No association between germline allele-specific expression of TGFBR1 and colorectal cancer risk in Caucasian and Ashkenazi populations.

BACKGROUND: Germline allele-specific expression (ASE) of the TGFBR1 gene has been reported as a strong risk factor for colorectal cancer (CRC) with an odds ratio close to 9. Considering the potential implications of the finding, we undertook the task of validating the initial results in this study. METHODS: Allele-specific expression was measured using the highly quantitative and robust technique of pyrosequencing. Individuals from two different populations were studied, one Caucasian-dominated and the other of Ashkenazi Jewish descent, with different sources of non-tumoral genetic material in each. RESULTS: Our results showed no statistically significant differences in the degree of ASE between CRC patients and controls, considering ASE as either a quantitative or a binary trait. Using defined cutoff values to categorise ASE, 1.0% of blood lymphocytes from informative Israeli cases (total n=96) were ASE positive (median 1.00; range 0.76-1.31) and 2.2% of informative matched controls (total n=90) were ASE positive (median 1.00; range 0.76-1.87). Likewise, normal mucosae from Spanish patients (median 1.03; range: 0.68-1.43; n=75) did not show significant differences in the degree of ASE when compared with the Israeli patients or controls. CONCLUSIONS: Taken together, these results suggest that ASE of TGFBR1 does not confer an increased risk of CRC.

Evaluation of variation in the phosphoinositide-3-kinase catalytic subunit alpha oncogene and breast cancer risk.

BACKGROUND: Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer. METHODS: A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC). RESULTS: Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR)=0.97, 95% confidence interval (CI) 0.95-0.99, P=4.6 × 10(-3)), but did not reach significance in the BCAC replication study alone (OR=0.98, 95% CI 0.96-1.01, P=0.139). CONCLUSION: Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer.

Balance Right in Multiple Sclerosis (BRiMS): a feasibility randomised controlled trial of a falls prevention programme.

BACKGROUND: Balance, mobility impairments and falls are problematic for people with multiple sclerosis (MS). The "Balance Right in MS (BRiMS)" intervention, a 13-week home and group-based exercise and education programme, aims to improve balance and minimise falls. This study aimed to evaluate the feasibility of undertaking a multi-centre randomised controlled trial and to collect the necessary data to design a definitive trial. METHODS: This randomised controlled feasibility study recruited from four United Kingdom NHS clinical neurology services. Patients ≥ 18 years with secondary progressive MS (Expanded Disability Status Scale 4 to 7) reporting more than two falls in the preceding 6 months were recruited. Participants were block-randomised to either a manualised 13-week education and exercise programme (BRiMS) plus usual care, or usual care alone. Feasibility assessment evaluated recruitment and retention rates, adherence to group assignment and data completeness. Proposed outcomes for the definitive trial (including impact of MS, mobility, quality of life and falls) and economic data were collected at baseline, 13 and 27 weeks, and participants completed daily paper falls diaries. RESULTS: Fifty-six participants (mean age 59.7 years, 66% female, median EDSS 6.0) were recruited in 5 months; 30 randomised to the intervention group. Ten (18%) participants withdrew, 7 from the intervention group. Two additional participants were lost to follow up at the final assessment point. Completion rates were > 98% for all outcomes apart from the falls diary (return rate 62%). After adjusting for baseline score, mean intervention-usual care between-group differences for the potential primary outcomes at week 27 were MS Walking Scale-12v2: - 7.7 (95% confidence interval [CI] - 17.2 to 1.8) and MS Impact Scale-29v2: physical 0.6 (CI - 7.8 to 9), psychological - 0.4 (CI - 9.9 to 9). In total, 715 falls were reported, rate ratio (intervention:usual care) for falls 0.81 (0.41 to 2.26) and injurious falls 0.44 (0.41 to 2.23). CONCLUSIONS: Procedures were practical, and retention, programme engagement and outcome completion rates satisfied a priori progression criteria. Challenges were experienced in completion and return of daily falls diaries. Refinement of methods for reporting falls is therefore required, but we consider a full trial to be feasible. TRIAL REGISTRATION: ISRCTN13587999 Date of registration: 29 September 2016.

Linguistic experience alters phonetic perception in infants by 6 months of age.

Linguistic experience affects phonetic perception. However, the critical period during which experience affects perception and the mechanism responsible for these effects are unknown. This study of 6-month-old infants from two countries, the United States and Sweden, shows that exposure to a specific language in the first half year of life alters infants' phonetic perception.

Spectral characteristics of sound transmission in the human respiratory system.

The amplitude of sound transmission from the mouth to a site overlying the extrathoracic trachea and two sites on the right posterior chest wall over the 100-600 Hz frequency range was measured in eight healthy adult subjects. An acoustic driver and a rigid tube were employed to introduce sound into the mouths of the subjects at resting lung volume, and the transmission measurements were performed using lightweight accelerometers. Similar spectral characteristics of acceleration were observed in all of the subjects showing peaks in the transmission. These characteristics included 1) two regions of increased transmission over the frequency range of the measurements, 2) a decrease in the magnitude of acceleration of the chest wall as compared to the tracheal site of roughly 20 dB at lower frequencies, 3) a strong trend of decreasing acceleration of the chest wall with increasing frequency. These spectra agreed favorably with the predictions of a theoretical model of the acoustical properties of the respiratory system. The model suggests the primary structural determinants of a number of the observed characteristics including the importance of the lung parenchyma in sound attenuation.

A model of acoustic transmission in the respiratory system.

A theoretical model of sound transmission from within the respiratory tract to the chest wall due to the motion of the walls of the large airways was developed. The vocal tract, trachea, and the first five bronchial generations are represented over the frequency range from 100 to 600 Hz by an equivalent acoustic circuit. This circuit allows the estimation of the magnitude of airway wall motion in response to an acoustic perturbation at the mouth. The radiation of sound through the surrounding lung parenchyma is represented as a cylindrical wave in a homogeneous mixture of air bubbles in water. The effect of thermal losses associated with the polytropic compressions and expansions of these bubbles by the acoustic wave is included and the chest wall is represented as a massive boundary to the wave propagation. The model estimates the magnitude of acceleration over the extrathoracic trachea and at three locations on the posterior chest wall in the same vertical plane. The predicted spectral characteristics of transmission are consistent with previous experimental observations. This theoretical approach suggests that the locations of the spectral peaks are a strong function of the geometry and the wall properties of the airways, while the attenuation at higher frequencies is primarily associated with the absorption of sound in the parenchyma.

An acoustical study of the fricative /s/ in the speech of individuals with dysarthria.

This paper reports on measurements of several acoustic attributes of the fricative consonant /s/ produced in word-initial position by normally speaking adults and by speakers with neuromotor dysfunctions. Several acoustic properties are evaluated: the spectrum shape of the fricative and its amplitude in relation to the following vowel, the presence or absence of voicing, the time variation of the spectrum during the fricative and in the transition to the following vowel, and the presence of inappropriate acoustic patterns preceding the /s/. Some of these properties are based on quantitative measurements of the spectrum of the /s/, and others are based on observations of the time-varying acoustic patterns in spectrograms. For the individuals with dysarthria, deviations of each of these properties from the normal range are interpreted in terms of specific deficits in the control of the speech-production system. For the most part, these parameters are highly correlated with the speakers' overall intelligibility, with the intelligibility of words containing the fricative /s/, and with perceptual ratings of the adequacy of the fricative production. The parameters that show the best correlation with intelligibility and perceptual ratings are (a) measures of deviations from normalcy in the time variation of the acoustic pattern within the consonant and at the consonant-vowel boundary and (b) the spectrum shape of the frication noise. These acoustic parameters are related to deviations in the temporal pattern of control of the articulators in producing fricative-vowel sequences and to lack of fine control of the tongue blade in achieving an appropriate target configuration for the fricative.

Diverse acoustic cues at consonantal landmarks.

The consonantal segments that underlie an utterance are manifested in the acoustic signal by abrupt discontinuities or dislocations in the spectral pattern. There are potentially two such discontinuities for each consonant, corresponding to the formation and release of a constriction in the oral cavity by the lips, the tongue blade, or the tongue body. Acoustic cues for the various consonant features of place, voicing and nasality reside in the signal in quite different forms on the two sides of each acoustic discontinuity. Examples of these diverse cues and their origin in acoustic theory are reviewed, with special attention to place features and features related to the laryngeal state and to nasalization. A listener appears to have the ability to integrate these diverse, brief acoustic cues for the features of consonants, although the mechanism for this integration process is unclear.

Critique: articulatory-acoustic relations and their role in speech perception.

These remarks are in response to "Role of articulation in speech perception: Clues from production"ony Björn Lindblom. It is suggested that the form in which the lexicon is stored includes both segments and distinctive features, and this representation is neutral with respect to articulatory and the acoustic domains. The process by which features are determined from the sound requires that patterns of acoustic properties be identified. In developing models of speech perception, knowledge of articulatory-acoustic relations can be a guide in defining these properties, but it is not necessary for the models to assign primary status to articulation.

Acoustic correlates of some phonetic categories.

Some of the acoustic properties that distinguish one speech sound from another are reviewed. The point of view is that the auditory system responds to sound with different acoustic properties in distinctive ways, and that these special responses play an important role in selection and classification of the inventory of sounds that are used in language. Examples of several of these acoustic properties are discussed and illustrated, including the presence or absence of rapid spectrum change, abruptness and amplitude change, voicing and aspiration, and gross spectral properties relating to place of articulation for consonant and vowels.

Effect of burst amplitude on the perception of stop consonant place of articulation.

We have examined the effects of the relative amplitude of the release burst on perception of the place of articulation of utterance-initial voiceless and voiced stop consonants. The amplitude of the burst, which occurs within the first 10-15 ms following consonant release, was systematically varied in 5-dB steps from -10 to +10 dB relative to a "normal" burst amplitude for two labial-to-alveolar synthetic speech continua--one comprising voiceless stops and the other, voiced stops. The distribution of spectral energy in the bursts for the labial and alveolar stops at the ends of the continuum was consistent with the spectrum shapes observed in natural utterances, and intermediate shapes were used for intermediate stimuli on the continuum. The results of identification tests with these stimuli showed that the relative amplitude of the burst significantly affected the perception of the place of articulation of both voiceless and voiced stops, but the effect was greater for the former than the latter. The results are consistent with a view that two basic properties contribute to the labial-alveolar distinction in English. One of these is determined by the time course of the change in amplitude in the high-frequency range (above 2500 Hz) in the few tens of ms following consonantal release, and the other is determined by the frequencies of spectral peaks associated with the second and third formants in relation to the first formant.

Invariant cues for place of articulation in stop consonants.

In a series of experiments, identification responses for place of articulation were obtained for synthetic stop consonants in consonant-vowel syllables with different vowels. The acoustic attributes of the consonants were systematically manipulated, the selection of stimulus characteristics being guided in part by theoretical considerations concerning the expected properties of the sound generated in the vocal tract as place of articulation is varied. Several stimulus series were generated with and without noise bursts at the onset, and with and without formant transitions following consonantal release. Stimuli with transitions only, and with bursts plus transitions, were consistently classified according to place of articulation, whereas stimuli with bursts only and no transitions were not consistently identified. The acoustic attributes of the stimuli were examined to determine whether invariant properties characterized each place of atriculation independent of vowel context. It was determined that the gross shape of the spectrum sampled at the consonantal release showed a distinctive shape for each place of articulation: a prominent midfrequency spectral peak for velars, a diffuse-rising spectrum for alveolars, and a diffuse-falling spectrum for labials. These attributes are evident for stimuli containing transitions only, but are enhanced by the presence of noise bursts at the onset.

Acoustic invariance in speech production: evidence from measurements of the spectral characteristics of stop consonants.

On the basis of theoretical considerations and the results of experiments with synthetic consonant-vowel syllables, it has been hypothesized that the short-time spectrum sampled at the onset of a stop consonant should exhibit gross properties that uniquely specify the consonantal place of articulation independent of the following vowel. The aim of this paper is to test this hypothesis by measuring the spectrum sampled at the onsets and offsets of a large number of consonant-vowel (CV) and vowel-consonant (VC) syllables containing both voiced and voiceless stops produced by several speakers. Templates were devised in an attempt to capture three classes of spectral shapes: diffuse-rising, diffuse-falling, and compact, corresponding to alveolar, labial, and velar consonants, respectively. Spectra were derived from the utterances by sampling at the consonantal release of CV syllables and at the implosion and burst release of VC syllables, and these spectra (smoothed by a linear prediction algorithm) were matched against the templates. It was found that about 85% of the spectra at initial consonant release and at final burst release were correctly classified by the templates, although there was some variability across vowel contexts. The spectra sampled at the implosion were not consistently classified. A preliminary examination of spectra sampled at the release of nasal consonants in CV syllables showed a somewhat lower accuracy of classification by the same templates. Overall, the results support an hypothesis that, in natural speech, the acoustic characteristics of stop consonants, specified in terms of the gross spectral shape sampled at the discontinuity in the acoustic signal, show invariant properties independent of the adjacent vowel or of the voicing characteristics of the consonant. The implication is that the auditory system is endowed with detectors that are sensitive to these kinds of gross spectral shapes, and that the existence of these detectors helps the infant to organize the sounds of speech into their natural classes.

Perceptual invariance and onset spectra for stop consonants in different vowel environments.

A series of listening tests with brief synthetic consonant-vowel syllables was carried out to determine whether the initial part of a syllable can provide cues to place of articulation for voiced stop consonants independent of the remainder of the syllable. The data show that stimuli as short as 10-20 ms sampled from the onset of a consonant-vowel syllable, can be reliably identified for consonantal place of articulation, whether the second and higher formants contain moving or straight transitions and whether or not an initial burst is present. In most instances, these brief stimuli also contain sufficient information for vowel indentification. Stimulus continua in which formant transitions ranged from values appropriate to [b], [d], [g] in various vowel environments, and in which stimulus durations were 20 and 46 ms, yielded categorical labeling functions with a few exceptions. These results are consistent with a theory of speech perception in which consonant place of articulation is cued by invariant properties derived from the spectrum sampled in a 10-20 ms time window adjacent to consonantal onset or offset.