Biomedical subjects

M Fallon

Publications and source records attributed to M Fallon.

At least 55 records · Page 3Linked to original sources

PubMed1993

Contralateral sound suppresses distortion product otoacoustic emissions through cholinergic mechanisms.

Presentation of an acoustic signal to one ear can suppress sound-evoked activity recorded at the opposite ear. The suppression appears to be mediated by medial olivocochlear (MOC) efferent neurons synapsing with outer hair cells (OHCs) and acting through the MOC neurotransmitter, acetylcholine (ACh). The purpose of the present investigation was to study the suppression of distortion product otoacoustic emissions (DPOAEs) by contralateral sound and to examine whether the suppression could be blocked by known antagonists of olivocochlear (OC) efferent activity. Urethane-anesthetized guinea pigs were used. Perilymph spaces of ipsilateral cochleae were alternately perfused with artificial perilymph and drugs at 2.5 microliters/min for 10 min. After each period of perfusion, DPOAEs were measured before, during and after contralateral wideband noise (WBN) stimulation. Pre-perfusion, contralateral WBN attenuated the ipsilateral DPOAEs between 1-3 dB. This suppression was blocked reversibly by strychnine (10 microM), curare (10 microM) and atropine (20 microM), known antagonists of OC efferent activity. These results confirm the findings of Puel and Rebillard (1990) that contralateral WBN can suppress DPOAEs in anesthetized guinea pigs. Furthermore, results suggest that this efferent control of the cochlear mechanical response can either be mediated by both nicotinic and muscarinic cholinergic receptors, or that a single receptor with as yet undescribed structure and pharmacology mediates effects seen.

Acoustic Stimulation↗

PubMed1993

Volume regulation in cochlear outer hair cells.

Many cells placed in a hypotonic medium initially swell and then rapidly undergo a regulatory volume decrease (RVD) to return towards original volume. Re-exposure to the isotonic solution results in the cells shrinking followed by a regulatory volume increase (RVI). Previous studies have shown that isolated outer hair cells (OHCs) placed in a hypotonic medium swell and maintain this shape until returned to the original medium. We re-examined this apparent lack of cell volume regulation in OHCs. OHCs were isolated from guinea pig cochleae, mechanically dissociated and dispersed, and placed in a Hank's balanced salt solution (HBS). In the cells studied, switching the perfusate to a hypotonic HBS (290-280 mmol/kg) for 15 min resulted in an immediate shortening of the OHCs (i.e., volume increase). In 26% of the cells, this increase was followed by a return to original length during the time the cell was perfused with the hypotonic medium, a RVD. Twelve percent of the cells demonstrating a RVD also displayed a RVI. Omitting collagenase and increasing Ca2+ concentration did not increase the percentage of cells displaying a RVD, while gadolinium (Gd3+, 10 microM) decreased the percentage to zero. This is the first report of isolated OHCs undergoing cell volume regulation.

Animals↗

PubMed1992

The effect of a new vitamin D analog, 22-oxa-1 alpha,25(OH)2D3, on bone mineral metabolism in normal male rats.

The in vivo effects of 22-oxa-1 alpha,25 dihydroxyvitamin D3 (OCT), on bone mineral metabolism were investigated in normal male Sprague-Dawley rats. The rats were administered either vehicle (control), low-dose OCT (25 ng/100 g body weight), or high-dose OCT (250 ng/100 g body wt). High-dose OCT increased serum ionized calcium (P less than 0.05) and decreased serum parathyroid hormone (PTH) (P less than 0.05) at all time points and increased serum bone Gla protein on days 7 and 28 (P less than 0.05) compared with controls. Low-dose OCT decreased serum PTH at all the time points (P less than 0.05) compared with controls. Tibial bone histomorphometry showed no significant differences between the two doses of OCT and controls. We found that OCT has minimal direct effects on bone metabolism in normal male rats in contrast to 1,25 dihydroxyvitamin D3. This property may be advantageous in the treatment with OCT of cell-proliferative diseases.

Analysis of Variance↗

PubMed1992

Effect of pharmacological purging on natural killer cell number and activity in human bone marrow.

We assayed natural killer (NK) cell activity and phenotype from human bone marrow (BM) following "purge" with 4-hydroperoxycyclophosphamide (4HC) at 60 micrograms/ml for 30 min in vitro. In all cases studied, lytic activity against the K562 cell line was either significantly decreased or abolished following 4HC purge. Although NK activity was significantly affected by 4HC treatment, no major differences in the phenotype between the purged and unpurged population were seen. Further, while in vitro culture of BM with IL2 resulted in a significant increment of NK activity, no IL-2 responsive cells were found in the 4HC purged BM after 14 days of culture. This study demonstrates that pharmacological purging of bone marrow results in a persistent functional decline of NK cell activity and may serve as a useful model for the study of the ontogeny of NK cells.

Bone Marrow↗

PubMed1992

Intracochlear application of acetylcholine alters sound-induced mechanical events within the cochlear partition.

Activation of olivocochlear (OC) efferent fibers has been suggested to alter micromechanical events occurring within the cochlear partition, possibly through an effect of the efferent neurotransmitter (acetylcholine; ACh) on outer hair cells (OHCs). Based on the widely-accepted assumption that otoacoustic emissions reflect OHC activity, we investigated the in vivo influence of ACh on OHCs by studying alterations in emission amplitude with local ACh application. Distortion product otoacoustic emissions (DPOAEs) were measured in anesthetized guinea pigs before, during, and after intracochlear application of ACh (250 microM) with the cholinesterase inhibitor, eserine (20 microM). Perfusion of ACh/eserine was associated with a desensitizing reduction in DPOAE amplitude of approximately 4.4 dB. This reduction was intensity-dependent, with greater and more consistent reductions observed for DPOAEs elicited by low- than by moderate-intensity primaries. The response reduction was not seen during consecutive ACh perfusions performed without an intervening artificial perilymph wash, and was effectively blocked in the presence of pharmacologic antagonists of OC efferent activity (curare, 50 microM; strychnine, 50 microM). Finally, a similar alteration in DPOAE amplitude was never seen during perfusion of the control (artificial perilymph) solution alone. It is argued that these results support the hypothesis that OC efferent activation can alter sound-induced cochlear mechanical events.

Acetylcholine↗

PubMed1992

Intense sound increases the level of an unidentified amine found in perilymph.

The hypothesis tested was that intense sound increases the levels of a substance such as glutamate, a putative neurotransmitter and neurotoxic substance, in the perilymph compartment of the cochlea. Artificial perilymph was perfused through the perilymphatic compartment of the guinea pig cochlea and the effluent collected during successive 10-min periods. The effects of perfusing an artificial perilymph containing normal levels of Na+ (NARP) were compared to the effects of perfusing an artificial perilymph containing very low concentrations of Na+ (VLNa). The effluent was collected during ambient noise and during increasing intensities of broad-band noise (10 min at 106, 112, 118 and 124 dB SPL). Levels of amines in the effluent were measured by HPLC utilizing precolumn o-phthalaldehyde (OPA) derivatization and fluorescence detection. VLNa increased the levels of glutamate and several other amines in effluent from the cochlea compared to levels obtained in NARP. Compared with its level during ambient room noise, the concentration of an unidentified amine labeled Unk 2.5 increased during intense noise (124 dB SPL). Intense noise induced no detectable changes in the concentrations of glutamate and fifteen other amines. The chemical identity and role of Unk 2.5 remain to be determined.

Amines↗

PubMed1992

Intracochlear salicylate reduces low-intensity acoustic and cochlear microphonic distortion products.

Salicylate is well-known to produce reversible hearing loss and tinnitus. The site and mechanism of salicylate's ototoxic actions, however, remain unresolved. Recent experiments demonstrating primarily low-intensity effects on cochlear afferent outflow and effects on otoacoustic emissions (OAEs) suggest that salicylate acts to compromise active, energy-enhancing processes within the cochlea (i.e., the active process). We tested this hypothesis by examining the effect of salicylate on distortion product emissions. Distortion product responses to two-tone stimulation were monitored in the guinea pig before, during, and after intracochlear administration of increasing concentrations of salicylate (0.6-5 mM). These responses were recorded as acoustic signals in the ear canal spectrum (ADP), and as present in the cochlear microphonic (CM) recorded from a wire in basal turn scala vestibuli (CMDP). We also recorded the CM response to a single tone. Cochlear perfusion of salicylate resulted in a dose-responsive reduction in ADPs that was greater for low intensities of stimulation. CMDPs also demonstrated a concentration-dependent reduction at low intensities, but were increased slightly, though not significantly, by salicylate when elicited by high intensity primaries. CM was essentially unchanged by intracochlear salicylate. These results are consistent with an action of salicylate that involves the outer hair cells (OHCs) and are in harmony with the hypothesis that salicylate may selectively compromise the active process.

Animals↗

PubMed1992

Evaluation of a collagen/hydroxylapatite implant for orbital reconstructive surgery.

A variety of autogenous and alloplastic materials have been used to correct enophthalmos. Hydroxylapatite (HA), is a calcium-phosphate-based compound that has been extensively studied as a bone replacement material. We studied the properties of a new dense particulate form of HA in a collagen matrix (PFC/HA) implanted in the subperiosteal space of ten rabbit orbits for a period of 6 months. All animals were studied with pre- and postoperative computed tomography (CT) scans, and measurements of induced proptosis and implant volume were made. The proptosis induced by the implant averaged 2.2 mm and was stable over a 6-month period. Implant volume was constant throughout the study. Three-dimensional computer-generated images of the soft tissue, skeletal, and implant surfaces confirmed the implant stability. All animals were studied histologically with fluorochrome bone markers, which revealed minimal foreign body reaction to the implant, no evidence of infection, and marked fibrovascular ingrowth. We found the PFC/HA to possess properties that make it an ideal implant material: ease of availability, ease of handling, no resorption, minimal immunogenicity, infection resistance, no observed migration, biointegration, and no risk of disease transmission. PFC/HA may make an excellent implant material to manage orbital volume.

Animals↗

PubMed1992

Evidence that cyclosporine G is less deleterious to rat bone in vivo than cyclosporine A.

We have previously shown that CsA administration to rats causes a high turnover bone loss with bone resorption exceeding bone formation. Similar findings have been reported in renal and cardiac transplantation patients administered CsA. Cyclosporine-G (CsG), a natural equipotent immunosuppressive analogue of CsA, has been shown to be less nephrotoxic than CsA. We therefore compared the effects of CsG and CsA on bone mineral metabolism. Sixty male Sprague-Dawley rats were divided into 3 equal groups as follows: group A (n = 20) was the control; group B (n = 20) received CsA 15 mg/kg by daily gavage; and group C received CsG 15 mg/kg by daily gavage for 28 days. Rats were bled weekly for measurement of circulating biochemical parameters of bone mineral metabolism and after sacrifice on day 28, the tibiae were removed for histomorphometric analysis. The tibial bone histomorphometry revealed that the percentage of bone volume was significantly reduced, and the osteoclast count increased in both the CsA and CsG group, but significantly less so in the CsG than the CsA group. Parameters reflecting bone formation in the CsG group were similar to controls but significantly different from the CsA group. Bone Gla protein levels in the CsA group were significantly increased compared with the control and CsG groups from day 14. Serum 1,25 dihydroxyvitamin D was increased significantly in the CsA group on days 14 and 28 compared with both control and CsG groups, and was significantly elevated in the CsG group compared with controls on the same days. We conclude that CsG is significantly less deleterious to bone mineral metabolism than CsA in the rat in vivo.

Animals↗

PubMed1991

Lowering extracellular calcium decreases the length of isolated outer hair cells.

Transduction by the inner hair cells is hypothesized to be modulated through a change in the length of the outer hair cells (OHC). It has been suggested that the slow change occurring in OHC length is mediated by an actin-myosin system requiring Ca2+ and ATP. This study was designed to systematically examine the effects of lowering extracellular Ca2+ on OHC length. OHCs were isolated from guinea pig cochleae, mechanically dissociated and dispersed, and placed in a Hank's balanced salt solution (HBS). Exposing the cells to a Ca(2+)-free HBS supplemented with 200 microns EDTA produced a shortening in OHC length with a concomitant increase in cell width. The shortening was reversed successfully by bathing the cells in 8 mM Ca2+. We speculate that the decrease in length due to lowering extracellular Ca2+ may be caused by a relaxation of a circumferential contractile mechanism which is thought to cause elongation of intact OHCs (Slepecky, 1989; Dulon et al., 1990).

Animals↗

PubMed1991

Guinea pigs show post-natal stability in frequency mapping at the basal turn.

Others have shown that in animals born with immature cochleae the basal turn undergoes changes in function during the early days of postnatal life. We examined whether similar changes could be detected in the guinea pig, an animal born with a functionally mature cochlea. Our results indicate that no changes occur in the function of the basal turn of the guinea pig cochlea immediately after birth.

Acoustic Stimulation↗

PubMed1991

Changing cation levels (Mg2+, Ca2+, Na+) alters the release of glutamate, GABA and other substances from the guinea pig cochlea.

We examined the effects of changes in cation levels (increased Mg2+ concentration combined with low Ca2+ concentration, and two low concentrations of Na+) on the perilymph levels of gamma-aminobutyric acid (GABA), glutamate (Glu), aspartate (Asp) and other substances. Artificial perilymph solutions containing normal (5 mM) and high (50 mM) levels of K+ were perfused through the perilymphatic compartment of the guinea pig cochlea to examine basal release (5 mM K+) and depolarization-induced release (50 mM K+). Each of the two K+ concentrations were contained in four different solutions: [I] normal artificial perilymph (NARP; NaCl, 137 mM; CaCl2, 2 mM; MgCl2, 1 mM;); [II] high Mg2+ (20 mM)/low Ca2+ (0.1 mM) (HMgLCa); [III] low Na+ (117 mM; LNa), and [IV] very low Na+ (NaCl, 0 mM; VLNa). The effluent was collected and assayed for eighteen primary amines by HPLC. Compared with NARP, the HMgLCa group had an increase in the high K(+)-induced release of Asp and Glu with no change in GABA. VLNa increased the normal K+ levels of Asp, Glu and GABA up to those observed with high K+ in NARP. VLNa increased the high K+ levels of Asp and Glu over fivefold compared with the high K+ levels in NARP, but decreased GABA. We ascribe the results to an interference with either a Na(+)-dependent uptake processes or a Na+/Ca2+ exchange carrier.

Amino Acids↗

PubMed1991

Magnitude of the negative summating potential varies with perilymph calcium levels.

Previous results demonstrated that nimodipine, an L-type of Ca2+ channel antagonist, abolished the negative summating potential (SP) recorded from anesthetized guinea pigs (Bobbin et al., 1990), suggesting that Ca2+ is involved in generation of the negative SP. Therefore we examined the effect of changing concentrations of perilymph Ca2+ on this cochlear potential. Perilymph spaces of guinea pig cochleae were perfused with artificial perilymph solutions containing zero mM Ca2+, zero mM Ca2+ with 2 mM EGTA, 30 mM Mg2+ and increasing levels of Ca2+ (2, 4, 8, 16 mM) at a rate of 2.5 microliters/min for 10 min. Immediately after each period of perfusion the compound action potential of the auditory nerve (CAP), cochlear microphonics (CM) and the negative SP evoked by 10 kHz tone bursts of varying intensities were recorded from a wire inserted in the basal turn scala vestibuli. Decreasing the level of Ca2+ decreased the magnitude of the negative SP, whereas increasing the level of Ca2+ progressively increased the magnitude of the negative SP. Mg2+ (30 mM) suppressed the CAP to the same extent as zero mM Ca2+ with 2 mM EGTA, but only slightly increased the magnitude of the negative SP. These results support the hypothesis that Ca2+ and L-type Ca2+ channels are involved in the function of the hair cells and the generation of the negative SP. Mg2+ appears to be a selective antagonist of the Ca2+ channel involved in transmitter release.

Animals↗

PubMed1991

Salmon calcitonin prevents cyclosporin-A-induced high turnover bone loss.

Cyclosporin-A (CsA) has greatly influenced the outcome of organ transplantation and has also been effective in the treatment of many autoimmune diseases. Unfortunately, it has deleterious effects on bone remodelling, causing a high turnover bone loss, with bone resorption exceeding bone formation. Salmon calcitonin (SCtn) has been shown to inhibit bone resorption in high turnover states such as Paget's disease and postmenopausal osteoporosis. In an attempt to attenuate the high turnover bone remodelling caused by CsA alone, we studied the bone mineral effects of CsA in combination with SCtn in male Sprague-Dawley rats. Group A (n = 20) received vehicle as control, group B (n = 20) received CsA (15 mg/kg BW) by daily gavage and SCtn vehicle sc, group C (n = 20) received SCtn (1.3 IU/kg BW) daily sc and CsA vehicle, and group D (n = 20) received a combination of CsA and Ctn daily, as described above. Rats were bled weekly for determination of circulating biochemical bone parameters. Eight rats from each group were killed on day 14 (short term), and the remaining rats were killed on day 28 (long term). Tibiae were removed for bone histomorphometry after death, which revealed a reduction of trabecular bone volume and an increase in osteoclast number induced by CsA alone. These changes were significantly attenuated by the combination of CsA and SCtn to resemble the histomorphometry of the control group. The inhibition of osteoclast number by SCtn is the most plausible mechanism by which the combination therapy attenuates the high turnover bone loss induced by CsA alone.

Animals↗

PubMed1991

Normal and degenerated intervertebral disk: in vivo and in vitro MR imaging with histopathologic correlation.

The components of the intervertebral disk serve two purposes. The hydrophilic matrix is contained by circumferential rings of fibrocartilage (outer anulus) and Sharpey's fibers. The gellike hydrophilic matrix acts as a cushion between the vertebral body endplates by providing an even distribution of axial and rotational compressive forces. The construction and integrity of the intervertebral disk are assessed well by MR. The purpose of this pictorial essay is to show the in vitro and in vivo MR appearances of the normal and degenerated disk, and to correlate these MR changes with their respective histopathologic findings.

Humans↗

PubMed1990

Acetylcholine, carbachol, and GABA induce no detectable change in the length of isolated outer hair cells.

The mechanical and electrical properties of cochlear outer hair cells (OHCs) are suggested to modulate transduction by inner hair cells. These properties of OHCs are presumably regulated by efferent neurons which use several transmitters including acetylcholine (Ach) and gamma aminobutyric acid (GABA). Since it had been suggested that Ach causes isolated OHCs to shorten visibly, this study was designed to investigate whether GABA also alters the length of OHCs. OHCs were isolated from the guinea pig cochlea by mechanical dispersion after collagenase treatment. Cells were initially selected by strict morphological criteria. In addition they were only included in further studies if they attained a constant length during 10 min of superfusion with buffer solution. Neither GABA (20 microM: 100 microM), Ach (5 mM; 10 microM with 10 microM eserine) or carbachol (10 microM; 100 microM) altered OHC length when applied in iso-osmotic Hank's balanced salt solution (total number of cells tested, 72). If a change in length occurred it must have been smaller than 0.3 microns, our detection ability. In contrast, high potassium and variations in osmolarity changed hair cell length by 3-10% in agreement with other reports.

Acetylcholine↗

PubMed1990

Combined treatment with cyclosporin A and cortisone acetate minimizes the adverse bone effects of either agent alone.

Although cyclosporin A (CsA) and cortisone acetate (CRT) adversely affect bone, their combined effect on bone is unknown. Sprague Dawley rats were therefore administered either vehicle or CsA (7.5 mg/kg/day) by gavage and saline or CRT (2 mg/100 mg/day) by s.c. injection for 28 days. Group A received vehicle plus saline, group B CsA plus saline, group C vehicle plus CRT, and group D CsA/CRT. Serial bloods were sampled over a 28-day period for ionized calcium (Ca), PTH, 1,25 dihydroxyvitamin D (1,25(OH)2D), and bone gla protein (BGP osteocalcin) and tibia were examined on day 28 for histomorphometry. Results were compared with group A. Ca and PTH levels in groups B, C, and D were similar to those in group A during the study period. Group B had lower body weights, elevated levels of BGP, and an increase in 1,25(OH)2D. Group C developed weight loss and a decrease in BGP and 1,25(OH)2D. Group D had weight loss, BGP levels between those of group A and group C, and 1,25(OH)2D values similar to group A. Bone histomorphometry revealed high turnover osteopenia in group B and hyperostosis in group C with a decrease in bone formation and osteoclastlike cells. Combination therapy returned these to control values. In conclusion, the adverse effects of either CsA or CRT on bone in rats are minimized by combined therapy.

Animals↗

PubMed1990

Hyperostosis induced by the bisphosphonate (2-PEBP) in the oophorectomized rat.

To prevent the high turnover bone remodeling associated with acute estrogen deficiency, the bisphosphonate [2-(2-pyridinyl) ethylidene-BP] (2-PEBP) was administered to oophorectomized (OX) rats. Three groups of 15 rats each (250 g) were studied. Group (Gp) A was sham operated, Gp B was OX, and Gp C received 2-PEBP (1.72 mg/kg/day) intraperitoneally for 3 days commencing 4 days postoophorectomy. Oophorectomy was confirmed with serum estradiol measurements. Blood samples were collected on days -7, 0, 7, 14, 21, and 28 for ionized calcium (Ca2+), PTH, and serum bone gla protein (BGP). Rats received tetracycline for bone histomorphometric labeling. All results were compared to Gp A. Body weight increased significantly in Gps B and C (P less than 0.005 by day 28). There was no significant difference in Ca2+, and PTH levels in Gps B and C were similar to Gp A. BGP levels were significantly higher on day 28 in Gp B (P less than 0.05). In Gp C, BGP levels were significantly decreased on days 7, 21, and 28 (P less than 0.03). Gp B revealed increased bone turnover without loss of bone volume (BV/TV). BV/TV was significantly increased in Gp C despite a decrease in parameters of bone formation and normal osteoclast number. In conclusion, 2-PEBP in the OX rat inhibited bone resorption more than formation with resultant hyperostosis. Serum BGP appeared to be a good marker of the changes observed on bone histomorphometry.

Animals↗