Investigating peripheral sources of speech-in-noise variability in listeners with normal audiograms.

A current initiative in auditory neuroscience research is to better understand why some listeners struggle to perceive speech-in-noise (SIN) despite having normal hearing sensitivity. Various hypotheses regarding the physiologic bases of this disorder have been proposed. Notably, recent work has suggested that the site of lesion underlying SIN deficits in normal hearing listeners may be either in "sub-clinical" outer hair cell damage or synaptopathic degeneration at the inner hair cell-auditory nerve fiber synapse. In this study, we present a retrospective investigation of these peripheral sources and their relationship with SIN performance variability in one of the largest datasets of young normal-hearing listeners presented to date. 194 participants completed detailed case history questionnaires assessing noise exposure, SIN complaints, tinnitus, and hyperacusis. Standard and extended high frequency audiograms, distortion product otoacoustic emissions, click-evoked auditory brainstem responses, and SIN performance measures were also collected. We found that: 1) the prevalence of SIN deficits in normal hearing listeners was 42% when based on subjective report and 8% when based on SIN performance, 2) hearing complaints and hyperacusis were more common in listeners with self-reported noise exposure histories than controls, 3) neither extended high frequency thresholds nor compound action potential amplitudes differed between noise-exposed and control groups, 4) extended high frequency hearing thresholds and compound action potential amplitudes were not predictive of SIN performance. These results suggest an association between noise exposure and hearing complaints in young, normal hearing listeners; however, SIN performance variability is not explained by peripheral auditory function to the extent that these measures capture subtle physiologic differences between participants.

Exploring the relationship between physiological measures of cochlear and brainstem function.

OBJECTIVE: Otoacoustic emissions and the speech-evoked auditory brainstem response are objective indices of peripheral auditory physiology that are used clinically for assessing hearing function. While each measure has been extensively explored, their interdependence and the relationships between them remain relatively unexplored. METHODS: Distortion product otoacoustic emissions (DPOAEs) and speech-evoked auditory brainstem responses (sABRs) were recorded from 28 normal-hearing adults. Through correlational analyses, DPOAE characteristics were compared to measures of sABR timing and frequency encoding. Data were organized into two DPOAE (Strength and Structure) and five brainstem (Onset, Spectrotemporal, Harmonics, Envelope Boundary, and Pitch) composite measures. RESULTS: DPOAE Strength shows significant relationships with sABR Spectrotemporal and Harmonics measures. DPOAE Structure shows significant relationships with sABR Envelope Boundary. Neither DPOAE Strength nor Structure is related to sABR Pitch. CONCLUSIONS: The results of the present study show that certain aspects of the speech-evoked auditory brainstem responses are related to, or covary with, cochlear function as measured by distortion product otoacoustic emissions. SIGNIFICANCE: These results form a foundation for future work in clinical populations. Analyzing cochlear and brainstem function in parallel in different clinical populations will provide a more sensitive clinical battery for identifying the locus of different disorders (e.g., language based learning impairments, hearing impairment).

Deficient brainstem encoding of pitch in children with Autism Spectrum Disorders.

OBJECTIVE: Deficient prosody is a hallmark of the pragmatic (socially contextualized) language impairment in Autism Spectrum Disorders (ASD). Prosody communicates emotion and intention and is conveyed through acoustic cues such as pitch contour. Thus, the objective of this study was to examine the subcortical representations of prosodic speech in children with ASD. METHODS: Using passively evoked brainstem responses to speech syllables with descending and ascending pitch contours, we examined sensory encoding of pitch in children with ASD who had normal intelligence and hearing and were age-matched with typically developing (TD) control children. RESULTS: We found that some children on the autism spectrum show deficient pitch tracking (evidenced by increased Frequency and Slope Errors and reduced phase locking) compared with TD children. CONCLUSIONS: This is the first demonstration of subcortical involvement in prosody encoding deficits in this population of children. SIGNIFICANCE: Our findings may have implications for diagnostic and remediation strategies in a subset of children with ASD and open up an avenue for future investigations.

Interdigitating dendritic cell sarcoma: a rare malignancy responsive to ABVD chemotherapy.

Interdigitating dendritic cell sarcoma (IDCS) is an aggressive neoplasm of which fewer than 25 cases have been reported in the world literature. This malignancy is difficult to diagnose because of its rarity, and because of the subtle histopathologic features that distinguish IDCS from similar tumors arising from reticular cells. To date, there exists no consensus on a standard chemotherapeutic regimen for IDCS. Patients with this malignancy have been treated with chemotherapy regimens used against non-Hodgkin's lymphomas. Responses to these regimens have been variable, but mostly unsuccessful. In this article we describe a case of IDCS occurring in a 44 year old female who presented with abdominal pain and inguinal adenopathy. Staging of the tumor with CT scan, PET scan, and bone marrow biopsy demonstrated inguinal and abdominal lymphadenopathies, a large mass encasing the small bowel, and extensive liver infiltration. Morphologic and cytochemical analysis of biopsies from the abdominal mass and inguinal node were consistent with a diagnosis of IDCS, and immunohistochemical stains of the lymph node were positive for CLA, Kp-1, S-100, while negative for CD1a, CD3, CD20, CKER, and HMB45. Treatment of this patient with ABVD chemotherapy resulted in rapid clinical improvement with a marked decrease in tumor burden after two cycles of ABVD, and a complete response after six cycles of therapy.

Abnormal neural encoding of repeated speech stimuli in noise in children with learning problems.

OBJECTIVES: This study investigated whether neurophysiologic responses to repeated speech stimuli, presented in quiet and noise, differed between normal children (NL) and children with learning problems (LP). METHODS: Subjects were normal-hearing, school-age children. NL subjects scored significantly better than LP subjects on measures of reading, spelling and speech sound discrimination. Stimuli (40 ms /da/) were presented to the right ear at 80 dB SPL. Stimuli were presented in trains of four, separated within trains by 360 ms. The interval between trains was 1060 ms. Stimuli were presented in quiet and in white noise (S/N+15). Cortical responses were recorded from an electrode placed along the midline at Cz. RESULTS: Correlations between the first and 4th responses were lower in noise than in quiet for LP subjects only. Response correlations in quiet were no different between groups. There were no root-mean-square (RMS) amplitude differences between groups. CONCLUSIONS: Response correlation in noise suggested that the LP population consisted of two subgroups, one whose responses appeared relatively normal, and another whose responses were severely degraded by repetition in noise. Response correlations in noise were related to behavioral measures of auditory processing and spelling. These findings suggest that abnormal, asynchronous, auditory cortical encoding may underlie some language-based learning problems.

Gas chromatography/combustion/isotope ratio mass spectrometry to control the misuse of androgens in breeding animals: new derivatisation method applied to testosterone metabolites and precursors in urine samples.

A new derivatisation reaction applied to the analysis of steroids by gas chromatography/combustion/isotope ratio mass spectrometry (GC/C/IRMS) was studied. The trimethylsilylated steroids were characterised by well-resolved chromatographic signals, no peak tailing, reproducible 13C/12C measurements (0.32 per thousand, n = 28), good signal-to-noise ratio and absolute intensity (5 x 10(-9) A, 20 ng), and a slow degradation of copper oxide pellets in the combustion furnace. In addition, two new metabolites and one precursor of testosterone in bovine have been brought into consideration and used for GC/C/IRMS measurements, namely, 3beta-hydroxy-5alpha-androstan-17-one (epiandrosterone), 3beta,17alpha-dihydroxy-5alpha-androstane, and 3beta,17alpha-dihydroxy-5-androstene. The new findings have been applied to an elimination study in bovine of testosterone metabolites after an intramuscular injection of testosterone enanthate. Significant differences (up to 4 per thousand) between testosterone metabolites and precursor were detectable at least three weeks after administration.

Parathyroidectomy promotes wound healing and prolongs survival in patients with calciphylaxis from secondary hyperparathyroidism.

BACKGROUND: Calciphylaxis is a rare but life-threatening condition occasionally affecting patients with secondary hyperparathyroidism. Parathyroidectomy has been advocated as the only potentially curative intervention. METHODS: Between January 1989 and May 2000, 13 patients with pathologic/clinical criteria of calciphylaxis were treated at our institution. Of these 13 patients, 7 were managed with medical therapy alone, and 6 were referred for parathyroidectomy. The medical records were reviewed, and patients/relatives were interviewed. RESULTS: All patients had cutaneous wounds requiring local debridement predominantly located on the lower extremities or abdominal wall. Six patients underwent subtotal (3.5 gland) parathyroidectomy without morbidity. All 6 had significant reductions in parathyroid hormone levels after surgery (mean decrease, 94% +/- 0%), and all reported resolution of pain and healing of cutaneous wounds. Of the remaining 7 patients who had medical management alone, 5 eventually died of complications related to calciphylaxis. In comparing the 2 groups, patients who underwent parathyroidectomy had a significantly longer median survival than those who did not have surgery (36 vs 3 months, P =.021). CONCLUSIONS: Calciphylaxis frequently causes gangrene, sepsis, and eventual death. Parathyroidectomy can be performed with minimal morbidity and is associated with resolution of pain, wound healing, and a significantly longer median survival. Therefore, patients with secondary hyperparathyroidism and signs/symptoms of calciphylaxis should be referred promptly for consideration of parathyroidectomy.

Identification of a mononucleotide repeat as a major target for mitochondrial DNA alterations in human tumors.

Mitochondrial DNA (mtDNA) mutations scattered through coding and noncoding regions have been reported in cancer. The mechanisms that generate such mutations and the importance of mtDNA mutations in tumor development are still not clear. Here we present the identification of a specific and highly polymorphic homopolymeric C stretch (D310), located within the displacement (D) loop, as a mutational hotspot in primary tumors. Twenty-two % of the 247 primary tumors analyzed harbored somatic deletions/insertions at this mononucleotide repeat. Moreover, these alterations were also present in head and neck preneoplastic lesions. We further characterized the D310 variants that appeared in the lung and head and neck tumors. Most of the somatic alterations found in tumors showed deletion/insertions of 1- or 2-bp generating D310 variants identical to constitutive polymorphisms described previously. Sequencing analysis of individual clones from lymphocytes revealed that patients with D310 mutations in the tumors had statistically significant higher levels of D310 heteroplasmy (more than one length variant) in the lymphocyte mtDNA as compared with the patients without D310 mutations in the tumor mtDNA. On the basis of our observations, we propose a model in which D310 alterations are already present in normal cells and achieve homoplasmy in the tumor through a restriction/amplification event attributable to random genetic drift and clonal expansion.

Detection of mitochondrial DNA mutations in primary breast cancer and fine-needle aspirates.

To determine the frequency and distribution of mitochondrial DNA mutations in breast cancer, 18 primary breast tumors were analyzed by direct sequencing. Twelve somatic mutations not present in matched lymphocytes and normal breast tissues were detected in 11 of the tumors screened (61%). Of these mutations, five (42%) were deletions or insertions in a homopolymeric C-stretch between nucleotides 303-315 (D310) within the D-loop. The remaining seven mutations (58%) were single-base substitutions in the coding (ND1, ND4, ND5, and cytochrome b genes) or noncoding regions (D-loop) of the mitochondrial genome. In three cases (25%), the mutations detected in coding regions led to amino acid substitutions in the protein sequence. We then screened an additional 46 primary breast tumors with a rapid PCR-based assay to identify poly-C alterations in D310, and we found seven more cancers with alterations. Using D310 mutations as clonal marker, we detected identical changes in five of five matched fine-needle aspirates and in four of four metastases-positive lymph nodes. The high frequency of D310 alterations in primary breast cancer combined with the high sensitivity of the PCR-based assays provides a new molecular tool for cancer detection.

Molecular detection of cervical intraepithelial neoplasia and cervical carcinoma by microsatellite analysis of Papanicolaou smears.

Carcinoma of the uterine cervix is one of the most common malignancies worldwide, yet it is clearly preventable by population screening. The Papanicolaou (Pap) smear has proved to be the most successful test for the detection of precancerous lesions and is largely responsible for the reduction of cervical cancer mortality and morbidity rates. However, the Pap smear is not perfect; false-negative results of various rates are reported. To improve the diagnostic efficacy of cervical cytology, we performed microsatellite analysis on paired Pap smear samples from cervical lesions. Nine microsatellite markers were chosen from chromosomal regions commonly displaying loss of heterozygostity (LOH) in cervical cancer and those displaying microsatellite instability (MI) in other squamous cell cancer. Microsatellite alterations were detected in 16/21 (76%) Pap smear DNA samples including 11 of 13 (85%) smears from invasive squamous cell carcinomas (SCCs) and 5 of 8 (63%) from squamous intraepithelial lesions (SILs). Microsatellite alterations detected in the Pap smear DNA were identical to those identified in seven paired primary tumors available for analysis. Moreover, this molecular approach detected genetic alterations in two cases apparently negative by cytologic examination. None (0/25) of the control patients displayed microsatellite alterations in paired Pap smears. Microsatellite analysis of cervical cytologic samples may provide a complementary method to analyze suspicious but not diagnostic cytologic samples further.

Long-term habituation of the speech-elicited mismatch negativity.

A significant issue in the use of the mismatch negativity evoked potential (MMN) concerns its low signal-to-noise ratio (SNR). One can improve the noise level by increasing the number of samples included in the averaged response. However, improvement achieved in this way assumes that the signal, the MMN, remains stable for extended test times, an assumption which has not been tested. If the MMN is not stable, or exhibits habituation over the test session, then SNR would be adversely affected. MMN response magnitude was measured in 5-min intervals over the course of a test session in response to various speech syllable contrasts. Significant long-term habituation of MMN was observed for all three subject populations tested: young adults, school-age children, and guinea pigs. The time course of the habituation and the stimulus conditions under which it occurs have important implications for research and clinical applications of the MMN. Recording procedures that minimize habituation effects may be used to advantage to improve the signal-to-noise ratio of the MMN.

Positron emission tomography in the detection and management of sarcomatous transformation in neurofibromatosis.

Benign neurofibromas undergo sarcomatous transformation in approximately 5% of patients with neurofibromatosis type I. The clinical and radiologic diagnosis of sarcomatous change remains difficult. Positron emission tomography with F-18 fluorodeoxyglucose is a method to assess increased glucose metabolism in malignant tissue such as sarcomas. In this case report, positron emission tomography accurately distinguished malignant from benign neurofibromas. The technique may be useful as a noninvasive screening tool for malignant transformation of neurofibromas.

Neurobiologic responses to speech in noise in children with learning problems: deficits and strategies for improvement.

OBJECTIVES: Some children with learning problems (LP) experience speech-sound perception deficits that worsen in background noise. The first goal was to determine whether these impairments are associated with abnormal neurophysiologic representation of speech features in noise reflected at brain-stem and cortical levels. The second goal was to examine the perceptual and neurophysiological benefits provided to an impaired system by acoustic cue enhancements. METHODS: Behavioral speech perception measures (just noticeable difference scores), auditory brain-stem responses, frequency-following responses and cortical-evoked potentials (P1, N1, P1', N1') were studied in a group of LP children and compared to responses in normal children. RESULTS: We report abnormalities in the fundamental sensory representation of sound at brain-stem and cortical levels in the LP children when speech sounds were presented in noise, but not in quiet. Specifically, the neurophysiologic responses from these LP children displayed a different spectral pattern and lacked precision in the neural representation of key stimulus features. Cue enhancement benefited both behavioral and neurophysiological responses. CONCLUSIONS: Overall, these findings contribute to our understanding of the preconscious biological processes underlying perception deficits and may assist in the design of effective intervention strategies.

Comparison of TriPath thin-layer technology with conventional methods on nongynecologic specimens.

OBJECTIVE: To evaluate the use of the TriPath PREP (previously called AutoCyte) TriPath Inc., Burlington, North Carolina, U.S.A.) in nongynecologic cytologic material by performing side-by-side comparison of conventional preparations with TriPath-prepared slides. STUDY DESIGN: An initial study of 613 cases (set A) was conducted to compare the TriPath PREP system with conventional methods for the evaluation of nongynecologic specimens, including urine, body cavity effusions, cerebrospinal fluid, pulmonary and gastrointestinal specimens. Paired cases were evaluated for cellularity, staining quality, preservation and representation of diagnostic material. Subsequent changes in the automated technique warranted reevaluation of the TriPath method. The follow-up study of 259 cases (set B) was conducted with the same design as set A. Results of evaluated parameters were analyzed using the chi 2 test. RESULTS: Results of the two sets were strikingly different. Prior to technical changes made by the laboratory, the TriPath method was significantly inferior. In the second set, the preferred material was most commonly the TriPath-prepared material. In particular, the majority of urine samples were prepared better by the automated, thin-layer system. CONCLUSION: The TriPath PREP system offers a reliable preparation of urine and has potential for other nongynecologic specimens, provided that careful attention is paid to technical details and some adjustments are made to account for specimen variability.

The accuracy of combined cytopathologic and flow cytometric analysis of fine-needle aspirates of lymph nodes.

We studied flow cytometry in 156 fine-needle aspirations (FNAs) of lymph nodes performed between June 1993 and September 1998. Information from flow cytometry was combined with cytomorphologic evaluation, and the diagnosis determined by using combined modalities was compared with tissue biopsy results or clinical follow-up. In 74 cases, a combined cytopathologic-flow cytometric diagnosis of lymphoma was made; histologic material was available for 52 patients; in no case was a benign process found. The lymphoma grade assigned agreed with histopathologic findings in 45 of 48 cases with a specific cytologic diagnosis. Treatment was initiated on the basis of the FNA alone for 17 of 52 patients with a history of lymphoma and in 22 additional patients with no follow-up biopsy. Among 71 cases in which the diagnosis using both modalities was benign, the only false-negative was 1 case of Hodgkin disease. Of the 156 cases, 11 were considered atypical or suggestive of lymphoma; biopsies from 8 of 10 patients revealed lymphoma. A combination of flow cytometry and cytomorphology of cells obtained by FNA of lymph nodes can distinguish between benign and malignant lymphoid infiltrates and support a diagnosis of lymphoma that permits definitive therapy in most cases.

Aging affects hemispheric asymmetry in the neural representation of speech sounds.

Hemispheric asymmetries in the processing of elemental speech sounds appear to be critical for normal speech perception. This study investigated the effects of age on hemispheric asymmetry observed in the neurophysiological responses to speech stimuli in three groups of normal hearing, right-handed subjects: children (ages, 8-11 years), young adults (ages, 20-25 years), and older adults (ages > 55 years). Peak-to-peak response amplitudes of the auditory cortical P1-N1 complex obtained over right and left temporal lobes were examined to determine the degree of left/right asymmetry in the neurophysiological responses elicited by synthetic speech syllables in each of the three subject groups. In addition, mismatch negativity (MMN) responses, which are elicited by acoustic change, were obtained. Whereas children and young adults demonstrated larger P1-N1-evoked response amplitudes over the left temporal lobe than over the right, responses from elderly subjects were symmetrical. In contrast, MMN responses, which reflect an echoic memory process, were symmetrical in all subject groups. The differences observed in the neurophysiological responses were accompanied by a finding of significantly poorer ability to discriminate speech syllables involving rapid spectrotemporal changes in the older adult group. This study demonstrates a biological, age-related change in the neural representation of basic speech sounds and suggests one possible underlying mechanism for the speech perception difficulties exhibited by aging adults. Furthermore, results of this study support previous findings suggesting a dissociation between neural mechanisms underlying those processes that reflect the basic representation of sound structure and those that represent auditory echoic memory and stimulus change.

Case report. Diagnosis of disseminated Mycobacterium avium complex infection by liver biopsy.

Mycobacterium avium complex (MAC) infection is a common complication of HIV/AIDS. Signs and symptoms of this infection are nonspecific and include fever, weight loss, diarrhea, and abnormal levels of liver enzymes, especially elevated alkaline phosphatase levels. Diagnosis can be achieved through several methods, but liver biopsy may be the most rapid and efficient. We present a case that illustrates the potential value of liver biopsy in diagnosing disseminated MAC infection.

Speech-evoked neurophysiologic responses in children with learning problems: development and behavioral correlates of perception.

OBJECTIVES: To evaluate the maturational progression of speech-evoked P1/N1/N2 cortical responses over the life span, determine whether responses are distinctive in clinical populations experiencing learning problems and elucidate the functional significance of these responses. DESIGN: The P1/N1/N2 complex was measured in 150 normal subjects (5 to 78 yr) and 86 subjects with learning problems (LP) (8 to 15 yr) to a synthetic CV syllable. Analyses included description and comparison of the developmental time course in both groups and evaluation of the relationship between P1/N1/N2 and children's performance on speech discrimination tasks and standardized learning measures. RESULTS: Findings revealed significant changes in waveform morphology, latency and amplitude as a function of age. Maturational patterns in the group of children with learning problems did not differ from the normal group. P1/N1/N2 parameters were significantly correlated with standardized tests of Spelling, Auditory Processing and Listening Comprehension in the LP group. Moreover, there was a predictive relationship between Auditory Processing and N2 latency. CONCLUSIONS: The P1/N1/N2 complex changes throughout life from school-age to old age. The developmental sequence throughout the school-age years is similar in normal and LP children. Thus, differences in the rate of P1/Nl/N2 latency and amplitude development do not appear to be distinctive in these two populations. The relationship between P1/N1/N2 parameters and standardized measures of learning (particularly between Auditory Processing and N2 latency) provides new information about the role of these responses in hearing and highlights the potential value in characterizing auditory processing deficits.

Consequences of neural asynchrony: a case of auditory neuropathy.

The neural representation of sensory events depends upon neural synchrony. Auditory neuropathy, a disorder of stimulus-timing-related neural synchrony, provides a model for studying the role of synchrony in auditory perception. This article presents electrophysiological and behavioral data from a rare case of auditory neuropathy in a woman with normal hearing thresholds, making it possible to separate audibility from neuropathy. The experimental results, which encompass a wide range of auditory perceptual abilities and neurophysiologic responses to sound, provide new information linking neural synchrony with auditory perception. Findings illustrate that optimal eighth nerve and auditory brainstem synchrony do not appear to be essential for understanding speech in quiet listening situations. However, synchrony is critical for understanding speech in the presence of noise.

Reconstruction of complex cranial wounds with demineralized bone matrix and bilayer artificial skin.

Complex wounds involving loss of both cranium and scalp are difficult to reconstruct. Current solutions include both autogenous and alloplastic materials. Tissue engineering provides interesting alternatives for reconstruction of missing bone and soft tissue. Demineralized bone matrix and Integra, artificial bilayer skin substitute, have been used successfully to reconstruct bone and skin as isolated defects, but never in combination. This study investigates the possibility of using demineralized bone matrix in a gel carrier and Integra for combined cranial and scalp defects. The study was divided into two parts. In the first, demineralized bone matrix in the forms of Grafton Flex (n = 12) and Grafton putty (n = 12) was used to reconstruct 15-mm critical size cranial defects in female adult New Zealand White rabbits. In the control group (n = 6), the defect was left empty. The second part of the study investigated the use of Integra and Grafton Flex to reconstruct a 15-mm cranial defect with an overlying full-thickness scalp defect (n = 6). The first study revealed bony healing of the critical-size cranial defect with demineralized bone matrix. The second study demonstrated successful reconstitution of scalp and cranium with both demineralized bone matrix and Integra. We conclude that complex cranial defects involving bone and soft tissue may be successfully reconstructed with their tissue-engineered substrates, demineralized bone matrix (Grafton) and Integra artificial skin.