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Biomedical subjects

M Tykocinski

Publications and source records attributed to M Tykocinski.

At least 19 recordsLinked to original sources
PubMed2001

Chronic electrical stimulation of the auditory nerve using high surface area (HiQ) platinum electrodes.

High surface area cochlear implant electrodes with much smaller geometric surface areas than current designs might be used in the future to increase the number of stimulating electrodes along the carrier. Potential problems with an increase in charge density for a common stimulus resulting from decreasing the geometric surface area would be reduced by the enlarged real surface area of such electrodes. Electrochemically modified (HiQ) platinum (Pt) electrodes, with a real surface area approximately 75 times greater than the current standard Pt electrodes of the same geometric size, had shown in vitro a low polarization (Z(pol)) and electrode impedance (Z(e)), as well as a low residual direct current (DC). In this study we examined the chronic performance of HiQ electrodes in cats, which were bilaterally implanted with a two-channel HiQ or standard Pt scala tympani electrode array and unilaterally stimulated for periods of up to 2390 h. Stimuli consisted of 50 micros/phase charge-balanced biphasic current pulses presented at 2000 pulses/s/channel with a 50% duty cycle. Electrode impedance (Z(e)), access resistance (R(a)) and polarization impedance (Z(pol)) were calculated from current and voltage measurements obtained periodically throughout the implantation period. Immediately following implantation HiQ electrodes showed a significantly smaller Z(pol), resulting in a reduced Z(e) (P<0.0001) compared to standard electrodes, while there was no significant difference between R(a) of both electrode designs (P=0.91). Subsequently, Z(e) generally increased mainly due to a rise in R(a), which dominated Z(e) and obliterated the effect of a lower Z(pol) on Z(e) in HiQ electrodes. Peak R(a) levels correlated closely (r=0.85) with the amount of intracochlear fibrous tissue found adjacent to the array. Following explantation of the array, voltage waveforms for both electrode designs recorded in saline were again very similar to those recorded immediately after implantation. Mean DC levels were consistently lower for HiQ electrodes compared with standard electrodes (22.45 nA vs 134.7 nA). Histopathological examination of corresponding cochlear sections comparing the stimulated test side with the unstimulated control side showed no significant difference (P>0.05) for either animals implanted with HiQ electrodes (n=6) or standard electrodes (n=2). Nor were there any significant differences between the spiral ganglion cell density of the basal turn implanted with HiQ or standard electrodes for both the stimulated test (P=0.31) and the unstimulated control side (P=0.84). Although these findings are based on a small group of animals implanted with standard electrodes (n=2), and those negative statistical results could potentially be due to the small sample size, similar spiral ganglion cell survival was found in a previous study of a larger group of animals using standard electrodes stimulated with the same stimulus paradigm as in the present study [Xu et al. (1997) Hear. Res. 105, 1-29]. Our data indicate that while some initial advantages of HiQ electrodes are lost during chronic implantation due to intracochlear fibrous tissue growth, low DC levels and the high surface area appear to be maintained, suggesting that HiQ electrodes may have important clinical applications.

Animals↗
PubMed2001

The contour electrode array: safety study and initial patient trials of a new perimodiolar design.

OBJECTIVE: The aim of these studies was to investigate the insertion properties and safety of a new intracochlear perimodiolar electrode array design (Contour). BACKGROUND: An electrode array positioned close to the neural elements could be expected to reduce stimulation thresholds and might potentially reduce channel interaction. METHODS: Two sequential studies were conducted. In study 1, the Contour electrode array was inserted in 12 human temporal bones. After cochlear surface preparation, the position of the array was noted and the basilar membrane was examined for insertion damage. On the basis of the outcome of this temporal bone study, study 2 investigated the Contour array, mounted on a Nucleus CI-24 M device and implanted in three adult patients. RESULTS: Study I showed that in 10 temporal bones, the Contour array was positioned close to the modiolus, and the basilar membrane was intact. In the two remaining bones, the arrays had pierced the basilar membrane and were positioned in the scala vestibuli apical to the penetration. Statistical analysis showed an equivalent probability of insertion-induced damage of the two array designs. In study 2, image analysis indicated that the Contour electrodes were positioned closer to the modiolus than the standard Nucleus straight array. Lower T and C levels, but higher impedance values, were recorded from electrodes close to the modiolus. Initial speech perception data showed that all patients gained useful open-set speech perception, two patients achieving scores of 100% on sentence material 3 months postoperatively. CONCLUSIONS: The temporal bone studies showed the Contour electrode array to be generally positioned closer to the modiolus than the standard Nucleus straight array, and to have an equivalent probability of causing insertion-induced damage.

Acoustic Impedance Tests↗
PubMed2001

The role of radiographic phase-contrast imaging in the development of intracochlear electrode arrays.

OBJECTIVE: This study describes the application of a new radiographic imaging modality, phase-contrast radiography, to in vitro human temporal bone imaging and investigates its use in the development of new electrode arrays for cochlear implants. BACKGROUND: The development of perimodiolar electrode arrays for cochlear implants requires detailed information from postoperative radiologic assessment on the position of the array in relation to the cochlear structures. Current standard radiographic techniques provide only limited details. MATERIALS AND METHODS: Nucleus standard electrode arrays and perimodiolar Contour electrode arrays were implanted into the scala tympani of 11 human temporal bones. Both conventional and phase-contrast radiographs were taken of each temporal bone for comparative purposes. RESULTS: Phase-contrast imaging provides better visualization of anatomic details of the inner ear and of the structure of the intracochlear electrode array, and better definition of electrode location in relation to cochlear walls. CONCLUSION: Phase-contrast radiography offers significant improvement over conventional radiography in images of in vitro human temporal bones. It seems to be a valuable tool in the development of intracochlear electrode arrays and cochlear implant research. However, this new radiographic technique still requires certain computational and physics challenges to be addressed before its clinical use can be established.

Cochlea↗
PubMed2000

Comparison of electrode position in the human cochlea using various perimodiolar electrode arrays.

OBJECTIVE: This study was conducted to evaluate the insertion properties and intracochlear trajectories of three perimodiolar electrode array designs and to compare these designs with the standard Cochlear/Melbourne array. BACKGROUND: Advantages to be expected of a perimodiolar electrode array include both a reduction in stimulus thresholds and an increase in dynamic range, resulting in a more localized stimulation pattern of the spiral ganglion cells, reduced power consumption, and, therefore, longer speech processor battery life. METHODS: The test arrays were implanted into human temporal bones. Image analysis was performed on a radiograph taken after the insertion. The cochleas were then histologically processed with the electrode array in situ, and the resulting sections were subsequently assessed for position of the electrode array as well as insertion-related intracochlear damage. RESULTS: All perimodiolar electrode arrays were inserted deeper and showed trajectories that were generally closer to the modiolus compared with the standard electrode array. However, although the precurved array designs did not show significant insertion trauma, the method of insertion needed improvement. After insertion of the straight electrode array with positioner, signs of severe insertion trauma in the majority of implanted cochleas were found. CONCLUSIONS: Although it was possible to position the electrode arrays close to the modiolus, none of the three perimodiolar designs investigated fulfilled satisfactorily all three criteria of being easy, safe, and atraumatic to implant.

Cochlear Implantation↗
PubMed2000

Characterization of human and mouse H19 regulatory sequences.

H19 is expressed in a large percentage of bladder tumors, but not expressed in healthy bladder tissue. The aim of this study is to define H19 optimal transcriptional regulatory sequences in tumor cells, which can potentially be used to control expression of a toxin gene in constructs to be used in bladder cancer gene therapy trials in mice and human. Transient expression assays revealed that elements responsible for promoter activity are contained within the 85 bp upstream region. The transcriptional activity of this region was strongly inhibited by the methylation of the Hpa II sites. A modest cell specificity is conferred by the upstream sequences. The human and murine promoter activities were significantly increased by the human H19 4.1 kb enhancer sequence. The 85 bp H19 upstream region contains all the elements to interact with the enhancer. We showed that the human H19 promoter is highly active in a murine bladder carcinoma cell line, justifying its use to drive the expression of a cytotoxin gene in gene therapy trials in mice.

Animals↗
PubMed1999

The expression of the H19 gene and its function in human bladder carcinoma cell lines.

The human H19 gene is a paternally imprinted oncofetal gene, highly expressed in several fetal tissues, down-regulated in nearly all adult tissues but re-expressed in carcinomas of tissues which express the gene in fetal life. It has no known protein product and till today, no function could be designated to H19 RNA. Cells derived from bladder carcinomas and hepatocellular carcinomas were transfected with plasmids carrying a luciferase reporter gene under the control of a 800 nucleotides long promoter region of the H19 gene either alone or together with different parts of a 5 kb downstream region, previously shown to possess enhancer activity. Our results provide evidence that three regions of the 3' downstream sequence can independently stimulate the H19 promoter activity in a tissue and cell specific manner. The growth rate of two cell populations, both derived from the same bladder carcinoma cell line and which differ in their H19 RNA content, were compared. The cells with a high H19 RNA level stopped their proliferation after 48 h when cultivated in a low serum containing media while the cells lacking H19 RNA continued their proliferation for at least an additional 48 h period.

Gene Expression↗
PubMed1998

The effect of retinoic acid on the activation of the human H19 promoter by a 3' downstream region.

The human H19 is paternally imprinted (maternally expressed). It is transcribed by RNA pol II, but has no protein product. Its function is unknown. We showed that the transcription of the human H19 gene is under the simultaneous control of both a 5' upstream (promoter) region and a 3' downstream region in cell lines derived from human choriocarcinomas. Moreover, the activation of the H19 promoter by retinoic acid in cells derived from human testicular germ cell tumors is dependent upon the 3' downstream region. The possibility that the action of retinoic acid on the H19 promoter is an indirect one and involves a member of the AP2 transcription factor family is discussed.

Antineoplastic Agents↗
PubMed1997

Reduction in excitability of the auditory nerve following electrical stimulation at high stimulus rates. II. Comparison of fixed amplitude with amplitude modulated stimuli.

We have previously shown that acute electrical stimulation of the auditory nerve using charge-balanced biphasic current pulses presented continuously can lead to a prolonged decrement in auditory nerve excitability (Tykocinski et al., Hear. Res. 88 (1995), 124-142). This work also demonstrated a reduction in electrically evoked auditory brainstem response (EABR) amplitude decrement when using an otherwise equivalent pulse train with a 50% duty cycle. In the present study we have extended this work in order to compare the effects of electrical stimulation using both fixed amplitude electrical pulse trains and amplitude modulated (AM) pulse trains that more accurately model the dynamic stimulus paradigms used in cochlear implants. EABRs were recorded from guinea pigs following acute stimulation using AM trains of charge-balanced biphasic current pulses. The extent of stimulus-induced reductions in the EABR were compared with our previous results using either fixed amplitude continuous, or 50% duty cycle pulse trains operating at 0.34 microC/phase (2 mA, 170 micros/phase) at 400 or 1000 pulses/s (Tykocinski et al., Hear. Res. 88 (1995) 124-142). The AM pulse train, operating at the same rates, was based on a 1-s sequence of the most extensively activated electrode of a Nucleus Mini-22 cochlear implant using the SPEAK speech processing strategy exposed to 4-talker babble, and delivered the same total charge as the fixed amplitude 50% duty cycle pulse train. Two hours of continuous stimulation induced a significant, rate-dependent reduction in auditory nerve excitability, and showed only a slight post-stimulus recovery for monitoring periods of up to 6 hours. Following 2 or 4 h of stimulation using an otherwise equivalent pulse train with a 50% duty cycle or the AM pulse train, significantly less reduction in the EABR was observed, and recovery to pre-stimulus levels was generally rapid and complete. These differences in the extent of the recovery between the continuous waveform and both the 50% duty cycle and AM waveforms were statistically significant for both 400 and 1000 pulses/s stimuli. Consistent with our previous results, the stimulus changes observed using AM pulse trains were rate dependent, with higher rate stimuli evoking more extensive stimulus-induced changes. The present findings show that while stimulus-induced reductions in neural excitability are dependent on the extent of stimulus-induced neuronal activity, the use of an AM stimulus paradigm further reduces post-stimulus neural fatigue.

Animals↗
PubMed1997

Submillimeter imaging and reconstruction of the inner ear.

OBJECTIVE: To present new radiological developments using high-resolution magnetic resonance imaging (MRI). MATERIALS AND METHODS: Using heavily T2-weighted sequences at a 1.5 Tesla scanner, maximum-intensity projections (MIP) of the inner ear were generated. The imaging time was less than 20 minutes, and imaging could be performed with adults and children of all age groups alike. This method enables us to visualize and identify the different neural structures of the internal auditory canal. Aplasia or schwannoma of a single or a variation of nerves could be clearly demonstrated. RESULTS: Three-dimensional reconstruction enabled unprecedented clear and precise presentation of the fluid content of the inner ear. The size and shape of 2 to 2 1/2 turns of the cochlea could be routinely demonstrated and analyzed in 45 subjects. Eight patients subsequently received an intracochlear implant electrode, and the intraoperative findings correlated with the imaging. CONCLUSION: The most recent high-resolution MRI techniques provide reliable visualization of submillimeter anatomical structures of the inner ear and auditory nerve.

Adult↗
PubMed1996

Episomal expression of wild-type CFTR corrects cAMP-dependent chloride transport in respiratory epithelial cells.

The isolation of the gene responsible for the Cl- ion transport defect in cystic fibrosis (CF) has provided important information about the relationship between the disease pathology and the underlying genetic and biochemical mechanisms. In addition, new areas of investigation and therapy are now possible. Most notably, the isolation of the CF gene, the cystic fibrosis transmembrane conductance regulator (CFTR) has been led to the development of different gene therapy strategies. To circumvent possible complications due to insertional mutagenesis and virally induced immune responses, we have employed Epstein-Barr virus (EBV)-based expression vectors for correction of the cAMP-dependent Cl- transport defect associated with CF. A CFTR-containing expression construct under the regulation of the Rous sarcoma virus (RSV) long terminal repeat (LTR) (pREP5/CFTR) was introduced into transformed human airway epithelial cells defective in cAMP-dependent Cl-transport. Transfected cells were assayed for Cl- ion transport by (36)Cl- efflux, SPQ, and patch clamp and showed restoration of intact cAMP-dependent transport. CFTR transcription from pREP5/CFTR was detected by Northern hybridization. The level of response to agonists appeared to be dependent on the level of CFTR expression. When cells were tested for functional expression of CFTR after removal of selection pressure, they showed a continuous decrease in responsiveness to forskolin as a function of time after removal of selection. This decrease correlated with a loss of CFTR mRNA in the loss of the PREP5/CFTR. After 12 to 15 weeks growth without selection both cAMP-dependent Cl- transport and plasmid-derived CFTR mRNA were not detectable. However, it was still possible to rescue cAMP-dependent Cl- transport in these transfected cells by reselection suggesting the presence of the CFTR containing plasmid in a portion of the cells. Analysis of DNA indicated that the pREP5/CFTR vector copy number was reduced from 30 copies per cell with continuous selection, to approximately 0.3 copies per cell after 20 weeks without hygromycin B.

Cells, Cultured↗
PubMed1995

Class I MHC alpha 3 domain can function as an independent structural unit to bind CD8 alpha.

Functional interactions between CD8-dependent cytotoxic T cells and their targets require physical contact between CD8 and a non-polymorphic determinant on the alpha 3 domain of the class I MHC molecule. We developed a cell-free assay to directly monitor this molecular interaction, specifically excluding the participation of other cellular proteins and lipids. This assay employed a soluble CD8 derivative and a plate-bound HLA-A2.1 derivative, alpha 3/MalE, in which the alpha 3 domain has been expressed independently of its neighboring polypeptide domains on the native class I MHC molecule and beta 2-microglobulin (beta 2-m). These proteins were produced using eukaryotic and prokaryotic expression systems, respectively. Our data demonstrated specific, saturable binding between soluble CD8 alpha (sCD8 alpha) and alpha 3/MalE, and the Kd of this interaction was determined to be 4.5 x 10(-7) M. Monoclonal antibodies (mAb) directed against either CD8 or the alpha 3 domain of class I MHC inhibited binding; mAb directed against other sites on class I MHC and beta 2-m did not. Our data suggest that the interaction between CD8 alpha and the alpha 3 domain of class I MHC does not require the participation of neighboring class I sequences or beta 2-m.

Base Sequence↗
PubMed1995

Reduction in excitability of the auditory nerve following electrical stimulation at high stimulus rates.

While recent studies have suggested that electrical stimulation of the auditory nerve at high stimulus rates (e.g., 1000 pulses/s) may lead to an improved detection of the fine temporal components in speech among cochlear implant patients, neurophysiological studies have indicated that such stimulation could place metabolic stress on the auditory nerve, which may lead to neural degeneration. To examine this issue we recorded the electrically evoked auditory brainstem response (EABR) of guinea pigs following acute bipolar intracochlear electrical stimulation using charge-balanced biphasic current pulses at stimulus rates varying from 100 to 1000 pulses/s and stimulus intensities ranging from 0.16 to 1.0 microC/phase. Charge density was held constant (approximately 75 microC cm-2 geom/phase) in those experiments. To monitor the recovery in excitability of the auditory nerve following this acute stimulation. EABR thresholds, wave I and III amplitudes and their latencies were determined for periods of up to 12 h following the acute stimulation. Higher stimulus rates and, to a lesser extent, higher intensities led to greater decrements in the post-stimulus EABR amplitude and prolonged the recovery period. While continuous stimulation at 100 pulses/s induced no decrement in the EABR, stimulation at 200 and 400 pulses/s produced an increasingly significant post-stimulus reduction of the EABR amplitude, which showed only partial recovery during the monitoring period. No EABR response could be evoked immediately following stimulation at 1000 pulses/s, using a probe intensity 16-19 dB below the stimulus intensity. However, partial EABR recovery was observed for wave III following stimulation at the lowest stimulus intensity (0.16 microC/phase). These stimulus-induced reductions in the EABR amplitude were also reflected in increased thresholds and latencies. Providing stimulus rate and intensity were held constant, stimulation at different charge densities (37.7, 75.5 and 150.7 microC cm-2 geom/phase) had no influence on the post-stimulus EABR recovery. Significantly, the introduction of a 50% duty cycle into the stimulus pulse train resulted in a more rapid and complete post-stimulus recovery of the EABR compared to continuous stimulation. These data suggest that stimulus rate is a major contributor to the observed reduction in excitability of the electrically stimulated auditory nerve. This reduction may be a result of an activity-induced depletion of neural energy resources required to maintain homeostasis. The present findings have implications for the design of safe speech-processing strategies for use in multichannel cochlear implants.

Animals↗
PubMed1995

Electrophysiologic effects following acute intracochlear direct current stimulation of the guinea pig cochlea.

Auditory brain stem responses to both acoustic (auditory brain stem response [ABR]) and electrical (electrically evoked auditory brain stem response [EABR]) stimuli, as well as the frequency-specific compound action potential (CAP), were recorded before and periodically following continuous intracochlear DC stimulation (2, 7, and 12 microA) for 2 hours in normal-hearing guinea pigs, by means of a banded intracochlear electrode array. Click-evoked ABR, frequency-specific CAP, and the EABR input-output function remained generally unchanged following stimulation at 2 microA DC. However, following stimulation at 7 and 12 microA, a significant decrement of the amplitude of the click-evoked ABR, frequency-specific CAP, and electrophonic component of the EABR was observed, while there was an increase in the amplitude of the EABR, associated with direct electrical stimulation of the auditory nerve.

Acoustic Stimulation↗