Heterogeneous addiction to transforming growth factor-beta signalling in recessive dystrophic epidermolysis bullosa-associated cutaneous squamous cell carcinoma.

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is associated with a high mortality rate due to the development of life-threatening, metastatic cutaneous squamous cell carcinoma (cSCC). Elevated transforming growth factor-beta (TGF-ß) signalling is implicated in cSCC development and progression in patients with RDEB. OBJECTIVES: To determine the effect of exogenous and endogenous TGF-ß signalling in RDEB cSCC with a view to assessing the potential of targeting TGF-ß signalling for RDEB cSCC therapy. METHODS: A panel of 11 patient-derived RDEB cSCC primary tumour keratinocyte cell lines (SCCRDEBs) were tested for their signalling and proliferation responses to exogenous TGF-ß. Their responses to TGF-ß receptor type-1 (TGFBR1) kinase inhibitors [SB-431542 and AZ12601011 (AZA01)] were tested using in vitro proliferation, clonogenicity, migration and three-dimensional invasion assays, and in vivo tumour xenograft assays. RESULTS: All SCCRDEBs responded to exogenous TGF-ß by activation of canonical SMAD signalling and proliferative arrest. Blocking endogenous signalling by treatment with SB-431542 and AZ12601011 significantly inhibited proliferation (seven of 11), clonogenicity (six of 11), migration (eight of 11) and invasion (six of 11) of SCCRDEBs. However, these TGFBR1 kinase inhibitors also promoted proliferation and clonogenicity in two of 11 SCCRDEB cell lines. Pretreatment of in vitro TGFBR1-addicted SCCRDEB70 cells with SB-431542 enhanced overall survival and reduced tumour volume in subcutaneous xenografts but had no effect on nonaddicted SCCRDEB2 cells in these assays. CONCLUSIONS: Targeting TGFBR1 kinase activity may have therapeutic benefit in the majority of RDEB cSCCs. However, the potential tumour suppressive role of TGF-ß signalling in a subset of RDEB cSCCs necessitates biomarker identification to enable patient stratification before clinical intervention.

Is the childhood home food environment a confounder of the association between child maltreatment exposure and adult body mass index?

Childhood maltreatment is consistently associated with adult obesity, leading to calls for tailored weight interventions for people with maltreatment histories. However, it is possible that the maltreatment-obesity association is spurious and driven by unmeasured confounding, in which case such interventions would be misplaced. The home food environment in childhood is a potential confounder, but its role in the association of maltreatment with obesity has not been examined. We used a longitudinal dataset (Project EAT) to examine the association of adult retrospective reports of maltreatment history in childhood (1+ types of maltreatment before age 18 years) with previously-collected prospective childhood reports of home food environment characteristics (availability of healthy foods, availability of sweet/salty snack food, family meal frequency, and food insufficiency). We then estimated the association between maltreatment and adult body mass index (BMI, kg/m2) with and without adjustment for these home food environment factors. After adjustment for sociodemographics, maltreatment had a 0.84 kg/m2 (95% CI: 0.28, 1.41) higher BMI at age 24-39 years, compared to those with no maltreatment, after adjustment for sociodemographics, parenting style, and BMI in childhood. Additional adjustment for home food environment factors had little effect on this association (ß = 0.78 kg/m2; 95% CI: 0.21,1.35), suggesting limited confounding influence of the home food environment factors. Findings provide additional robust evidence that childhood maltreatment is a risk factor for obesity that may warrant tailored interventions.

Associations of childhood maltreatment with binge eating and binge drinking in emerging adult women.

Background: Binge drinking and binge eating are prevalent, frequently co-occurring, high-risk behaviors among emerging adult women, each with physical and psychological consequences. The mechanisms driving their co-occurrence are not well understood, though a history of adverse childhood experiences (ACEs) may increase the risk for both binge behaviors. Objective: To assess the association between ACE subtypes and individual and co-occurring binge drinking and eating in emerging adult women. Participants and Setting: A diverse sample of women participating in the population-based study EAT 2018: Eating and Activity over Time (N = 788; aged 18-30; 19% Asian, 22% Black, 19% Latino, and 36% White). Methods: Multinomial logistic regression estimated associations among ACE subtypes (i.e., sexual abuse, physical abuse, emotional abuse, household dysfunction), and binge drinking, binge eating, and their co-occurrence. Results are reported as predicted probabilities (PP) of each outcome. Results: Over half of the sample (62%) reported at least one ACE. In models mutually adjusted for other ACEs, physical and emotional abuse showed the strongest associations with binge behaviors. Experiences of physical abuse had the strongest association with a ten-percentage point higher predicted probability of binge drinking (PP = 37%, 95% [CI 27-47%]) and seven-percentage point higher PP of co-occurring binge eating and drinking (PP = 12%, 95% CI [5-19%]). Emotional abuse had the strongest association with an 11-percentage point higher PP binge eating only (PP = 20%, 95% CI [11-29%]). Conclusions: This study found childhood physical and emotional abuse to be particularly relevant risk factors for binge drinking, binge eating, and their co-occurrence among emerging adult women.

Are these emergency department performance data real?

We have recently demonstrated that the distribution of total time spent by patients in emergency departments (EDs) in England shows a peak immediately prior to the current Department of Health target of 4 hours. We aimed to investigate whether this suggested that performance data were being manipulated. We collected data from 117 EDs, and 616,067 patient episodes were included in the analysis. Evidence of manipulation of performance data appears to be present in a small proportion of episodes, but because of the numbers involved, it could equate to over 50,000 episodes per year in EDs in England.

Integrity of the auditory pathway in young children with congenital and postmeningitic deafness.

This study compares the functional integrity of the auditory pathways of congenitally deaf and postmeningitically deaf children. We used the electrical auditory brain stem response evoked by promontory stimulation to assess 49 profoundly deaf children before cochlear implantation. The age at implantation ranged from 21 months to 15 years (mean 4.5 years). The onset of deafness was either congenital or up to the age of 2 years (mean 5 months). The cause of deafness was meningitis in 19 children (39%) and congenital in 30 (61%). The number of children with identifiable waveform components (eV, eIII, and eII) was significantly greater in the congenitally deaf group. We also analyzed the amplitudes, the latencies, and 4 parameters of the amplitude input-output functions. All the statistically significant differences were in favor of better responses in the congenitally deaf children. These results suggest that the functional status of the peripheral neurons of the auditory pathways may be more intact in congenitally deaf children than in postmeningitic children.

Prolongation of the cochlear microphonic in man. Cochlear microphonic ringing.

During routine extra-tympanic electrocochleographic (ECochG) recording we have observed that in many cases more cycles are seen in the cochlear microphonic (CM) recording than are present in the acoustic stimulus. We have termed this phenomenon CM 'ringing'. Ringing is present in 69% of our normal subjects and in 43% of patients with deafness of different aetiologies. In the cochlear and Ménière subgroups those cases showing ringing have a significantly larger CM amplitude (p less than 0.001 and p less than 0.01 respectively). The possible origin of this phenomenon is discussed.

Simultaneous recording of extra-tympanic electrocochleography and brainstem evoked responses in clinical practice.

Normal and clinical cases were investigated with simultaneous recording of extra tympanic electrocochleography and brainstem evoked responses. In group 3 cases where a non-recruiting hearing loss greater than or equal to 40 db. at 2 KHz and/or 4 KHz is present, brainstem recordings alone are not adequate for differential diagnosis of deafness due to the frequent inability to identify wave I. Therefore, electrocochleography is essential in these cases for determining the N1-V interpeak latency. Ideally cases as characterized in group 3 should be investigated by simultaneous recording of the brainstem evoked response and electrocochleography, preferably by a non-invasive technique. The test procedure is acceptable as a routine clinical investigation and avoids delay in diagnosis.

Effect of hearing loss in electrocochleographic investigation of endolymphatic hydrops using tone-pip and click stimuli.

Extratympanic electrocochleography (ECochG) was performed on 37 patients referred to the Evoked Potential Clinic with suspected Ménière's disease. The patients were classified according to their hearing impairment and audiometric configuration. Click and tone-pip stimuli with tone frequencies of 1 and 4 kHz were presented at a rate of 10 per second. Amplitude, latency and general waveform characteristics of the summation potential (SP) and action potential (AP) were analysed for each averaged response with respect to the level and configuration of the hearing loss. The highest incidence of abnormal percentage SP was in patients with average hearing loss in the range of 40-64 dB HL using the click stimulus. In low tone hearing loss, hydrops was identified from an enhanced SP in significantly more patients using the click and 4 kHz tone-pip than the 1 kHz stimulus. Measurement of the width of the 1 kHz tone-pip response waveform was abnormal in some patients even though the click and 4 kHz responses were normal. The optimum stimulus for identification of hydrops from an enhanced SP is dependent on the level and configuration of the hearing loss.

Raised ABR threshold after suction aspiration of glue from the middle ear: three case studies.

Between 1991 and 1993, 13 children (25 hearing ears) underwent recordings of the auditory brain stem response (ABR) under a general anaesthetic. The anaesthetic technique was similar for each child. Fourteen of these ears had fluid aspirated after myringotomy with insertion of grommets prior to the auditory brain stem response investigation. On subsequent hearing assessment six of these 14 ears (43 per cent) showed clear evidence of a threshold shift of 15 dB or greater. Eleven ears had either dry myringotomies or did not have a myringotomy prior to ABR and none of these showed evidence of a temporary threshold shift. Using Fisher's Exact probability test this difference is significant (p = 0.034). We feel it is important to report these observations so that unexpected high ABR thresholds following aspiration of glue are interpreted with caution.

Selective dysacusis--a preliminary report.

The symptom of poor speech discrimination in the presence of background noise is a well-recognized feature of elevated hearing thresholds due to cochlear damage. Similar symptoms occasionally occur in patients with no detectable audiological abnormality. In a study to evaluate the frequency selectivity of such patients consistent abnormalities were found using an electrophysiological technique based on extratympanic electrocochleography. These findings indicated that frequency specific responsiveness of the cochlea may be affected before conventional behavioural tests reveal abnormalities. This syndrome has been described as selective dysacusis.

Retrospective study of intra-operative testing with the Nucleus CI24M cochlear implant and use of the back-up device.

The combined use of integrity testing (IT) and impedance telemetry (ImTe) intra-operatively is evaluated. One hundred and fifty children implanted with the Nucleus device were studied. In 81% of patients, normal results were obtained on all electrodes from both ImTe and IT. In seven cases where the back-up device was used, the intra-operative analysis of the device and subsequent postoperative quality assurance testing did not always correlate. In conclusion, intra-operatively, only ImTe is needed to verify the function of the implant if all impedance values are normal. However, in the case of abnormal ImTe results, additional IT data provide valuable assistance with the decision of whether to leave the implant in place or to use the backup device.

Neighborhood deprivation and adverse birth outcomes among diverse ethnic groups.

PURPOSE: Living in a socioeconomically deprived neighborhood has been associated with an increased risk of adverse birth outcomes. However, variation in the effect of neighborhood deprivation among diverse ethnic groups has not been studied. METHODS: Using linked hospital discharge and birth data for 517,994 singleton live births in New York City from 1998 through 2002, we examined the association between neighborhood deprivation, preterm birth (PTB), and term low birthweight (TLBW) (>or=37 weeks and <2500g). Adjusted odds ratios (aORs) for PTB (<32 and 33-36 weeks) and TLBW were estimated using logistic regression. RESULTS: The aOR for PTB of less than 32 weeks for the highest quartile of deprivation compared to the lowest was 1.24 (95% confidence limit [CL] = 1.13, 1.36), for PTB 33-36 weeks was 1.06 (95% CL = 1.01, 1.11), and for TLBW was 1.19 (95% CL = 1.11, 1.27). Measures of association varied by ethnicity; aORs of the greatest magnitude for PTB were found among Hispanic Caribbean women (PTB < 32 weeks: aOR = 1.63, 95% CL = 1.27, 2.10; PTB 33-36 weeks: aOR = 1.32, 95% CL = 1.02, 1.70), and for TLBW among African women (aOR = 1.47, 95% CL = 1.02, 2.13). CONCLUSIONS: The mechanisms linking neighborhood deprivation to adverse birth outcomes may differ depending on individual ethnicity and/or cultural context and should be investigated in future research.

On-line computer scoring of the auditory brainstem response for estimation of hearing threshold.

Auditory brainstem responses (ABRs) to click stimuli have become established as a useful indicator of hearing thresholds in infants and young children. Although the investigation is objective in so far as the patient is concerned, a subjective element remains in the decision by the operator as to whether or not an ABR is present in an averaged waveform. A simple on-line computer detection technique is described which removes some of the reliance placed upon the operator. The technique employs a scanning window for correlation and amplitude analysis of pairs of averaged ABR waveforms. The reliability and accuracy of computer and operator scoring of 25 thresholds in normally hearing adults and 50 thresholds in infants and young children with suspected hearing impairment have been investigated. In the adult group, 96% of computer estimates of the threshold were within +/- 10 dB of the subjective hearing threshold, compared with 92% for operator scoring. There were 92% of computer and operator scores within +/- 10 dB of each other. In the patient group there was equally good agreement between computer and operator scoring with 90% of the thresholds within +/- 10 dB of each other; the incidence of possible false-positive thresholds was also lower with computer scoring. This on-line scoring technique, therefore, offers useful assistance to the operator; requires only limited computing power, and is suitable for use in a routine clinical environment.

Effects of high-pass filtering on the detection of the auditory brainstem response.

The effects of high-pass filtering on the slow components of the click-evoked auditory brainstem response (ABR) have been assessed in eight normally hearing adults. Eight high-pass Butterworth-type filters (36 dB/octave) were investigated with cut-off frequencies at 10, 20, 30, 40, 50, 60, 80 and 100 Hz (-3 dB points). The low-pass filter was kept constant at 1 kHz. A 20 dB nHL stimulus was presented to the subjects at a rate of 26/s. Two averaged ABR waveforms, each consisting of 2048 individual sweeps, were recorded for each filter setting with a post-stimulus sweep time of 19.2 ms. In the visual interpretation of the recordings the correlation between each waveform, and the amplitude of the response relative to the noise, strongly affects the decision as to whether a response is present. A mathematical analysis of these parameters, using a scanning correlation window technique, showed that a 20 Hz filter is optimum for the best detection of the ABR close to hearing threshold.

Automated system for screening hearing using the auditory brainstem response.

Routine screening of hearing using the auditory brainstem response (ABR) in infants, such as neonates in the special care baby unit, requires a system which is quick, user-friendly and gives a simple outcome. A system which consists of a stimulator/amplifier unit for recording the ABR controlled by a standard Master Series BBC Microcomputer is described which fulfils these requirements. The test procedure is highly automated, and a pass or refer decision for the screen on each ear is given by a machine-scoring algorithm which detects the ABR waveform.