Atomic force microscopy for quantitative understanding of peptide-induced lipid bilayer remodeling.

A number of peptides are known to bind lipid bilayer membranes and cause these natural barriers to leak in an uncontrolled manner. Though membrane permeabilizing peptides play critical roles in cellular activity and may have promising future applications in the therapeutic arena, significant questions remain about their mechanisms of action. The atomic force microscope (AFM) is a single molecule imaging tool capable of addressing lipid bilayers in near-native fluid conditions. The apparatus complements traditional assays by providing local topographic maps of bilayer remodeling induced by membrane permeabilizing peptides. The information garnered from the AFM includes direct visualization and statistical analyses of distinct bilayer remodeling modes such as highly localized pore-like voids in the bilayer and dispersed thinned membrane regions. Colocalization of distinct remodeling modes can be studied. Here we examine recent work in the field and outline methods used to achieve precise AFM image data. Experimental challenges and common pitfalls are discussed as well as techniques for unbiased analysis including the Hessian blob detection algorithm, bootstrapping, and the Bayesian information criterion. When coupled with robust statistical analyses, high precision AFM data is poised to advance understanding of an important family of peptides that cause poration of membrane bilayers.

A walk in the PARC: developing and implementing 21st century chemical risk assessment in Europe.

Current approaches for the assessment of environmental and human health risks due to exposure to chemical substances have served their purpose reasonably well. Nevertheless, the systems in place for different uses of chemicals are faced with various challenges, ranging from a growing number of chemicals to changes in the types of chemicals and materials produced. This has triggered global awareness of the need for a paradigm shift, which in turn has led to the publication of new concepts for chemical risk assessment and explorations of how to translate these concepts into pragmatic approaches. As a result, next-generation risk assessment (NGRA) is generally seen as the way forward. However, incorporating new scientific insights and innovative approaches into hazard and exposure assessments in such a way that regulatory needs are adequately met has appeared to be challenging. The European Partnership for the Assessment of Risks from Chemicals (PARC) has been designed to address various challenges associated with innovating chemical risk assessment. Its overall goal is to consolidate and strengthen the European research and innovation capacity for chemical risk assessment to protect human health and the environment. With around 200 participating organisations from all over Europe, including three European agencies, and a total budget of over 400 million euro, PARC is one of the largest projects of its kind. It has a duration of seven years and is coordinated by ANSES, the French Agency for Food, Environmental and Occupational Health & Safety.

DNAscan: personal computer compatible NGS analysis, annotation and visualisation.

BACKGROUND: Next Generation Sequencing (NGS) is a commonly used technology for studying the genetic basis of biological processes and it underpins the aspirations of precision medicine. However, there are significant challenges when dealing with NGS data. Firstly, a huge number of bioinformatics tools for a wide range of uses exist, therefore it is challenging to design an analysis pipeline. Secondly, NGS analysis is computationally intensive, requiring expensive infrastructure, and many medical and research centres do not have adequate high performance computing facilities and cloud computing is not always an option due to privacy and ownership issues. Finally, the interpretation of the results is not trivial and most available pipelines lack the utilities to favour this crucial step. RESULTS: We have therefore developed a fast and efficient bioinformatics pipeline that allows for the analysis of DNA sequencing data, while requiring little computational effort and memory usage. DNAscan can analyse a whole exome sequencing sample in 1 h and a 40x whole genome sequencing sample in 13 h, on a midrange computer. The pipeline can look for single nucleotide variants, small indels, structural variants, repeat expansions and viral genetic material (or any other organism). Its results are annotated using a customisable variety of databases and are available for an on-the-fly visualisation with a local deployment of the gene.iobio platform. DNAscan is implemented in Python. Its code and documentation are available on GitHub: https://github.com/KHP-Informatics/DNAscan . Instructions for an easy and fast deployment with Docker and Singularity are also provided on GitHub. CONCLUSIONS: DNAscan is an extremely fast and computationally efficient pipeline for analysis, visualization and interpretation of NGS data. It is designed to provide a powerful and easy-to-use tool for applications in biomedical research and diagnostic medicine, at minimal computational cost. Its comprehensive approach will maximise the potential audience of users, bringing such analyses within the reach of non-specialist laboratories, and those from centres with limited funding available.

Body site matters: an evaluation and application of a novel histological methodology on the quantification of mucous cells in the skin of Atlantic salmon, Salmo salar L.

Mucous cell size and distribution were investigated in the skin of five salmon using a novel stereology-based methodology: one (48 cm) fish to test 15 tissue treatment combinations on measures of cell area and density on the dorsolateral region and, using the most suitable treatment, we mapped mucous cell differences between body regions on four (52 cm) salmon, comprising a male and a female on each of two diets. The section site, decalcification, embedding medium and plane of sectioning all impacted significantly on mucous cell size, whereas mucous cell density is more robust. There were highly significant differences in both mucosal density and mean mucous cell size depending on body site: the dorsolateral skin of the four salmon had significantly denser (about 8% of skin area) and larger (mean about 160 µm(2)) mucous cells, whereas the lowest mean density (about 4%) and smallest mean area (115 µm(2)) were found on the head. We found that 100 random measurements may be sufficient to distinguish differences >7 µm(2) in mean mucous cell areas. The results further suggest that salmon exhibit a dynamic repeatable pattern of mucous cell development influenced by sex, diet and possibly strain and season.

CASP8 variants D302H and -652 6N ins/del do not influence the risk of colorectal cancer in the United Kingdom population.

Polymorphisms in CASP8 at 2q33.1 have been associated with the risk of developing cancer, specifically, the D302H variant (rs1045485) with breast cancer in the European population and the -652 6N ins/del promoter variant (rs3834129) with multiple tumours including colorectal cancer (CRC) in the Chinese population. We evaluated the relationship between -652 6N ins/del and D302H variants and risk of developing CRC in the UK population by genotyping 4016 cases and 3749 controls. Both variants showed no evidence of an association with risk of developing CRC (P=0.42 and 0.22, respectively). In contrast, the recently identified CRC susceptibility allele rs6983267 mapping to 8q24 was significantly associated with disease risk (P=8.94 x 10(-8)). It is thus very unlikely that variation in CASP8 defined by -652 6N ins/del or D302H influences the risk of CRC in European populations. The implications of our findings both in terms of population-specific effects and publication bias are discussed.

Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration.

BACKGROUND: The haplotype H1 of the tau gene, MAPT, is highly associated with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). OBJECTIVE: To investigate the pathogenic basis of this association. METHODS: Detailed linkage disequilibrium and common haplotype structure of MAPT were examined in 27 CEPH trios using validated HapMap genotype data for 24 single nucleotide polymorphisms (SNPs) spanning MAPT. RESULTS: Multiple variants of the H1 haplotype were resolved, reflecting a far greater diversity of MAPT than can be explained by the H1 and H2 clades alone. Based on this, six haplotype tagging SNPs (htSNPs) that capture 95% of the common haplotype diversity were used to genotype well characterised PSP and CBD case-control cohorts. In addition to strong association with PSP and CBD of individual SNPs, two common haplotypes derived from these htSNPs were identified that are highly associated with PSP: the sole H2 derived haplotype was underrepresented and one of the common H1 derived haplotypes was highly associated, with a similar trend observed in CBD. There were powerful and highly significant associations with PSP and CBD of haplotypes formed by three H1 specific SNPs. This made it possible to define a candidate region of at least approximately 56 kb, spanning sequences from upstream of MAPT exon 1 to intron 9. On the H1 haplotype background, these could harbour the pathogenic variants. CONCLUSIONS: The findings support the pathological evidence that underlying variations in MAPT could contribute to disease pathogenesis by subtle effects on gene expression and/or splicing. They also form the basis for the investigation of the possible genetic role of MAPT in Parkinson's disease and other tauopathies, including Alzheimer's disease.

Tetrazolium-based assays for cellular viability: a critical examination of selected parameters affecting formazan production.

The hydrogen acceptor 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) is commonly utilized to estimate cellular viability in drug screening protocols. The present investigation was prompted, in part, by observations that reduction of MTT to its colored reaction product, MTT formazan, varied between cell lines and with culture age. A correlation was established between the D-glucose concentration of the culture medium at the time of assay and the production of MTT formazan for cell lines representing seven tumor histologies. A decrease in the concentration of D-glucose from culture medium was accompanied by a decrease in MTT specific activity (MTT formazan/microgram cell protein) for a number of cell lines. Cells which extensively metabolized D-glucose exhibited the greatest reduction in MTT specific activity. Further evidence that the D-glucose concentration of the culture medium played an important role in MTT reduction was provided by experiments which demonstrated that transfer of cells to a glucose-free medium (L-15) was accompanied by an immediate decrease in MTT reduction which was pH independent. These studies suggested that cellular transport and constant metabolism of glucose were required for maximum MTT reduction. Decreases in the cellular concentration of the reduced pyridine nucleotides NADH and NADPH were accompanied by concomitant decreases in MTT formazan production. MTT formazan varied significantly among cell lines in both the kinetics of its formation and the degree of saturability exhibited. Apparent IC50 values for Adriamycin varied, in a cell line-specific manner, with MTT exposure time. These results indicate that MTT specific activity is significantly influenced by a number of parameters and suggest that assay conditions should be established which minimize their effects.

Rare variants analysis of cutaneous malignant melanoma genes in Parkinson's disease.

A shared genetic susceptibility between cutaneous malignant melanoma (CMM) and Parkinson's disease (PD) has been suggested. We investigated this by assessing the contribution of rare variants in genes involved in CMM to PD risk. We studied rare variation across 29 CMM risk genes using high-quality genotype data in 6875 PD cases and 6065 controls and sought to replicate findings using whole-exome sequencing data from a second independent cohort totaling 1255 PD cases and 473 controls. No statistically significant enrichment of rare variants across all genes, per gene, or for any individual variant was detected in either cohort. There were nonsignificant trends toward different carrier frequencies between PD cases and controls, under different inheritance models, in the following CMM risk genes: BAP1, DCC, ERBB4, KIT, MAPK2, MITF, PTEN, and TP53. The very rare TYR p.V275F variant, which is a pathogenic allele for recessive albinism, was more common in PD cases than controls in 3 independent cohorts. Tyrosinase, encoded by TYR, is the rate-limiting enzyme for the production of neuromelanin, and has a role in the production of dopamine. These results suggest a possible role for another gene in the dopamine-biosynthetic pathway in susceptibility to neurodegenerative Parkinsonism, but further studies in larger PD cohorts are needed to accurately determine the role of these genes/variants in disease pathogenesis.

Brain-derived neurotrophic factor differentially regulates excitatory and inhibitory synaptic transmission in hippocampal cultures.

Brain-derived neurotrophic factor (BDNF) has been postulated to be a key signaling molecule in regulating synaptic strength and overall circuit activity. In this context, we have found that BDNF dramatically increases the frequency of spontaneously initiated action potentials in hippocampal neurons in dissociated culture. Using analysis of unitary synaptic transmission and immunocytochemical methods, we determined that chronic treatment with BDNF potentiates both excitatory and inhibitory transmission, but that it does so via different mechanisms. BDNF strengthens excitation primarily by augmenting the amplitude of AMPA receptor-mediated miniature EPSCs (mEPSCs) but enhances inhibition by increasing the frequency of mIPSC and increasing the size of GABAergic synaptic terminals. In contrast to observations in other systems, BDNF-mediated increases in AMPA-receptor mediated mEPSC amplitudes did not require activity, because blocking action potentials with tetrodotoxin for the entire duration of BDNF treatment had no effect on the magnitude of this enhancement. These forms of synaptic regulations appear to be a selective action of BDNF because intrinsic excitability, synapse number, and neuronal survival are not affected in these cultures. Thus, although BDNF induces a net increase in overall circuit activity, this results from potentiation of both excitatory and inhibitory synaptic drive through distinct and selective physiological mechanisms.

Echocardiographic assessment of the effect of an antihypertensive regimen on left ventricular performance.

A regimen consisting of chlorthalidone, hydralazine and propranolol would be useful in some hypertensive patients with coronary artery disease or aortic dissection if it could be shown that reflex cardiac stimulation induced by hydralazine is completely neutralized by propranolol. Nine hypertensive patients were treated with chlorthalidone during week 1, chlorthalidone and hydralazine during week 2 and a combination of chlorthalidone, hydralazine and propranolol during week 3. Blood pressure, heart rate, mean velocity of circumferential fiber shortening (VCF) measured echocardiographically and plasma renin activity were measured weekly. This potent three drug regimen reduced mean blood pressure from 142 to 102 mm Hg, and with the third drug, propranolol, heart rate, VCF and plasma renin activity returned to control levels from the greater elevated levels produced by the diuretic drug and hydralazine. In six additional patients VCF (an index of left ventricular contractility) was found to be proportionate to the rate of rise of aortic pressure (dP/dt) or aortic shearing force. This regimen appears safe for use in patients with ischemic heart disease and aortic dissection.

Pharmacokinetics of acrivastine after oral and colonic administration.

Six healthy male volunteers participated in this randomized, crossover open-label pharmacokinetic study consisting of two dosing segments separated by a washout period of at least 5 days. During each dosing segment, each volunteer received 12 mg of acrivastine, an investigational histamine H1-receptor antagonist, in a syrup form either orally or by colonic administration in random order. After oral and colonic administration, respectively, the following mean +/- SD pharmacokinetic parameters were obtained: Cmax 179 +/- 11 and 13.8 +/- 5.2 ng/ml; tmax, 0.85 +/- 0.13 and 3.60 +/- 0.56 hr; AUC0-12 hr, 576 +/- 57 and 104 +/- 46 hr.ng/ml. Differences between the oral and colonic administration for all three parameters were statistically significant (P less than 0.001). The mean +/- SD relative bioavailability of acrivastine from colonic compared to oral dosing was 0.18 +/- 0.09. It may be concluded, therefore, that appreciable absorption of acrivastine from the colon does not take place. These results suggest that comparison of pharmacokinetic profiles of some drugs after oral and colonic administration may be a useful technique for predicting bioavailability from a sustained release oral formulation.

Pharmacokinetics of oral and transdermal triprolidine.

In this open, nonrandomized, three-way crossover study, six healthy male volunteers received single doses of triprolidine (TPL) hydrochloride syrup orally (2.5 mg) and wore transdermal TPL patches (5 mg and 10 mg doses) to compare the pharmacokinetic profiles and dose tolerance of the two formulations. A washout period of at least 1 week was scheduled between the three dosing periods. Blood samples were collected at defined times, and plasma concentrations were determined using a radioimmunoassay. Maximum plasma drug concentration (Cmax) decreased from 5.6 +/- 2.9 ng/mL (mean +/- SD) with oral dosing to 2.0 +/- 1.0 ng/mL and 4.2 +/- 2.0 ng/mL following 5 mg and 10 mg transdermal doses, respectively. Time to reach peak concentration (tmax) increased from 2.0 +/- 1.2 hours with oral dosing to 12.0 +/- 5.9 and 14.3 +/- 9.9 hours following 5 mg and 10 mg transdermal doses, respectively. The differences between AUC0-alpha values with the oral syrup and the 5 mg and 10 mg transdermal doses were not significant when normalized to 2.09 mg (TPL base). The bioavailabilities of the 5 mg and 10 mg transdermal doses relative to the oral 2.09 mg doses were 0.89 +/- 0.32 and 1.04 +/- 0.33, respectively. Mild erythema and pruritus were the most common adverse effects secondary to TPL transdermal application. Drowsiness observed following oral TPL, was not evident following either transdermal dose. The results of this study, therefore, indicate that TPL can be absorbed transdermally, providing consistent plasma concentrations.

Child maltreatment: risk of adjustment problems and dating violence in adolescence.

OBJECTIVE: To examine the relationship between child maltreatment, clinically relevant adjustment problems, and dating violence in a community sample of adolescents. METHOD: Adolescents from 10 high schools (N= 1,419; response rate = 62%) in southwestern Ontario completed questionnaires that assessed past maltreatment, current adjustment, and dating violence. Logistic regression was used to compare maltreated and nonmaltreated youths across outcome domains. RESULTS: One third (n = 462) of the school sample reported levels of maltreatment above the cutoff score on the Childhood Trauma Questionnaire. Girls with a history of maltreatment had a higher risk of emotional distress compared with girls without such histories (e.g., odds ratios [OR] for anger, depression, anxiety, and posttraumatic stress-related problems were 7.1, 7.2, 9.3, and 9.8, respectively). They were also at greater risk of violent and nonviolent delinquency (OR = 2.7) and carrying concealed weapons (OR = 7.1). Boys with histories of maltreatment were 2.5 to 3.5 times as likely to report clinical levels of depression, posttraumatic stress, and overt dissociation as were boys without a maltreatment history. They also had a significantly greater risk of using threatening behaviors (OR = 2.8) or physical abuse (OR = 3.4) against their dating partners. CONCLUSIONS: Maltreatment is a significant risk factor for adolescent maladjustment and shows a differential pattern for male and female adolescents.

Propranolol-hydralazine combination in essential hypertension.

The efficacy of a propranolol-hydralazine combination tablet was compared with that of each of its two components in the twice-daily treatment of mild to moderate essential hypertension (diastolic blood pressure: 100 to 125 mmHg). After a three-week, single-blind, placebo period, a 9- to 18-week, single-blind, dose-finding phase with the combination was performed. The daily doses of propranolol/hydralazine were 40 mg/25 mg, 80 mg/25 mg, 80 mg/50 mg, 120 mg/50 mg, 160 mg/50 mg, and 160 mg/100 mg. Of 83 patients, 73 (88%) had decreases in diastolic blood pressure equal to or greater than 10 mmHg. Thirty-eight (46%) patients had a diastolic blood pressure equal to or less than 90 mmHg while taking 80 mg propranolol/50 mg hydralazine or less given BID. Mean systolic and diastolic pressures were reduced by 16.8 mmHg (10.9%) and 17.6 mmHg (16.7%), respectively (P less than 0.001). A ten-week, double-blind, parallel-treatment phase followed in which patients were randomly assigned to the combination tablet or to propranolol or hydralazine. There were significantly larger increases in mean systolic (P less than 0.01) and mean diastolic (P less than 0.03) blood pressure when the components were taken alone than with the combination from the mean of the last three weekly dose-finding visits to the mean of the last four biweekly parallel-treatment visits. The changes in systolic/diastolic blood pressures were: hydralazine (n = 30), 14.43/8.62 mmHg; propranolol (n = 24), 9.87/6.09 mmHg; and the combination (n = 27), 1.47/1.53 mmHg. During the parallel-treatment phase, the proportions of patients with new complaints were: hydralazine, 16/31 (52%); propranolol, 10/25 (40%); and the combination, 11/27 (41%). In the hydralazine group, three patients had cardiovascular events (severe tachycardia, mild palpitations, and skipped heart beats) and two patients had mild anxiety; no such occurrences were noted in the propranolol or combination group. The mean change (increase) in heart rate from the end of dose-finding to the end of the double-blind period was significantly larger for patients taking hydralazine than for patients taking propranolol or the combination. Mean changes for these groups were: hydralazine, 12.4 beats/min; propranolol, 2.9 beats/min; and the combination, 1.8 beats/min (P = 0.0001). This study found the combination of propranolol plus hydralazine to be safe and more effective than either component.

Morphological and immunocytochemical characteristics of human tumor cell lines for use in a disease-oriented anticancer drug screen.

A panel of 60 human tumor cell lines is currently being used in the U.S. National Cancer Institute's in vitro anticancer drug screen. The panel is organized into 7 subpanels; 6 leukemia/lymphoma lines comprise one subpanel, and 54 other lines are organized into subpanels representing solid tumors of the central nervous system (CNS), colon, lung, ovaries, kidneys and melanomas. In the present study, the leukemia and lymphoma cell lines were analyzed by flow cytometry for appropriate CD antigens; all but 1 line showed patterns of expression consistent with their reported derivations. The solid tumor lines were characterized individually using morphological and immunocytochemical techniques to determine their relative degrees of representativity for the subpanels within which they are currently grouped. Histological, histochemical and ultrastructural examinations were performed on cell lines grown under identical conventional culture conditions and as xenografts in nude mice. Immunocytochemistry using panels of antibodies raised against 6 types of intermediate filaments, 7 adenocarcinoma-associated antigens, 7 melanoma/neuro-ectodermal-associated antigens, 3 neuroendocrine-associated antigens, 9 urinary tract associated antigens, and 4 markers of muscle differentiation was done on cells grown in monolayer culture. Central nervous system (CNS) cell lines lacked expression of glial fibrillary acidic protein, but all had other features consistent with derivation from glioblastoma. Lines derived from adenocarcinomas of the colon, lung and ovary, for the most part, expressed adenocarcinoma-associated antigens and showed histological and/or ultrastructural evidence of gland formation and other adenomatous features. Most of these lines were poorly differentiated. Lines derived from large-cell and squamous-cell cancers also showed some characteristics consistent with their reported origins, except for one line which showed immunocytochemical and morphologic characteristics consistent with rhabdomyosarcoma. The 2 lines derived from small cell lung cancer (SCLC) lacked neurosecretory granules and 3 other SCLC markers but showed morphologic features consistent with SCLC. Most melanoma cell lines strongly expressed melanoma-associated antigens and were morphologically similar to human melanoma. Five lines produced premelanosomes, melanosomes or melanin. Most of the renal cancer cell lines showed morphologic or immunocytochemical features consistent with renal clear cell carcinoma. Collectively, these morphological and immunocytochemical analyses provide information concerning tissue of origin, tumor type, degree of differentiation and other biologic features essential to the use of these lines in a disease-oriented in vitro antitumor drug screen and to the interpretation of data derived therefrom.

Development of radioimmunoassay for guanethidine.

A radioimmunoassay was developed for measuring plasma concentrations of the antihypertensive agent guanethidine at the nanogram level. Guanethidine was conjugated covalently to human serum albumin by two procedures, and the degree of conjugation was determined using tracer amounts of 3H-guanethidine. Immunization of sheep ethidine, as determined in competitive binding studies using 3H-guanethidine and a dextran-coated charcoal technique for the separation of free and antibody-bound drug. The major human metabolities, an N -oxide and a ring-opened derivative, were not cross-reactive in antibody binding studies. Constituents of human plasma or serum do not appear to interfere with the assay. Preliminary results from immunoassay of plasma samples from patients receiving guanethidine indicate potential use for assessing dosage regimens and studying pharmacokinetics.

Perception of voiceless fricatives by normal-hearing and hearing-impaired children and adults.

This study examined the perceptual-weighting strategies and performance-audibility functions of 11 moderately hearing-impaired (HI) children, 11 age-matched normal-hearing (NH) children, 11 moderately HI adults, and 11 NH adults. The purpose was to (a) determine the perceptual-weighting strategies of HI children relative to the other groups and (b) determine the audibility required by each group to achieve a criterion level of performance. Stimuli were 4 nonsense syllables (see text). The vowel, transition, and fricative segments of each nonsense syllable were identified along the temporal domain, and each segment was amplified randomly within each syllable during presentation. Point-biserial correlation coefficients were calculated using the amplitude variation of each segment and the correct and incorrect responses for the corresponding syllable. Results showed that for /see text/ and /see text/, all four groups heavily weighted the fricative segments during perception, whereas the vowel and transition segments received little or no weight. For /see text/, relatively low weights were given to each segment by all four groups. For /see text/, the NH children and adults weighted the transition segment more so than the vowel and fricative segments, whereas the HI children and adults weighted all three segments equally low. Performance-audibility functions of the fricative segments of /see text/ and /see text/ were constructed for each group. In general, maximum performance for each group was reached at lower audibility levels for /see text/ than for /see text/ and steeper functions were observed for the HI groups relative to the NH groups. A decision theory approach was used to confirm the audibility required by each group to achieve a > or =90% level of performance. Results showed both hearing sensitivity and age effects. The HI listeners required lower levels of audibility than the NH listeners to achieve similar levels of performance. Likewise, the adult listeners required lower levels of audibility than the children, although this difference was more substantial for the NH listeners than for the HI listeners.

Recognition of speech produced in noise.

A two-part study examined recognition of speech produced in quiet and in noise by normal hearing adults. In Part I 5 women produced 50 sentences consisting of an ambiguous carrier phrase followed by a unique target word. These sentences were spoken in three environments: quiet, wide band noise (WBN), and meaningful multi-talker babble (MMB). The WBN and MMB competitors were presented through insert earphones at 80 dB SPL. For each talker, the mean vocal level, long-term average speech spectra, and mean word duration were calculated for the 50 target words produced in each speaking environment. Compared to quiet, the vocal levels produced in WBN and MMB increased an average of 14.5 dB. The increase in vocal level was characterized by increased spectral energy in the high frequencies. Word duration also increased an average of 77 ms in WBN and MMB relative to the quiet condition. In Part II, the sentences produced by one of the 5 talkers were presented to 30 adults in the presence of multi-talker babble under two conditions. Recognition was evaluated for each condition. In the first condition, the sentences produced in quiet and in noise were presented at equal signal-to-noise ratios (SNR(E)). This served to remove the vocal level differences between the speech samples. In the second condition, the vocal level differences were preserved (SNR(P)). For the SNR(E) condition, recognition of the speech produced in WBN and MMB was on average 15% higher than that for the speech produced in quiet. For the SNR(P) condition, recognition increased an average of 69% for these same speech samples relative to speech produced in quiet. In general, correlational analyses failed to show a direct relation between the acoustic properties measured in Part I and the recognition measures in Part II.

The relation between stimulus context, speech audibility, and perception for normal-hearing and hearing-impaired children.

In this study, the influence of stimulus context and audibility on sentence recognition was assessed in 60 normal-hearing children, 23 hearing-impaired children, and 20 normal-hearing adults. Performance-intensity (PI) functions were obtained for 60 semantically correct and 60 semantically anomalous sentences. For each participant, an audibility index (AI) was calculated at each presentation level, and a logistic function was fitted to rau-transformed percent-correct values to estimate the SPL and AI required to achieve 70% performance. For both types of sentences, there was a systematic age-related shift in the PI functions, suggesting that young children require a higher AI to achieve performance equivalent to that of adults. Improvement in performance with the addition of semantic context was statistically significant only for the normal-hearing 5-year-olds and adults. Data from the hearing-impaired children showed age-related trends that were similar to those of the normal-hearing children, with the majority of individual data falling within the 5th and 95th percentile of normal. The implications of these findings in terms of hearing-aid fitting strategies for young children are discussed.