Transcriptome of iPSC-derived neuronal cells reveals a module of co-expressed genes consistently associated with autism spectrum disorder.

Evaluation of expression profile in autism spectrum disorder (ASD) patients is an important approach to understand possible similar functional consequences that may underlie disease pathophysiology regardless of its genetic heterogeneity. Induced pluripotent stem cell (iPSC)-derived neuronal models have been useful to explore this question, but larger cohorts and different ASD endophenotypes still need to be investigated. Moreover, whether changes seen in this in vitro model reflect previous findings in ASD postmortem brains and how consistent they are across the studies remain underexplored questions. We examined the transcriptome of iPSC-derived neuronal cells from a normocephalic ASD cohort composed mostly of high-functioning individuals and from non-ASD individuals. ASD patients presented expression dysregulation of a module of co-expressed genes involved in protein synthesis in neuronal progenitor cells (NPC), and a module of genes related to synapse/neurotransmission and a module related to translation in neurons. Proteomic analysis in NPC revealed potential molecular links between the modules dysregulated in NPC and in neurons. Remarkably, the comparison of our results to a series of transcriptome studies revealed that the module related to synapse has been consistently found as upregulated in iPSC-derived neurons-which has an expression profile more closely related to fetal brain-while downregulated in postmortem brain tissue, indicating a reliable association of this network to the disease and suggesting that its dysregulation might occur in different directions across development in ASD individuals. Therefore, the expression pattern of this network might be used as biomarker for ASD and should be experimentally explored as a therapeutic target.

Quantity over quality? Prey-field characteristics influence the foraging decisions of little penguins (Eudyptula minor).

Quantifying prey characteristics is important for understanding the foraging behaviour of predators, which ultimately influence the structure and function of entire ecosystems. However, information available on prey is often at magnitudes which cannot be used to infer the fine-scale behaviour of predators, especially so in marine environments where direct observation of predator-prey interactions is rarely possible. In the present study, animal-borne video data loggers were used to determine the influence of prey type and patch density on the foraging behaviour of the little penguin (Eudyptula minor), an important predator in southeastern Australia. We found that numerical density positively influenced time spent foraging at a patch. However, when accounting for calorific value in density estimates, individuals spent longer at dense patches of low-quality prey. This may reflect a trade-off between capture effort and calorific gain as lower quality prey were captured at higher rates. During the breeding season, foraging trip distance and duration is constrained by the need to return to the colony each day to feed offspring. The results of the study suggest that, under these spatio-temporal constraints, little penguins maximize foraging performance by concentrating efforts at larger quantities of prey, irrespective of their calorific quality.

Validating accelerometry-derived proxies of energy expenditure using the doubly labelled water method in the smallest penguin species.

Understanding energy use is central to understanding an animal's physiological and behavioural ecology. However, directly measuring energy expenditure in free-ranging animals is inherently difficult. The doubly labelled water (DLW) method is widely used to investigate energy expenditure in a range of taxa. Although reliable, DLW data collection and analysis is both financially costly and time consuming. Dynamic body acceleration (e.g. VeDBA) calculated from animal-borne accelerometers has been used to determine behavioural patterns, and is increasingly being used as a proxy for energy expenditure. Still its performance as a proxy for energy expenditure in free-ranging animals is not well established and requires validation against established methods. In the present study, the relationship between VeDBA and the at-sea metabolic rate calculated from DLW was investigated in little penguins (Eudyptula minor) using three approaches. Both in a simple correlation and activity-specific approaches were shown to be good predictors of at-sea metabolic rate. The third approach using activity-specific energy expenditure values obtained from literature did not accurately calculate the energy expended by individuals. However, all three approaches were significantly strengthened by the addition of mean horizontal travel speed. These results provide validation for the use of accelerometry as a proxy for energy expenditure and show how energy expenditure may be influenced by both individual behaviour and environmental conditions.

Risk factors for childhood sensorineural hearing loss in the Oxford region.

We have used a comprehensive register of hearing-impaired children born in the former Oxford Health Region to study risk factors for sensorineural hearing loss. The occurrence of a wide variety of risk factors was documented from the case notes of 145 children; these were all the cases known at the time of the study with all degrees of hearing loss born between 1984 and 1988. Comparison with the normal Regional population showed that maternal age over 35 years and Asian ethnic origin were significant risk factors for congenital (non-acquired) hearing loss (odds ratio 1.7 and 2.5 respectively). Black/Asian children were also significantly more likely to have acquired losses. Low birthweight (below 2500 g) also gave a significantly increased risk, with an odds ratio of 4.5, rising to 9.6 for birthweight less than 1500 g. We also found that significantly more hearing-impaired cases were in lower social classes compared with the general population. A high proportion of cases (24%) had cranio-facial abnormalities (CFA), including many non-aural abnormalities and dysmorphic features, which therefore should be counted as high risk. Hearing losses acquired due to perinatal causes were almost all mild or moderate. Four factors-admission to special care baby unit for more than 72 hours, CFA, family history, and meningitis-accounted for 69% of all cases in this study. Targeted neonatal screening based on the first three factors, plus obligatory testing following meningitis, therefore, should be highly efficient at detecting deafness early.

Prediction of 8-month MEE from neonatal risk factors and test results in SCBU and full-term babies.

The incidence and persistence of middle ear effusion (MEE) may be affected by children's birth history and environment. Factors such as bottle-feeding, presence of parental smoking, admission to special care and a history of colds are all thought to increase the risk of persistent MEE. The aim of the present study was to determine those risk factors and neonatal test results that best predict presence of MEE (as measured by 220 Hz tympanometry) at 8 months of age. One hundred Special Care Baby Unit (SCBU) and non-SCBU babies were assessed neonatally and at 8 months of age with tympanometry. At each assessment, various risk factors were collected. Failure of 8-month tympanometry was best predicted by neonatal (660 Hz) tympanometry and the presence or absence of breast-feeding for SCBU babies. This provides further evidence that 660 Hz tympanometry may provide information about neonatal MEE. For non-SCBU babies the risk of failing 8-month tympanometry was most significantly affected by a history of colds and parental smoking. The number of babies with each combination of risk factors in the present study is rather small and this has caused confidence intervals (CIs) to be wide and some unexpected results. However, an extended study with a larger and more balanced sample may facilitate accurate prediction neonatally of those children at risk of 8-month MEE.

Direct hearing aid referrals: a prospective study.

General practitioners from a designated catchment area were invited to participate in a direct hearing aid referral project and were issued with a standard referral form outlining the criteria for referral. A total of 175 patients was referred with a fully completed referral form and were initially assessed by a senior audiology technician or higher grade. A total of 135 patients (77%) was suitable for hearing aid fitting and 40 (23%) were considered to be inappropriate referrals, of which 17 (9.7%) required further referral for an ENT opinion. For the purpose of safety, each patient was independently examined by an ENT doctor. The management decisions of the audiology technicians were in total agreement with those of the ENT doctors. Our results also suggested that patients below the age of 60 are generally unsuitable for direct referral.

Acoustic correlates of tonal tinnitus.

A sensitive microphone has been developed which can pick up tonal signals (spontaneous acoustic emissions) in the sealed ear-canal of certain subjects. Various properties of these frequency components suggest that they arise from an active, frequency-selective self-limiting feedback process within the cochlea and that they rely on internal reflection from the middle ear. An external tone can synchronize, frequency-lock, suppress of frequency-shift the acoustic component. These interactions are frequency-dependent in a way suggestive of cochlear tuning properties. Positive or negative middle-ear pressure can also influence the components by increasing their frequency and in some cases can enhance one component at the expense of a neighbouring one. Some subjects hear these components as tinnitus and can report on the measured changes. Other subjects do not hear the measured signals, which otherwise behave similarly. A third group of subjects have tinnitus but no objective sound can be detected. In this last group there are, nevertheless, sometimes notches or other discontinuities in the audiogram which correspond to their tinnitus pitch-matches. It appears likely that the recordable type of tinnitus is essentially non-pathological and represents hypersensitivity of the system, whereas the non-recordable type might be associated with local pathological changes at the end-organ or more centrally.

Age effect in hearing - a comparative analysis of published threshold data.

Numerical data from the literature on presbyacusis, in the form of pure-tone hearing threshold levels as a function of age, are subjected to critical evaluation and analysis. A formula is derived for predicting the age effect for otologically screened groups of males and females. Further, the complete distribution of hearing levels for each audiometric frequency in the range 0.125-12 kHz and at any age can be estimated with the aid of tabulated coefficients and some simple rules. The study was undertaken in connection with the work of ISO on standardization of normative audiometric data.

Health visitor screening versus vigilance: outcomes of programmes for detecting permanent childhood hearing loss in west Berkshire.

The Health Visitor Distraction Test (HVDT) screen for hearing was replaced in West Berkshire in 1989 with a vigilance programme incorporating a questionnaire. The detection of permanent congenital deafness (bilateral > 50 dB HL) for all children born since 1984 has been audited to compare the two regimes. Sixty-two cases met the criteria, giving an ascertainment of 1.0 per 1000. Performance was similar under the two systems for severe/profound losses (> 70 dB HL), but there was a longer tail of late-detected moderate losses (50-70 dB HL) under the vigilance regime. The sensitivity of the Health Visitor questionnaire in referring those with permanent hearing loss was very similar to that of the HVDT (39% compared with 42%). Coverage for the questionnaire was approximately 87%, but only 78% for the known cases. Referral rate was lower under the vigilance programme, at approximately 3%. The results suggest that a vigilance programme is likely to perform as well as the HVDT but no better. Despite subsequent modifications to the vigilance programme, the poor pickup of moderate losses probably indicates the limitations of parental and professional observation in detecting partial hearing problems. The evidence adds support to the recent recommendations for universal neonatal screening.

Tympanometry and otoacoustic emissions in a cohort of special care neonates.

Otoacoustic emission (OAE) screening and oto-admittance testing (678 Hz probe tone) were performed on both ears of 84 special care neonates, as part of a larger study of middle-ear effusion in neonates and infants. OAE results, tympanometry, and acoustic reflex results are all strongly and significantly associated. No evidence was found of any maturational effects in the results. Based on the findings, a tentative classification scheme for neonatal tympanograms is suggested. We conclude that 678 Hz tympanometry is a useful indicator of middle-ear status in very young babies, and that middle-ear effusion does strongly affect OAEs in neonates. OAEs are also strongly affected by negative middle-ear pressure (MEP), and mean MEP in ears failing OAE screens was significantly more negative than in those passing. The prevalence of abnormal tympanometry, which may indicate middle-ear effusion or dysfunction, was 20% of ears (29% of babies) in this group. It appears that middle-ear effusion could account for about half of the ears failing an OAE screen on the special care baby unit. We also find that length of stay on the special care baby unit is an important risk factor for development of middle-ear effusion: those on the unit for over 30 days have about four times the risk of bilateral abnormal tympanometry.