spiral ganglion or the peripheral processes of the ganglion cells. Because the ganglion cell axons should be similar on either side of the Schwann-glial border, but the vacuoles were confined to the central nervous system, it is concluded that the degenerative process affects glial cells as opposed to neurons.

Aging↗
PubMed1989

Antigen-specific immune response in the inner ear.

The specificity of inner ear immune responses was investigated by challenging each inner ear of presensitized animals with different antigens. Animals presensitized systemically with keyhole limpet hemocyanin (KLH) and bovine serum albumin (BSA) were challenged with KLH in the right and BSA in the left inner ears. Two weeks later perilymph anti-KLH levels were increased significantly in the right inner ears compared to the levels in the left inner ears. In contrast, perilymph anti-BSA levels were increased significantly in the left inner ears compared to the levels in the right inner ears. These results suggested that the rise in perilymph antibody following inner ear antigen challenge was predominantly the result of an antigen-specific immune response in the inner ear and not simply the result of an increase in vascular permeability of serum contamination from the experimental procedure itself.

Animals↗
PubMed1989

Development of morphological and physiological changes in the cochlea induced by cytomegalovirus.

The effect of viral infection in the cochlea was investigated by inoculation of live cytomegalovirus or inactivated virus. Auditory thresholds were measured on the day of inoculation and on the terminal day. Two to 8 days following inoculation, the animals were killed and the cochleas were evaluated histologically. The compound nerve potential showed an increase in threshold prior to the cochlear microphonic, indicating the nerve was affected prior to the outer hair cells. All experimental cochleas contained inflammatory and cytomegalic inclusion cells and showed degenerative changes. The number of infected cells was small relative to the histopathology. Control cochleas had normal structure and function. The degeneration, therefore, might be mediated by inflammation as well as by the cytopathic effect of the virus. Viral infections, therefore, might be better managed with anti-inflammatory therapy in addition to antiviral agents.

Animals↗
PubMed1988

The spatial representation of frequency in the rat dorsal cochlear nucleus and inferior colliculus.

The spatial distribution of neural activity produced by tones was assessed in the rat dorsal cochlear nucleus (DCN) and inferior colliculus (IC), using the 2-deoxyglucose (2-DG) technique. Eight pure tones, spanning the range of reported single unit characteristic frequencies in the rat, were presented at 40 dB above behavioral threshold. The relationship between frequency of stimulation and location of neural activity within each nucleus was evaluated quantitatively. Based on the 2-DG uptake pattern across animals, a tonotopic axis in the transverse plane was defined for each nucleus. This axis transected the centers of regions of evoked 2-DG uptake for each frequency. There was an orderly relationship between stimulus frequency and the location of evoked neural activity along the axis. Each pure tone stimulus activated an approximately equal proportion of this axis, for all frequencies tested, in both the DCN and IC. This suggests the existence of equal 'spatial bandwidths, in rat central auditory structures, across its entire frequency range. Equal spatial bandwidths could facilitate signal analysis strategies which require interaction between neurons with closely-related CFs. In the horizontal plane, however, the proportion of stimulated tissue was not equal across frequency. High-frequency (greater than 8 kHz) tones produced increased neural activity along a much greater extent of the anterior-to-posterior axis of the IC than did low-frequency tones.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

The development of endolymphatic hydrops following CMV inoculation of the endolymphatic sac.

The effect of inoculation of cytomegalovirus (CMV) into the endolymphatic sac was examined in CMV-seronegative and seropositive animals. Seronegative animals developed hearing loss, infection in the epithelial cells of the endolymphatic sac and perisaccular connective tissue, and endolymphatic hydrops. Control animals inoculated with inactivated CMV showed no hearing loss, viral infection, or endolymphatic hydrops. Seropositive animals showed complete protection from hearing loss and viral infection, yet a monocytic infiltrate was seen surrounding the endolymphatic sac. Associated with this localized immune response was mild evidence of endolymphatic hydrops in 40% (2/5) of the animals. Control seropositive animals inoculated with inactivated CMV showed no hearing loss or morphological changes. CMV then, can infect cells of the endolymphatic sac resulting in hearing loss and endolymphatic hydrops. The immune response to CMV in seropositive animals is protective, but is associated with endolymphatic sac inflammation.

Animals↗
PubMed1987

Frequency map of the spiral ganglion in the cat.

A frequency map of the cat spiral ganglion has been determined on the basis of reconstructed cochleas in which individual spiral ganglion cells were labeled with horseradish peroxidase following determination of their characteristic frequency; the cochleas were the same as those used by Liberman and Oliver [J. Comp. Neurol. 223, 163-176 (1984)]. By matching this map to one previously described for the organ of Corti [M. C. Liberman, J. Acoust. Soc. Am. 72, 1441-1449 (1982)], an estimate of the afferent innervation density of the inner hair cells was derived. Counts of myelinated nerve fibers at the habenula perforata and inner hair cells were also performed and yielded similar results in all but the most basal 10%-15% of the cochlea. Between 0.1 and 20 kHz there is a gradual monotonic increase as a function of frequency in the number of spiral ganglion cells terminating on each inner hair cell, from about eight ganglion cells per inner hair cell to about 30 ganglion cells per inner hair cell. Above 20 kHz, it seems there is a decrease to about ten ganglion cells per inner hair cell. The greatest innervation density is at approximately the region of the basilar membrane with the greatest density of inner hair cells per millimeter.

Animals↗
PubMed1983

The spiral ganglion and hair cells of Bronx waltzer mice.

Inner hair cells and spiral ganglion cells were counted in a mutant mouse strain (Bronx waltzer) reported to have very few of these cells (6) in order to determine if the remaining ganglion cells would be predominantly type II cells. These cell counts indicate a 50% reduction of spiral ganglion cells in Bronx waltzer cochleas compared to normal mice. Averaged throughout the cochlea about 11% of the remaining cells are type II cells while in normal mice this percentage is 5%. In some regions however, as many as 20% of the remaining cells are type II cells. Counts of IHC in surface preparations reveal 37 normal looking IHC (about 5% of the normal population) in each of two Bronx waltzer mouse cochleas. There were also about 120 shrunken IHC in each cochlea, representing 17% of the normal cell population. While there appears to be an increased proportion of type II cells in the Bronx waltzer spiral ganglion there are also many more type I cells than might be expected from the small number of IHC.

Animals↗
PubMed1982

Hair cell counts in an age-graded series of rat cochleas.

Hair cells of Sprague-Dawley rats aged 2-33 months were counted in order to assess the magnitude, location and time course of cell degeneration. The mean number of hair cell places (hair cells plus phalangeal scars) was approximately 4700: 960 inner hair cell places and 3470 outer hair cell places. These numbers do not vary systematically with age. Hair cell degeneration was observed in all animals. At 31-33 months of age, animals had inner hair cell losses ranging from 1.6 to 4.2% and outer hair cell losses ranging from 2.1 to 23.3%. The loss of hair cells was greatest in the upper apex, where the 31-33-month-old animals had 3.1-9.2% inner hair cell losses and 7.4-46.8% outer hair cell losses. Outer hair cell losses were also large in the basal end, where inner hair cell losses were small. In the older animals, hair cell losses were consistently most prominent in the third row of outer hair cells. Following examination of the hair cell population, the ganglion cells in the apical region were evaluated in a number of cochleas. No significant correlation was found between the magnitude of inner hair cell and ganglion cell losses.

Age Factors↗
PubMed1979

Spiral ganglion cell counts in an age-graded series of rat cochleas.

Spiral ganglion cells in the cochleas of Sprague-Dawley rats in various age groups were counted in order to assess the extent and location of cell degeneration with age. Cells in every tenth section of serially sectioned plastic embedded cochleas were counted in the light microscope. The median cell number for the 1- to 2-month-old animals was 15,800 cells. This number was first seen to be significantly reduced (-14%) in the 23-month-old animals. At 27 to 29 months the ganglion cell number was reduced by 20%, while at 33 to 34 months there was a 17% loss. Losses were found throughout the length of the ganglion with the greatest losses at the lower basal and apical ends. In the oldest group, these losses amounted to 28% and 33%, respectively. Type II ganglion cells first showed a significant decrease in number in the 27- to 29-month-old group, when a 32% loss was seen. The same loss was seen in the 33- to 34-month-old group. Unlike the type I cells which are lost throughout the length of the ganglion, type II cells were not significantly reduced in number at the basal end, but decreased by as much as 42% in the middle and apical regions.

Age Factors↗
PubMedDate not supplied

Immunologic responses in experimental cytomegalovirus labyrinthitis.

To better understand the pathogenesis of cytomegalovirus labyrinthitis, a guinea pig model was created. Following inoculation at several sites (cardiac, perilymph, and endolymphatic sac) in both seronegative and seropositive animals, the immunologic, histologic, and electrophysiologic responses were measured. Seronegative animals uniformly showed progressive hearing loss with marked inflammation and degeneration of neural elements. In animals inoculated into the endolymphatic sac, an associated endolymphatic hydrops developed in addition to deafness. Seropositivity protected the hearing, but endolymphatic sac inoculations resulted in mild hydrops due to local inflammation that was devoid of evidence of viral replication. The question of whether hearing loss was attributable to local inflammatory responses rather than the cytopathic effects of the virus was then examined. To test this hypothesis, animals were immunosuppressed with cyclophosphamide prior to intracochlear inoculation of cytomegalovirus. The immunosuppressed animals showed significantly better hearing than the controls, and this correlated directly with the degree of cellular infiltration of the scala tympani. These studies confirm the importance of host immune responses in the pathogenesis of hearing loss due to cytomegalovirus.

Animals↗
PubMedDate not supplied

Experimental cytomegalovirus infection: viremic spread to the inner ear.

The entry route of viruses into the inner ear is still controversial. Guinea pig cytomegalovirus (CMV) has been used to create an animal model of systemic infection as well as labyrinthitis. In this study, seronegative guinea pigs were administered intracardiac inoculations of varying doses of guinea pig CMV. After three or eight days, the animals were killed and necropsy specimens examined for viral antigen. In the specimens examined three days after inoculation, no label was seen in the cochlea. However, label was found in the spleen with doses of 100 microL, and also in the liver in animals inoculated with 300 microL of virus. After eight days, an animal that received 200 microL of the virus showed labeling in the modiolar blood vessels and perivascular infiltrates. Two of the four animals that received 300 microL of the virus showed labeling in spiral ganglion cells. None of the animals showed viral antigen within the stria vascularis, nor were there signs of acute labyrinthitis. At eight days, animals inoculated with greater than 100 microL of virus showed labeled cells in multiple organs. These data suggest that the entry route of guinea pig cytomegalovirus into the inner ear might involve viremic spread to modiolar blood vessels and subsequent spread to spiral ganglion cells.

Animals↗
PubMedDate not supplied

Temporal sequence of viral antigen expression in the cochlea induced by cytomegalovirus.

Injection of guinea-pig cytomegalovirus into seronegative guinea pig cochleas results in viral labyrinthitis. The location of infected cells 1-8 days following inoculation was examined using an immunohistochemical assay for viral antigens. Mesothelial cells below the basilar membrane and those lining the scala tympani, especially below the osseous spiral lamina, were the first cells to express antigen. This occurred 2 days following inoculation. Infection then spread rapidly toward the brain and through the perilymphatic duct to involve inflammatory cells, mesothelial cells of Reissner's membrane, spiral ganglion cells, and the vestibular ganglion cells. In any one cochlea, more mesothelial cells and inflammatory cells expressed viral antigen than any other cell type. It seems then, that there is a differential susceptibility to viral infection and antigen expression in the various cell types of the cochlea. Typical cytomegalic inclusions were common in mesothelial cells. However, many cells labelled for viral antigens did not contain inclusions. The identification of viral antigens then, is a more sensitive technique for demonstrating infection than is the location of cytomegalic inclusion cells.

Animals↗
PubMedDate not supplied

Endotoxin-induced otitis media with effusion in the mouse. Immunohistochemical analysis.

A model of endotoxin-induced otitis media with effusion was developed in healthy BALB/c mice. Endotoxin extracted from Salmonella typhimurium (10 micrograms/ml) was injected into the middle ear bulla transtympanically and the resultant inflammatory response was analyzed using immunohistochemical methods. Serous effusions were observed otoscopically and mucosal edema and infiltrate were studied histologically, both peaking at 3 days and essentially resolving by 7 days. However, persistence of a small area of inflammation in the round window niche was consistently present at 2 weeks. The specific cellular responses to endotoxin were analysed by histologic and immunohistologic examination of the murine temporal bone. We used antibodies to identify T-lymphocytes (anti-Lyt-1, -Lyt-2), macrophages and neutrophils (anti-Mac-1), and immunoglobulins (anti-IgA, -IgG, -IgM). In the mucosal/submucosal infiltrate Mac-1+ and Lyt-1+ cells peaked from days 1 to 3. Within the luminal effusion Mac-1+ and Lyt-1+ cells as well as diffuse (not cell-associated) IgG, IgM, and IgA staining were most prevalent from days 1 to 3, while IgG-bearing plasma cells formed the majority of the luminal cells observed at 1 to 2 weeks. No significant influx of T-suppressor cells was observed at any time. The round window niche and anterior portion of the tympanic bulla mucosa were found to be the most reactive areas. These results suggest that endotoxin alone is capable of producing an inflammatory infiltrate in the mouse consistent with otitis media with effusion, and that the interaction of endotoxin with resident immunocytes of the middle ear, as well as serum derived immune cells, is consistent with the known phlogistic properties of endotoxin.

Animals↗
PubMedDate not supplied

Spiral modiolar vein: its importance in inner ear inflammation.

The inner ear responds immunologically to foreign proteins and pathogens introduced into the cochlea. The route of entry of the cells participating in the inner ear inflammatory process is the spiral modiolar vein with its collecting venules. Since this vein is located adjacent to the scala tympani, the end result of cellular infiltration is fibro-osseous obliteration of this scala preferentially. This observation has implications for the placement of cochlear implant electrodes of patients with labyrinthitis as the cause of hearing loss.

Adult↗