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Biomedical subjects

B C Moore

Publications and source records attributed to B C Moore.

At least 19 recordsLinked to original sources
PubMed2006

Morphologic and growth responses in Chironomus tentans to arsenic exposure.

Laboratory bioassays consisting of sediments spiked with three concentrations (30, 130, and 260 microg g-1 As dry wt) of arsenic (As+3) were used to assess morphologic responses and growth in Chironomus tentans larvae. Chironomid larvae were raised in contaminated sediments from egg stage to emergence, and mouthpart abnormalities, larval length, and larval head width were used as end points to determine differences between metal-spiked and control specimens. C. tentans exhibited significantly higher mouthpart deformity proportions, smaller body sizes, smaller head widths, and slower development than control larvae. Our results demonstrate a dose-response relationship between As and mentum deformities in C. tentans. However, the proportion of deformed larvae did not increase with time in the treatment tanks. Results demonstrate that As induces mouthpart abnormalities at various concentrations. This research provides more support for the use of chironomid abnormalities as a tool for the assessment of heavy-metal pollution in aquatic systems.

Abnormalities, Drug-Induced↗
PubMed2004

Complete genome sequence of the genetically tractable hydrogenotrophic methanogen Methanococcus maripaludis.

The genome sequence of the genetically tractable, mesophilic, hydrogenotrophic methanogen Methanococcus maripaludis contains 1,722 protein-coding genes in a single circular chromosome of 1,661,137 bp. Of the protein-coding genes (open reading frames [ORFs]), 44% were assigned a function, 48% were conserved but had unknown or uncertain functions, and 7.5% (129 ORFs) were unique to M. maripaludis. Of the unique ORFs, 27 were confirmed to encode proteins by the mass spectrometric identification of unique peptides. Genes for most known functions and pathways were identified. For example, a full complement of hydrogenases and methanogenesis enzymes was identified, including eight selenocysteine-containing proteins, with each being paralogous to a cysteine-containing counterpart. At least 59 proteins were predicted to contain iron-sulfur centers, including ferredoxins, polyferredoxins, and subunits of enzymes with various redox functions. Unusual features included the absence of a Cdc6 homolog, implying a variation in replication initiation, and the presence of a bacterial-like RNase HI as well as an RNase HII typical of the Archaea. The presence of alanine dehydrogenase and alanine racemase, which are uniquely present among the Archaea, explained the ability of the organism to use L- and D-alanine as nitrogen sources. Features that contrasted with the related organism Methanocaldococcus jannaschii included the absence of inteins, even though close homologs of most intein-containing proteins were encoded. Although two-thirds of the ORFs had their highest Blastp hits in Methanocaldococcus jannaschii, lateral gene transfer or gene loss has apparently resulted in genes, which are often clustered, with top Blastp hits in more distantly related groups.

Archaeal Proteins↗
PubMed2002

The potential association between menta deformities and trace elements in Chironomidae (Diptera) taken from a heavy metal contaminated river.

Elevated morphological deformity rates in Chironomidae larvae have been attributed to such pollutants as oil tars, pesticides, organochlorines, and heavy metals. The potential of chironomids as biological indicators of heavy metal contamination and bioavailability in a contaminated ecosystem was assessed. Chironomid larvae and river sediment were collected from the Coeur d' Alene River system, Idaho, USA, contaminated with heavy metals from mining activities. Chironomid larvae collected at contaminated sites exhibited mouthpart deformity proportions between 3.8 and 10.3% compared to the control site of 0.9%. As, Cd, Cu, Ni, Pb, and Zn were determined in both larvae and sediment samples. Significant correlation between metal concentrations and deformity rates were observed for all metals except Ni. The data also suggests that feeding habits may influence differences in pollution tolerance among genera.

Animals↗
PubMed2001

Psychophysical evaluation of cochlear hair cell damage due to the A3243G mitochondrial DNA mutation.

Mitochondrial dysfunction is an important cause of human deafness, implicated in genetic deafness, toxin and noise damage. We assessed the mechanism of cochlear dysfunction in a population of 11 subjects with a specific mitochondrial disorder caused by the A3243G mitochondrial DNA mutation. Psychophysical tests were carried out to assess the inner and outer hair cell functions in vivo. Inner hair cell function was assessed using a measure of hearing threshold in the presence of "threshold-equalizing noise" which can indicate "dead regions" where the transduction mechanism fails. Outer hair cell function was assessed by using the notched-noise method to measure auditory filter width, dependent on active mechanisms in the outer hair cell. The results support the conclusion that this mitochondrial disorder causes both inner and outer hair cell dysfunctions. Evidence of inner hair cell dysfunction was found mainly in basal (high frequency) regions of the cochlea and occurred even in some subjects with only mild hearing loss. Evidence of outer hair cell dysfunction was found in some instances where pure tone threshold was at or close to normal. The common occurrence of dead regions in the basal cochlea has treatment implication for this form of deafness; such people may not be helped by amplification of high frequencies.

Adult↗
PubMed2001

The influence of external and internal noise on the detection of increments and decrements in the level of sinusoids.

This paper examines the influence of external and internal noise on the detection of increments and decrements in the level of sinusoidal pedestals. In experiment 1, the pedestals were presented either 18 dB above the masked threshold in broadband noise (condition 18-Masked) or 18 dB above the absolute threshold (condition 18-Abs). Pedestal frequencies were 250, 1000 or 4000 Hz, and increment/decrement durations ranged from 5 to 200 ms. For condition 18-Masked, thresholds decreased with increasing pedestal frequency, while for condition 18-Abs, thresholds did not change significantly with pedestal frequency. These results are consistent with the idea that, in condition 18-Masked, thresholds were influenced by the inherent fluctuations produced by the background noise at the output of the auditory filter centred at the pedestal frequency. These fluctuations would decrease in rate with decreasing centre frequency, and this might have a greater deleterious effect on performance. In contrast, the characteristics of the internal noise that presumably limited performance in condition 18-Abs do not appear to vary with pedestal frequency. In experiment 2, a 4000 Hz pedestal was used. It was presented either in quiet or in the presence of narrowband noise centred at 4000, or 7000 Hz, or both. The noise bandwidth ranged from 50 to 400 Hz. The increment/decrement duration ranged from 5 to 100 ms. The noise centred at 7000 Hz produced only a small deterioration in performance relative to that measured in quiet. The noise centred at 4000 Hz had a larger effect, and the effect increased with decreasing noise bandwidth. This is consistent with the idea that slow fluctuations at the output of the auditory filter impair increment and decrement detection more than rapid fluctuations. A model is proposed to account for the results, based on a simulated auditory filter, a compressive non-linearity, a sliding temporal integrator, a logarithmic transform and a template mechanism. Analysis using the model suggests that the effect of centre frequency observed in experiment 1, when background noise was present, cannot be explained entirely in terms of the fluctuations produced by the background noise at the output of the auditory filter centred at the pedestal frequency.

Acoustic Stimulation↗
PubMed2001

Detection and intensity discrimination of brief tones as a function of duration by hearing-impaired listeners.

For normal listeners, difference limens for intensity (DLs) for Gaussian-shaped tone pulses are largest at medium pulse durations (corresponding to about five cycles of the tonal carrier) when the pedestals are 10 dB above threshold, either in quiet or in a pink noise background. One explanation for this is that worst performance occurs when the internal representation of the tone pulses is most compact in time and frequency, affording minimal opportunity for 'multiple looks' (Van Schijndel et al., J. Acoust. Soc. Am. 105 (1999) 3425-3435). However, the mid-duration worsening is largest for medium overall levels, suggesting an involvement of compression on the basilar membrane (BM), which is also greatest at medium levels (Baer et al., J. Acoust. Soc. Am. 106 (1999) 1907-1916). If this is so, the mid-duration worsening should be reduced when BM compression is reduced by outer hair cell damage. To test this, subjects with sensorineural hearing losses were tested using 1-kHz or 4-kHz Gaussian-shaped tone pulses, in quiet or in pink noise that raised thresholds by 10-20 dB. For subjects with mild losses, poorest performance was sometimes found for medium durations. For more severe losses, intensity DLs tended to improve monotonically or remain roughly constant with increasing duration. Performance overall tended to be better for subjects with greater hearing losses. The results are more consistent with an explanation based on BM compression than with an explanation based on multiple looks.

Acoustic Stimulation↗
PubMed2001

Comparison of the electroacoustic characteristics of five hearing aids.

This paper describes a comparison of the electroacoustic characteristics of five hearing aids: (1) a linear BTE aid of the type dispensed under the UK National Health Service (NHS), the BE19; (2) an analogue programmable BTE aid incorporating two-channel wide dynamic range compression, the ReSound BT2; (3) and (4) two digital BTE aids incorporating multi-channel wide dynamic range compression, the Phonak Claro and the Danavox Danalogic; (5) a disposable ITE hearing aid with single-channel compression, the Songbird. Measurements of frequency response using a 2 cc coupler showed that the NHS aid had a distinct undesired peak around 1 kHz. The response rolled off at low and high frequencies, and no gain was applied above about 4000 Hz. The BT2 and Claro both showed somewhat irregular responses with effective upper frequency limits of 5000-6000 Hz. The Danalogic had a reasonably smooth response and provided gain up to 6000 Hz. The Songbird had a smooth response and provided gain up to about 7000 Hz. All aids showed reasonably low harmonic and intermodulation distortion (probably below audible levels for hearing-impaired listeners), the Phonak Claro being the best in this respect. Measures of the effective input noise were obtained using two new methods. The NHS aid had the highest (worst) effective input noise, whereas the Songbird had the lowest, especially at low frequencies. The BT2 and the two digital aids had similar noise levels on one measure, but the BT2 was superior on the other measure. The compression circuits were characterized by measuring attack and release times and by using a method described by Stone and Moore (1992). The aids varied markedly in the extent to which they compressed amplitude modulation at the rates typically occurring in speech (2-10 Hz), the Claro providing the least compression and the Danalogic and Songbird aids providing the most. Overall, the results indicate that the NHS aid performed more poorly in several respects than the other aids. There were no great differences in electroacoustic characteristics between the remaining analogue aids and the digital aids, although the Songbird had a somewhat wider frequency range and lower effective input noise than the other aids.

Acoustic Stimulation↗
PubMed2001

Comparison of three procedures for initial fitting of compression hearing aids. I. Experienced users, fitted bilaterally.

We compared the effectiveness of three procedures for the initial fitting of hearing aids with multi-band compression: (1) CAMEQ, which aims to amplify speech so as to give equal loudness per critical band over the frequency range important for speech intelligibility, and to give similar overall loudness to 'normal': (2) CAMREST, which aims to amplify speech so as to restore 'normal' specific loudness patterns, over a wide range of speech levels; (3) DSL I/O, which aims to map the dynamic range of normally hearing people into the reduced dynamic range of hearing-impaired people, with 'full' restoration of audibility. Ten experienced hearing aid users with moderate sensorineural loss were fitted bilaterally with Danalogic 163D digital hearing aids, using each procedure in turn; the order was counterbalanced across subjects. The fitting required specification of gains for input levels of 55 and 80 dB SPL at six centre frequencies. Real-ear measurements were made to ensure that target gains were reached (+/-3 dB). Immediately after fitting with a given procedure, and one week after fitting, the gains were adjusted when required by the minimum amount necessary to achieve acceptable fittings. The amount of adjustment required provides one measure of the adequacy of the initial fitting. On average, the adjustments were smallest for the CAMEQ procedure. The gain changes were slightly larger for the CAMREST procedure and were largest of all for DSL I/O. For the latter, the gain changes were mostly negative, especially for high frequencies and the higher input level. This indicates that the DSL I/O procedure prescribes more high-frequency gain than is preferred by adult users. After these gain adjustments, users wore the aids for at least three weeks before filling out the APHAB questionnaire and taking part in laboratory measurements of the speech reception threshold (SRT) for sentences in quiet and in steady and fluctuating background noise at levels of 60 and 75 dB SPL. Following these tests, the hearing aids were re-fitted with the next procedure. The scores on the APHAB test and the SRTs did not differ significantly for the three procedures. We conclude that the CAMEQ and CAMREST procedures provide more appropriate initial fittings than DSL I/O.

Acoustic Stimulation↗
PubMed2001

Effects of slow- and fast-acting compression on the detection of gaps in narrow bands of noise.

The inherent amplitude fluctuations in narrow bands of noise may limit the ability to detect gaps in the noise; 'dips' in the noise may be confused with the gap to be detected. For people with cochlear hearing loss, loudness recruitment may effectively magnify the fluctuations and this could partly account for the reduced ability to detect gaps in noise bands that is usually found for such people. Previously, we tested these ideas by processing the envelopes of noise bands to alter the amount of envelope fluctuation. We showed that instantaneous compression, implemented via processing of the Hilbert envelope, led to smaller (that is, better) gap detection thresholds for subjects with cochlear hearing loss. In the present experiment, we determined whether fast-acting compression of the type sometimes used in hearing aids could also lead to improved gap detection. A behind-the-ear (BTE) digital hearing aid was programmed to implement multi-band compression, either fast-acting or slow-acting (control condition). A reference condition using unaided listening was also used. Stimuli were delivered via an earphone placed over the hearing aid. Overall stimulus levels at the output of the hearing aid were similar across conditions. Thresholds for detecting gaps in noise bands centred at 4 kHz were measured as a function of noise bandwidth (10-500 Hz). To prevent the detection of spectral changes introduced by the gap, stimuli were presented in a broad-band background noise. Three normally hearing subjects and three subjects with bilateral cochlear hearing loss were tested. Gap thresholds varied non-monotonically with noise bandwidth, being maximal around 50 Hz. Gap thresholds were generally higher for the hearing-impaired than for the normally hearing subjects. For the latter, gap thresholds were similar for the three conditions. For the hearing-impaired subjects, gap thresholds were similar for the unaided condition and the condition using slow compression. However, fast compression led to smaller gap thresholds, especially for noise bandwidths up to 50 Hz. The results show that fast compression can improve the ability of hearing-impaired subjects to detect gaps in sounds with slowly fluctuating envelopes.

Adult↗
PubMed2001

The use of psychophysical tuning curves to explore dead regions in the cochlea.

OBJECTIVE: "Dead regions" are regions in the cochlea with no functioning inner hair cells (IHCs) and/or neurons. Amplification (using a hearing aid) over a frequency range corresponding to a dead region may not be beneficial and may even impair speech intelligibility. The objective of this article is to illustrate the use of psychophysical tuning curves (PTCs) as a tool for investigating dead regions and to illustrate the variety of audiogram configurations that can be associated with dead regions. We explore the influence of signal level and signal frequency to test the hypothesis that the frequency at the tip of the tuning curve defines the boundary of the dead region. DESIGN: PTCs were measured for five subjects with sensorineural hearing loss who were suspected of having dead regions. One had a relatively "flat" loss, one had a mild mid-frequency loss and three had high-frequency losses, varying in severity from 70 dB to more than 120 dB. For each PTC, the level and frequency of the sinusoidal signal were fixed, and the level of a narrowband noise masker needed just to mask the signal was determined as a function of the masker frequency. When the signal falls in a frequency region that is not "dead," the signal is detected via IHCs with characteristic frequencies (CFs) at or close to the signal frequency. In such a case, the tip of the PTC (the masker frequency at which the masker level is lowest) lies at or close to the signal frequency. When a dead region is present, the signal is detected via IHCs with CFs different from that of the signal frequency. In such a case, the tip of the PTC is shifted away from the signal frequency. RESULTS: PTCs with frequency-shifted tips (indicative of dead regions) were found for all subjects. The frequencies at the tips sometimes decreased slightly with increasing signal level. For the subject with a relatively flat loss, PTCs with tips close to 3000 Hz were obtained for signal frequencies of 400, 1000 and 1500 Hz. A PTC with a tip at 5000 Hz was found for a signal frequency of 6000 Hz. These results suggest that this subject had an "island" of surviving IHCs and neurons with CFs ranging from 3000 to 5000 Hz, with extensive dead regions on either side. For the subject with a mid-frequency loss, the pattern of results suggested a mid-frequency dead region. For the subjects with high-frequency loss, the results suggested the presence of high-frequency dead regions, in one case starting at a frequency where absolute thresholds were only slightly higher than normal. CONCLUSIONS: PTCs can be used to detect and delimit dead regions. Often, the frequency at the tip of the PTC can be used to define approximately one boundary of the dead region. However, the detection of beats can affect the shape of the PTC around the tip when the signal frequency lies just inside the dead region. The level of the signal can also have some effect on the frequency at the tip of the PTC. Very low signal levels can lead to variable results. Dead regions can start at frequencies where absolute thresholds are near normal.

Adult↗
PubMed2001

Influence of rate of change of frequency on the overall pitch of frequency-modulated tones.

The mechanism(s) determining pitch may assign less weight to portions of a sound where the frequency is changing rapidly. The present experiments explored the possible effect of this on the overall pitch of frequency-modulated sounds. Pitch matches were obtained between an adjustable unmodulated sinusoid and a sinusoidal carrier that was frequency modulated using a highly asymmetric function with the form of a repeating U or inverted U shaped function. The amplitude was constant during the 400-ms presentation time of each stimulus, except for 10-ms raised-cosine onset and offset ramps. In experiment 1, the carrier level was 50 dB SPL and the geometric mean of the instantaneous frequency of the modulated carrier, fc, was either 0.5, 1, 2, or 8 kHz. The modulation rate (fm) was 5, 10, or 20 Hz. The overall depth (maximum to minimum) of the FM was 8% of fc. For all carrier frequencies, the matched frequency was shifted away from the mean carrier frequency, downwards for the U shaped function stimuli and upwards for the repeated inverted U shaped function stimuli. The shift was typically slightly greater than 1% of fc, and did not vary markedly with fc. The effect of fm was small, but there was a trend for the shifts to decrease with increasing fm for fc = 0.5 kHz and to increase with increasing fm for fc = 2 kHz. In experiment 2, the carrier level was reduced to 20 dB SL and matches were obtained only for fc = 2 kHz. Shifts in matched frequency of about 1% were still observed, but the trend for the shifts to increase with increasing fm no longer occurred. In experiment 3, matches were obtained for a 4-kHz carrier at 50 dB SPL. Shifts of about 1% again occurred, which did not vary markedly with fm. The shifts in matched frequency observed in all three experiments are not predicted by models based on the amplitude- or intensity-weighted average of instantaneous frequency (EWAIF or IWAIF). The shifts (and the pitch shifts observed earlier for two-tone complexes and for stimuli with simultaneous AM and FM) are consistent with a model based on the assumption that the overall pitch of a frequency-modulated sound is determined from a weighted average of period estimates, with the weight attached to a given estimate being inversely related to the short-term rate of change of period and directly related to a compressive function of the amplitude.

Adolescent↗
PubMed2001

Effects of low-pass filtering on the intelligibility of speech in quiet for people with and without dead regions at high frequencies.

A dead region is a region of the cochlea where there are no functioning inner hair cells (IHCs) and/or neurons; it can be characterized in terms of the characteristic frequencies of the IHCs bordering that region. We examined the effect of high-frequency amplification on speech perception for subjects with high-frequency hearing loss with and without dead regions. The limits of any dead regions were defined by measuring psychophysical tuning curves and were confirmed using the TEN test described in Moore et al. [Br. J. Audiol. 34, 205-224 (2000)]. The speech stimuli were vowel-consonant-vowel (VCV) nonsense syllables, using one of three vowels (/i/, /a/, and /u/) and 21 different consonants. In a baseline condition, subjects were tested using broadband stimuli with a nominal input level of 65 dB SPL. Prior to presentation via Sennheiser HD580 earphones, the stimuli were subjected to the frequency-gain characteristic prescribed by the "Cambridge" formula, which is intended to give speech at 65 dB SPL the same overall loudness as for a normal listener, and to make the average loudness of the speech the same for each critical band over the frequency range important for speech intelligibility (in a listener without a dead region). The stimuli for all other conditions were initially subjected to this same frequency-gain characteristic. Then, the speech was low-pass filtered with various cutoff frequencies. For subjects without dead regions, performance generally improved progressively with increasing cutoff frequency. This indicates that they benefited from high-frequency information. For subjects with dead regions, two patterns of performance were observed. For most subjects, performance improved with increasing cutoff frequency until the cutoff frequency was somewhat above the estimated edge frequency of the dead region, but hardly changed with further increases. For a few subjects, performance initially improved with increasing cutoff frequency and then worsened with further increases, although the worsening was significant only for one subject. The results have important implications for the fitting of hearing aids.

Aged↗
PubMed2001

Temporal modulation transfer functions obtained using sinusoidal carriers with normally hearing and hearing-impaired listeners.

Temporal modulation transfer functions were obtained using sinusoidal carriers for four normally hearing subjects and three subjects with mild to moderate cochlear hearing loss. Carrier frequencies were 1000, 2000 and 5000 Hz, and modulation frequencies ranged from 10 to 640 Hz in one-octave steps. The normally hearing subjects were tested using levels of 30 and 80 dB SPL. For the higher level, modulation detection thresholds varied only slightly with modulation frequency for frequencies up to 80 Hz, but decreased for high modulation frequencies. The decrease can be attributed to the detection of spectral sidebands. For the lower level, thresholds varied little with modulation frequency for all three carrier frequencies. The absence of a decrease in the threshold for large modulation frequencies can be explained by the low sensation level of the spectral sidebands. The hearing-impaired subjects were tested at 80 dB SPL, except for two cases where the absolute threshold at the carrier frequency was greater than 70 dB SPL; in these cases a level of 90 dB was used. The results were consistent with the idea that spectral sidebands were less detectable for the hearing-impaired than for the normally hearing subjects. For the two lower carrier frequencies, there were no large decreases in threshold with increasing modulation frequency, and where decreases did occur, this happened only between 320 and 640 Hz. For the 5000-Hz carrier, thresholds were roughly constant for modulation frequencies from 10 to 80 or 160 Hz, and then increased monotonically, becoming unmeasurable at 640 Hz. The results for this carrier may reflect "pure" effects of temporal resolution, without any influence from the detection of spectral sidebands. The results suggest that temporal resolution for deterministic stimuli is similar for normally hearing and hearing-impaired listeners.

Adult↗
PubMed2001

Melody recognition using three types of dichotic-pitch stimulus.

The recognition of 10 different 16-note melodies, constructed using either dichotic-pitch stimuli or diotic pure-tone stimuli, was measured. The dichotic pitches were created by placing a frequency-dependent transition in the interaural phase of a noise burst. Three different configurations for the transition were used in order to give Huggins pitch, binaural-edge pitch, and binaural-coherence-edge pitch. Forty-nine inexperienced listeners participated. The melodies evoked by the dichotic stimuli were consistently identified well in the first block of trials, indicating that the sensation of dichotic pitch was relatively immediate and did not require prolonged listening experience. There were only small improvements across blocks of trials. The mean scores were 97% (pure tones), 93% (Huggins pitch), 89% (binaural-edge pitch), and 77% (binaural-coherence-edge pitch). All pairwise differences were statistically significant, indicating that Huggins pitch was the most salient of the dichotic pitches and binaural-coherence-edge pitch was weakest. To account for these differences in salience, a simulation of lateral inhibition was applied to the recovered spectrum generated by the modified equalization cancellation model [J. F. Culling, A. Q. Summerfield, and D. H. Marshall, J. Acoust. Soc. Am. 103, 3509-3526 (1998)]. The height of the peak in the resulting "edge-enhanced" recovered spectrum reflected the relative strength of the different dichotic pitches.

Acoustic Stimulation↗
PubMed2001

Induction of morphological deformities in Chironomus tentans exposed to zinc- and lead-spiked sediments.

Laboratory experiments were used to assess morphological responses of Chironomus tentans larvae exposed to three levels of zinc and lead. Chironomus tentans egg masses were placed into triplicate control and metal-spiked aquaria containing the measured concentrations 1,442, 3,383, and 5,562 microg/g Pb dry weight and 1,723, 3,743, and 5,252 microg/g Zn dry weight. Larvae were collected at 10-d intervals after egg masses were placed in aquaria until final emergence. Larvae were screened for mouthpart deformities and metal body burdens. Deformities increased with time of exposure in both Zn and Pb tanks. Deformity rates between the three Zn concentrations differed statistically, with low and medium Zn levels containing the highest overall deformity rates of 12%. Deformity rates for larvae held in the Pb aquaria were found to differ significantly. Larvae in the low-Pb tanks had a deformity rate of 9%. Larvae and water from both the Zn and Pb aquaria had increasing metal concentrations with increasing sediment metal concentration. Results demonstrate that Zn and Pb each induce chironomid mouthpart deformities at various concentrations. However, a clear dose-related response was not demonstrated. Our research provides more support for the potential use of chironomid deformities as a tool for the assessment of heavy metal pollution in aquatic systems.

Animals↗
PubMed2001

Activation of the p53 DNA damage response pathway after inhibition of DNA methyltransferase by 5-aza-2'-deoxycytidine.

Transcriptional silencing of tumor suppressor genes by DNA methylation occurs in cancer cell lines and in human tumors. This has led to the pursuit of DNA methyltransferase inhibition as a drug target. 5-Aza-2'-deoxycytidine [5-aza-CdR (decitabine)], a potent inhibitor of DNA methyltransferase, is a drug currently in clinical trials for the treatment of solid tumors and leukemia. The efficacy of 5-aza-CdR may be related to the induction of methylation-silenced tumor suppressor genes, genomic hypomethylation, and/or enzyme-DNA adduct formation. Here, we test the hypothesis that 5-aza-CdR treatment is perceived as DNA damage, as assessed by the activation of the tumor suppressor p53. We show that 1) colon tumor cell lines expressing wild-type p53 are more sensitive to 5-aza-CdR mediated growth arrest and cytotoxicity; 2) the response to 5-aza-CdR treatment includes the induction and activation of wild-type but not mutant p53 protein; and 3) the induction of the downstream p53 target gene p21 is partially p53-dependent. The induction of p53 protein after 5-aza-CdR treatment did not correlate with an increase in p53 transcripts, indicating that hypomethylation at the p53 promoter does not account for the p53 response. It is relevant that 5-aza-CdR has shown the greatest promise in clinical trials for the treatment of chronic myelogenous leukemia, a malignancy in which functional p53 is often retained. Our data raise the hypothesis that p53 activation may contribute to the clinical efficacy and/or toxicity of 5-aza-CdR.

Antimetabolites, Antineoplastic↗
PubMed2000

The relative role of beats and combination tones in determining the shapes of masking patterns at 2 kHz: I. Normal-hearing listeners.

Masking patterns for a 2-kHz sinusoidal masker at 45, 65 or 85 dB SPL were measured for three normal-hearing subjects, using a 3-AFC method with feedback (condition 1). The patterns showed distinct irregularities, particularly at the highest masker level. In condition 2, a lowpass noise was added to mask combination tones. The noise increased thresholds mainly for the 85 dB masker, for signal frequencies of 2.3-3.0 kHz. In condition 3, a pair of high-frequency tones ('modulation detection interference (MDI) tones') was used to introduce beats at the same rate as produced by the interaction of the masker and signal. Thresholds were higher than for condition 1, particularly for signal frequencies adjacent to the masker frequency. In condition 4, the lowpass noise was presented simultaneously with the MDI tones. Thresholds were well predicted as a combination of the effects of the lowpass noise and the MDI tones. In condition 5, a pair of low-frequency MDI tones was added to the masker. The thresholds had the same overall pattern as in condition 4. We conclude that the shapes of masking patterns measured using a 2-kHz masker are influenced by the detection of beats for masker-signal frequency separations up to at least 300 Hz and by the detection of combination tones for separations between 300 and 1000 Hz.

Acoustic Stimulation↗
PubMed2000

Effects of frequency and level on auditory stream segregation.

This study examined the effect of center frequency and level on the perceptual grouping of rapid tone sequences. The sequence ABA-ABA-...was used, where A and B represent sinusoidal tone bursts (10-ms rise/fall, 80-ms steady state, 20-ms interval between tones) and - represents a silent interval of 120 ms. In experiment 1, tone A was fixed in frequency at 62, 125, 250, 500, 1000, 2000, 4000, 6000, or 8000 Hz. Both tones had a level of approximately 40 dB SL. Tone B started with a frequency well above that of tone A, and its frequency was swept toward that of tone A so that the frequency separation between them decreased in an exponential manner. Subjects were required to indicate when they could no longer hear the tones A and B as two separate streams, but heard only a single stream with a "gallop" rhythm. This changeover point between percepts is called the fission boundary. The separation between tones A and B at the fission boundary was roughly independent of the frequency of tone A when expressed as the difference in number of equivalent rectangular bandwidths (ERBs) between A and B, but varied more with frequency when the difference was expressed in barks or cents. In experiment 2, the center frequency was fixed at 250, 1000, or 4000 Hz, and the level of the A and B tones was 40, 55, 70, or 85 dB SPL. The frequency separation of the A and B tones at the fission boundary tended to increase slightly with increasing level, in a manner consistent with the broadening of the auditory filter with increasing level. The results support the "peripheral channeling" explanation of stream segregation advanced by Hartmann and Johnson [Music Percept. 9, 155-184 (1991)], and indicate that the perception of fusion or fission in alternating-tone sequences depends partly upon the degree of overlap of the excitation patterns evoked by the successive sounds in the cochlea, as assumed in the theory of Beauvois and Meddis [J. Acoust. Soc. Am. 99, 2270-2280 (1996)].

Adult↗