Biomedical subjects

J W Hall

Publications and source records attributed to J W Hall.

At least 19 recordsLinked to original sources

PubMed2001

Structural and functional characterization of human CXCR4 as a chemokine receptor and HIV-1 co-receptor by mutagenesis and molecular modeling studies.

The human CXC chemokine receptor 4 (CXCR4) is a receptor for the chemokine stromal cell-derived factor (SDF-1alpha) and a co-receptor for the entry of specific strains of human immunodeficiency virus type I (HIV-1). CXCR4 is also recognized by an antagonistic chemokine, the viral macrophage inflammatory protein II (vMIP-II) encoded by human herpesvirus type VIII. SDF-1alpha or vMIP-II binding to CXCR4 can inhibit HIV-1 entry via this co-receptor. An approach combining protein structural modeling and site-directed mutagenesis was used to probe the structure-function relationship of CXCR4, and interactions with its ligands SDF-1alpha and vMIP-II and HIV-1 envelope protein gp120. Hypothetical three-dimensional structures were proposed by molecular modeling studies of the CXCR4.SDF-1alpha complex, which rationalize extensive biological information on the role of CXCR4 in its interactions with HIV-1 envelope protein gp120. With site-directed mutagenesis, we have identified that the amino acid residues Asp (D20A) and Tyr (Y21A) in the N-terminal domain and the residue Glu (E268A) in extracellular loop 3 (ECL3) are involved in ligand binding, whereas the mutation Y190A in extracellular loop 2 (ECL2) impairs the signaling mediated by SDF-1alpha. As an HIV-1 co-receptor, we found that the N-terminal domain, ECL2, and ECL3 of CXCR4 are involved in HIV-1 entry. These structural and mutational studies provide valuable information regarding the structural basis for CXCR4 activity in chemokine binding and HIV-1 viral entry, and could guide the design of novel targeted inhibitors.

Aspartic Acid↗

PubMed2001

Gap duration discrimination in listeners with cochlear hearing loss: effects of gap and marker duration, frequency separation, and mode of presentation.

This study examined the effects of cochlear hearing loss on gap duration discrimination (GDD), with particular interest in whether cochlear hearing loss results in increased difficulty for across-channel temporal judgments. The hypothesis being tested was that listeners with cochlear loss would perform as well as normal-hearing listeners for all within-channel conditions but would exhibit relatively greater performance deficits in the across-channel conditions. A subsidiary aim was to determine whether, in normal-hearing listeners, the across-channel effects previously observed for minimal-duration standard gaps also existed for relatively long standard gaps. Two experiments were undertaken, one dealing with monaural conditions and one dealing with dichotic conditions. The monaural results indicated that across-frequency GDD was poorer than isofrequency GDD, even for the longer gap durations of 35 and 250 ms examined here. However, the results showed no effect of hearing loss on GDD. Rather, GDD appeared to be sensitive to listener age, with younger listeners showing better performance in both within-channel and across-channel conditions. In addition, both within-channel and across-channel performance was sensitive to the duration of the leading gap marker. Finally, the pattern of dichotic "across-ear" performance was similar, but not equivalent, to that of monaural across-frequency performance.

Adult↗

PubMed2001

A comparison of threshold estimation methods in children 6-11 years of age.

Estimating detection threshold for auditory stimuli in children can be problematic because of lapses in attention and the time limits usually imposed by scheduling restrictions or fatigue. Data reported here were collected to compare the stability of threshold estimation procedures in testing children ages 6 to 11 in a three-alternative, forced-choice paradigm. Stimuli consisted of a 1-kHz tonal signal and a Gaussian noise masker, bandpass filtered between 500-2,000 Hz and presented at 25-dB spectrum level. The signal was either presented for 400 ms in the presence of a continuous masker (simultaneous masking) or for 10 ms just prior to a 400-ms masker (backward masking). For each masking paradigm the 79% correct threshold was assessed via each of three procedures: 3-down, 1-up adaptive staircase (Levitt), maximum likelihood estimation (MLE), and method of constant stimuli. Percent correct was measured at the end of the study for a signal 10 dB above the previously determined threshold in order to estimate the most appropriate psychometric function asymptote for fitting data collected via the method of constant stimuli. Both the MLE and Levitt procedures produced equally stable threshold estimates for both conditions and age groups. This was the case despite considerable variability in backward-masking thresholds.

Adult↗

PubMed2001

Gap detection for similar and dissimilar gap markers.

Detection thresholds for temporal gaps between markers of dissimilar frequency are usually elevated with respect to thresholds for gaps between markers of similar frequency. Because gaps between markers of dissimilar frequency represent both a spectrally based perceptual discontinuity as well as a temporal discontinuity, it is not clear what factors underlie the threshold elevation. This study sought to examine the effects of perceptual dissimilarities on gap detection. The first experiment measured gap detection for configurations of narrow-band gap markers comprised of pure tones, frequency-modulated tones, and amplitude-modulated tones. The results showed that gap thresholds for frequency-disparate pure-tone markers were elevated with respect to isofrequency tonal markers, but that perceptual discontinuities between markers restricted to the same frequency region did not uniformly elevate threshold. The second experiment measured gap detection for configurations of markers where the leading and trailing markers could differ along the dimensions of bandwidth, duration, and pitch. The results showed that, in most cases, gap detection deteriorated when the bandwidth of the two markers differed, even when the spectral content of the narrower-band marker was completely subsumed by the spectral content of the wider-band marker. This finding suggests that gap detection is sensitive to spectral dissimilarity between markers in addition to spectral discontinuity. The effects of marker duration depended on the marker bandwidth. Pitch differences across spectrally similar markers had no effect.

Adult↗

PubMed2000

A novel peptide antagonist of CXCR4 derived from the N-terminus of viral chemokine vMIP-II.

The viral macrophage inflammatory protein-II (vMIP-II) encoded by Kaposi's sarcoma-associated herpesvirus is unique among all known chemokines in that vMIP-II shows a broad-spectrum interaction with both CC and CXC chemokine receptors including CCR5 and CXCR4, two principal coreceptors for the cell entry of human immunodeficiency virus type 1 (HIV-1). To elucidate the mechanism of the promiscuous receptor interaction of vMIP-II, synthetic peptides derived from the N-terminus of vMIP-II were studied. In contrast to the full-length protein that recognizes both CXCR4 and CCR5, a peptide corresponding to residues 1-21 of vMIP-II (LGASWHRPDKCCLGYQKRPLP) was shown to strongly bind CXCR4, but not CCR5. The IC(50) of this peptide in competing with CXCR4 binding of (125)I-SDF-1alpha is 190 nM as compared to the IC(50) of 14.8 nM of native vMIP-II in the same assay. The peptide selectively prevented CXCR4 signal transduction and coreceptor function in mediating the entry of T- and dual-tropic HIV-1 isolates, but not those of CCR5. Further analysis of truncated peptide analogues revealed the importance of the first five residues for the activity with CXCR4. These results suggest that the N-terminus of vMIP-II is essential for its function via CXCR4. In addition, they reveal a possible mechanism for the distinctive interactions of vMIP-II with different chemokine receptors, a notion that may be further exploited to dissect the structural basis of its promiscuous biological function. Finally, the potent CXCR4 peptide antagonist shown here could serve as a lead for the development of new therapeutic agents for HIV infection and other immune system diseases.

Amino Acid Sequence↗

PubMed2000

Molecular modeling and site-directed mutagenesis of CCR5 reveal residues critical for chemokine binding and signal transduction.

The CC chemokine receptor CCR5 is the receptor for several chemokines and coreceptor for the entry of HIV-1. Whereas many studies focus on CCR5 interaction with HIV-1, residues in CCR5 important for chemokine binding and subsequent signal transduction remain poorly understood. Here we use an approach combining protein structure modeling and site-directed mutagenesis to probe the structure of CCR5 and its interactions with chemokine ligands and HIV-1. Structural models of CCR5 rationalize extensive biological data about the role of CCR5 in HIV-1 envelope glycoprotein gp120 binding and HIV-1 entry. Furthermore, we carry out site-directed mutagenesis guided by structural analysis of the complex of CCR5 and a chemokine. This leads to the novel observation that certain residues, such as Tyr10 and Lys26, in the N terminus of CCR5 play a critical structural role for ligand binding and signaling. Single glycine substitution of these residues significantly decreases chemokine binding and signal transduction. These results provide new insight into the structural basis for CCR5 receptor-ligand interaction and may guide the design of novel inhibitors.

Chemokines↗

PubMed2000

Screening for and assessment of infant hearing impairment.

With the identification of hearing loss at birth and appropriate intervention within 6 months after birth, language can develop normally, even in children with severe hearing impairment. Universal newborn hearing screening (UNHS) is now endorsed by numerous national groups, including the American Academy of Pediatrics. Two electrophysiologic techniques--automated auditory brainstem response (ABR) and otoacoustic emissions (OAEs)--are used for the identification of communicatively significant hearing loss in newborn infants. UNHS is legislatively supported by more than one half of the United States, including the most populous. Successful hearing screening and intervention programs require the support and expertise of pediatricians, including perinatologists.

Child, Preschool↗

PubMed2000

Development of the ear and hearing.

Knowledge of the development of the peripheral auditory system, especially the middle ear and inner ear (cochlea), contributes to meaningful interpretation of audiologic measures infants, including newborn screening outcome. An understanding of the effects of noise on neonatal auditory system and hearing function is also dependent on maturational factors. This paper is a brief overview of principles and trends in the development of the middle and inner ear. The emphasis is on maturation of human peripheral auditory system structure and function, although reference is also made to animal research.

Aging↗

PubMed2000

Universal newborn hearing screening with automated auditory brainstem response: a multisite investigation.

OBJECTIVE: The purpose of the study was to assess the feasibility of performing universal newborn hearing screening in different clinical settings and tracking the infants who did not pass initial screening through their confirmatory testing. STUDY DESIGN: Between December 1996 and December 1997, a total of 11,711 infants were enrolled from five clinically different study sites. Universal newborn hearing screening was performed using automated auditory brainstem response (AABR) testing. Infants who did not pass the initial screening were tested again prior to discharge. Data regarding the rate of referral for follow-up testing, age of infant at screening, the duration of time required for screening, and type of personnel performing the test were collected. Formal audiology appointments were made prior to discharge for infants who required follow-up testing, and letters were sent with phone calls made to those who failed to keep their appointments for repeat testing. Outpatient testing consisted of a repeat AABR and, if necessary, a diagnostic auditory brainstem-evoked response, otoacoustic emission testing, and tympanometry. RESULTS: At the time of hospital discharge, the refer rate was < 2% (215 of 11,711 newborns) using AABR screening. Sensorineural hearing loss (SNHL) was confirmed in 32 of these infants, resulting in an overall incidence of confirmed SNHL of 2.7 per thousand newborns. The false-positive rate ranged from 0.3% to 2.5%, with a cumulative false-positive rate of 0.9% (1.5% if all infants lost to follow-up are included as false-positives). No false-negatives were identified. The average time of testing was 7.1 minutes independent of the personnel performing the testing and the age of testing was < 24 hours in 70% of the infants tested. The total number of infants lost to follow-up was 61 (29% of patients referred or 0.5% of the study population). CONCLUSION: This study demonstrated that the refer rate for universal hearing screening with the AABR was acceptably low when performed by a variety of personnel in typical nursery settings within the first 24 hours after birth. A low rate of screening failures with the AABR minimizes costs associated with subsequent follow-up assessments and lessens any potential impact of false-positive screening on the parent-newborn relationship.

Audiology↗

PubMed1999

Attachment of C-terminus of SDF-1 enhances the biological activity of its N-terminal peptide.

The N-terminus of stromal cell-derived factor 1 (SDF-1) is known to be a critical site for CXCR4 receptor binding and signaling. However, the functional role of other regions, in particular the C-terminal helix of SDF-1, has yet to be defined. In this study, we designed and synthesized a peptide model of SDF-1 containing its N- and C-terminal regions. The attachment of the C-terminus of SDF-1, which by itself had no activity in receptor binding and signaling, dramatically increased the effect of the N-terminal fragment in inducing chemotaxis and intracellular Ca(2+) influx in sup T1 cells compared with the peptide containing only the N-terminal sequence. The enhancement in activity was not due to the increase in receptor affinity as the N,C-terminal peptide did not show higher CXCR4 binding than the N-terminal peptide. On the other hand, the intracellular Ca(2+) influx activated by the N,C-terminal peptide, but not the N-terminal peptide, was completely abolished by the addition of heparin, suggesting that the C-terminal fragment of the peptide binds glycosaminoglycans (GAGs) and exerts an effect to modulate biological activity. These data raise the possibility that the C-terminus in native SDF-1 is one of interaction sites with GAGs and may be associated with biological function of SDF-1. Furthermore, this study demonstrates an approach for the design of novel agonists or antagonists of other chemokine receptors that possess enhanced biological activity.

Binding Sites↗

PubMed1999

The role of positively charged residues in CXCR4 recognition probed with synthetic peptides.

A high positive charge is the common characteristic shared by the beta-sheet region of stromal cell-derived factor-1 (SDF-1) and CXCR4 antagonists such as ALX40-4C consisting of nine D-arginines. This raises the question that the positively charged residues may play a role in recognition of CXCR4. To test this hypothesis, two studies were carried out using synthetic peptides. In the first study, peptide analogs possessing amino acid sequences from both the N-terminus and the beta-sheet region of SDF-1 were used as models to study the functional role of the beta-sheet region of SDF-1. The attachment of positively charged residues to the N-terminal peptide sequence of SDF-1 was found to enhance the ability of the peptides in CXCR4 binding and inhibiting CXCR4-mediated T-tropic HIV-1 entry. In the second study, two peptides containing nine arginines and the N-terminal signal sequence of SDF-1 were used as models to study the receptor binding mechanism of CXCR4 antagonists of high positive charges such as ALX40-4C. One peptide did not show signaling activity as indicated by the lack of calcium influx while another peptide induced unusual calcium influx distinct from that induced by the SDF-1 N-terminal peptide. In addition, the signal induced by the SDF-1 N-terminal peptide was inhibited by ALX40-4C. Therefore, the first study provides experimental support for the role of the highly positive beta-sheet region of SDF-1 in CXCR4 binding. The second study suggests that the binding site of ALX40-4C in CXCR4 may partially overlap with that of the SDF-1 N-terminal peptide. Both findings should be valuable for the design of SDF-1 agonists and antagonists.

Amino Acid Sequence↗

PubMed1999

Tinnitus. Current evaluation and management.

Evaluation and management of tinnitus presents a significant challenge to the internist and the otolaryngologist. Tinnitus may be divided into two basic categories: subjective and objective. The importance of a thorough history and physical examination is emphasized in this article. The steps in a complete evaluation and the rationale for referral to an otolaryngologist are outlined. Multidisciplinary care of the tinnitus patient is best coordinated by the otolaryngologist.

Audiometry↗

PubMed1999

Recommended permissible noise criteria for occupied, newly constructed or renovated hospital nurseries. The Sound Study Group of the National Resource Center.

OBJECTIVE: To base permissible noise criteria for occupied, new nurseries on research findings. STUDY DESIGN: An interdisciplinary group of clinicians reviewed the literature regarding the effect of sound on the fetus, newborn, and preterm infant and based recommended criteria on the best evidence. An external panel subsequently reviewed the criteria. RESULTS: The recommended criteria: Patient bed areas and the spaces opening onto them shall be designed to produce minimal ambient noise and to contain and absorb much of the transient noise that arises within the nursery. The overall, continuous sound in any bed space or patient care area shall not exceed: (1) an hourly Leq of 50 dB and (2) an hourly L10 of 55 dB, both A-weighted, slow response. The 1-second duration Lmax shall not exceed 70 dB, A-weighted, slow response. CONCLUSION: The permissible noise criteria will protect sleep, support stable vital signs, and improve speech intelligibility for many infants most of the time.

Female↗

PubMed1999

Development of adult-like performance in backward, simultaneous, and forward masking.

Some researchers have argued that specific language impairment (SLI) is associated with deficits in processing certain temporal aspects of auditory stimuli. One recent study (Wright et al., 1997) suggests that backward masking in particular poses a problem for children with SLI, as compared to simultaneous or forward masking. Interpretation of this finding is complicated by the fact that very little is known about the development of normal, adult-like performance in these masking paradigms. The study reported here examined performance for children 5-11 years old on forward, simultaneous, and backward masking and compared their performance to that of adults. The data show a trend for improvement in performance with age in all three masking paradigms. There was no evidence for later or more gradual improvement in performance on the backward-masking paradigm. However, backward-masking thresholds were more variable than those in the other conditions and were subject to greater individual differences, even in the adult data set. Manipulation of masker bandwidth yielded no evidence for more adult-like performance in the child data with the wider bandwidth masker. Additional data collected on two naive adult observers show a marked improvement in backward-masking performance over time, suggesting that detection with these stimuli might be particularly subject to practice effects.

Adult↗

PubMed1999

Modulation gap detection: effects of modulation rate, carrier separation, and mode of presentation.

Modulation gap detection (MGD) is a procedure that measures the sensitivity to an interruption in the modulation pattern imposed upon one or more carrier frequencies. The MGD task was developed to test conditions where a temporal event traverses frequency, but without a concomitant interruption in the spectral continuity of the stimulus. This contrasts with across-frequency gap detection where there is an inherent spectral discontinuity associated with the temporal gap, and where there is a marked decline in performance when the markers of the temporal gap are widely separated in frequency. The purpose of this study was to test the hypothesis that a wideband temporal analysis will be facilitated if there exists a spectral continuity throughout the temporal event. Experiment 1 established the procedure of MGD and indicated that a modulation rate of 8 Hz was optimal for the task. Experiment 2 showed that performance declined markedly when the carrier frequencies of the modulation markers were widely separated in frequency. This finding indicates that spectral continuity across the temporal event is not a sufficient prerequisite for the auditory system to undertake a wideband temporal analysis. Experiment 3 revealed that dichotic MGD also results in poor performance, similar to that seen for widely separated carrier frequencies in the monaural case. This supports the hypothesis that the "channels" across which temporal events are poorly processed do not necessarily correspond to peripheral frequency channels.

Audiometry, Pure-Tone↗

PubMed1999

Differential diagnosis and management of central auditory processing disorder and attention deficit hyperactivity disorder.

Children diagnosed with attention deficit hyperactivity disorder (ADHD) frequently present difficulties performing tasks that challenge the central auditory nervous system. The relationship between ADHD and central auditory processing disorder (CAPD) is examined from the perspectives of cognitive neuroscience, audiology, and neuropsychology. The accumulating evidence provides a basis for the overlapping clinical profiles yet differentiates CAPD and ADHD as clinically distinct entities. Common and distinctive management strategies are outlined.

Attention Deficit Disorder with Hyperactivity↗

PubMed1998

Chronic conductive hearing loss in adults: effects on the auditory brainstem response and masking-level difference.

OBJECTIVE: To determine whether chronic conductive hearing loss in adults results in changes in the auditory brainstem response (ABR) similar to those observed in children with histories of otitis media with effusion. DESIGN: Test of effect of unilateral conductive hearing loss on adult ABR using age-matched control group and subjects as their own controls. SUBJECTS: Twelve adults with a history of unilateral conductive ear disease. An age-matched control group of 21 adults was also tested. METHODS: The ABR, an electrophysiologic test of auditory brainstem functioning, was used to evaluate possible brainstem abnormalities in the impaired listeners. In addition, the masking-level difference, a behavioral test of binaural auditory processing in the brainstem, was used. RESULTS: When comparing the patients' diseased ears with their healthy ears, significant delays were seen for wave V as well as for the I-V and III-V interwave intervals. For comparison with the control population, significant prolongations were again seen for wave V and for the III-V interwave intervals. In addition, reduced masking-level differences and significant correlations between the masking-level differences and the ABRs, independent of hearing threshold, were noted. CONCLUSIONS: The results suggest that chronic conductive impairment in adults leads to changes in the ABR similar to those observed in children with histories of otitis media with effusion. As such, these changes do not appear to be related to a critical period of development.

Adult↗

PubMed1998

The effect of otitis media with effusion on complex masking tasks in children.

OBJECTIVE: To determine whether there is a relationship between the presumed complexity of auditory processing and the time course of recovery of auditory function in children with a history of otitis media with effusion (OME). DESIGN: Longitudinal testing over a 1-year period following insertion of tympanostomy tubes in clinical and control groups. SUBJECTS: A total of 34 children with a history of OME were tested. Twenty-five were tested both just before the placement of tympanostomy tubes and on up to 3 separate occasions (1 month, 6 months, and 1 year) after the placement of the tubes. With subject attrition, there were 27, 16, and 10 listeners at the 1-month, 6-month, and 1-year tests, respectively. An age-matched control group of 29 children was tested. METHODS: The comodulation masking release (CMR) paradigm was used to measure the ability of the listener to detect a signal in a noise background composed of a simple (1 amplitude modulation pattern) or more complex (2 amplitude modulation patterns) masking background. RESULTS: Children with a history of OME had reduced masking release before and 1 month after insertion of tympanostomy tubes for both the simple and complex CMR tasks. After surgery, the CMR results for simple task was not significantly different from that in controls by 6 months, but CMR for the complex task remained significantly reduced even 1 year after surgery. CONCLUSION: Our results suggest a slower recovery of auditory function for more complex auditory tasks in children with a history of OME.

Auditory Perception↗