An exploration of the accentuation effect: errors in memory for voice fundamental frequency (F0) and speech rate

The accentuation effect demonstrates how memory often reflects category typical representations rather than the specific features of learned items. The present study investigated the impact of manipulating fundamental frequency (F0) and speech rate (syllables per second) on immediate target matching performance (selecting a voice from a pair to match a previously heard target voice) for a range of synthesised voices. It was predicted that when participants were presented with high or low frequency target voices, voices even higher or lower in frequency would be selected. The same pattern was also predicted for speech rate. Inconsistent with the accentuation account, the results showed a general bias to select voices higher in frequency for high, moderate, and low frequency target voices. For speech rate, listeners selected voices faster in rate for slow rate target voices. Overall it seems doubtful that listeners rely solely on categorical information about voices during recognition

Cell cycle times of short-term cultures of brain cancers as predictors of survival

Tumour cytokinetics estimated in vivo as potential doubling times (Tpot values) have been found to range in a variety of human cancers from 2 days to several weeks and are often related to clinical outcome. We have previously developed a method to estimate culture cycle times of short-term cultures of surgical material for several tumour types and found, surprisingly, that their range was similar to that reported for Tpot values. As Tpot is recognised as important prognostic variable in cancer, we wished to determine whether culture cycle times had clinical significance. Brain tumour material obtained at surgery from 70 patients with glioblastoma, medulloblastoma, astrocytoma, oligodendroglioma and metastatic melanoma was cultured for 7 days on 96-well plates, coated with agarose to prevent proliferation of fibroblasts. Culture cycle times were estimated from relative 3H-thymidine incorporation in the presence and absence of cell division. Patients were divided into two groups on the basis of culture cycle times of ⩽10 days and >10 days and patient survival was compared. For patients with brain cancers of all types, median survival for the ⩽10-day and >10-day groups were 5.1 and 12.5 months, respectively (P=0.0009). For 42 patients with glioblastoma, the corresponding values were 6.5 and 9.0 months, respectively (P=0.03). Lower grade gliomas had longer median culture cycle times (16 days) than those of medulloblastomas (9.9 days), glioblastomas (9.8 days) or melanomas (6.7 days). We conclude that culture cycle times determined using short-term cultures of surgical material from brain tumours correlate with patient survival. Tumour cells thus appear to preserve important cytokinetic characteristics when transferred to culture

Emergence of Anti-Cancer Drug Resistance: Exploring the Importance of the Microenvironmental Niche via a Spatial Model

Practically, all chemotherapeutic agents lead to drug resistance. Clinically, it is a challenge to determine whether resistance arises prior to, or as a result of, cancer therapy. Further, a number of different intracellular and microenvironmental factors have been correlated with the emergence of drug resistance. With the goal of better understanding drug resistance and its connection with the tumor microenvironment, we have developed a hybrid discrete-continuous mathematical model. In this model, cancer cells described through a particle-spring approach respond to dynamically changing oxygen and DNA damaging drug concentrations described through partial differential equations. We thoroughly explored the behavior of our self-calibrated model under the following common conditions: a fixed layout of the vasculature, an identical initial configuration of cancer cells, the same mechanism of drug action, and one mechanism of cellular response to the drug. We considered one set of simulations in which drug resistance existed prior to the start of treatment, and another set in which drug resistance is acquired in response to treatment. This allows us to compare how both kinds of resistance influence the spatial and temporal dynamics of the developing tumor, and its clonal diversity. We show that both pre-existing and acquired resistance can give rise to three biologically distinct parameter regimes: successful tumor eradication, reduced effectiveness of drug during the course of treatment (resistance), and complete treatment failure

A comparison of hazard perception and hazard prediction tests across China, Spain and the UK

Hazard perception (HP) is the ability to spot on-road hazards in time to avoid a collision. This skill is traditionally measured by recording response times to hazards in video clips of driving, with safer, experienced drivers often out-performing inexperienced drivers. This study assessed whether HP test performance is culturally specific by comparing Chinese, Spanish and UK drivers who watched clips filmed in all three countries. Two test-variants were created: a traditional HP test (requiring timed hazard responses), and a hazard prediction test, where the film is occluded at hazard-onset and participants predict what happens next. More than 300 participants, across the 3 countries, were divided into experienced and inexperienced-driver groups. The traditional HP test did not discriminate between experienced and inexperienced drivers, though participant nationality influenced the results with UK drivers reporting more hazards than Chinese drivers. The hazard prediction test, however, found experienced drivers to out-perform inexperienced drivers. No differences were found for nationality, with all nationalities being equally skilled at predicting hazards. The results suggest that drivers’ criterion level for responding to hazards is culturally sensitive, though their ability to predict hazards is not. We argue that the more robust, culturally-agnostic, hazard prediction test appears better suited for global export

Induction of endothelial cell apoptosis by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid

5,6-Dimethylxanthenone-4-acetic acid, synthesised in this laboratory, reduces tumour blood flow, both in mice and in patients on Phase I trial. We used TUNEL (TdT-mediated dUTP nick end labelling) assays to investigate whether apoptosis induction was involved in its antivascular effect. 5,6-Dimethylxanthenone-4-acetic acid induced dose-dependent apoptosis in vitro in HECPP murine endothelial cells in the absence of up-regulation of mRNA for tumour necrosis factor. Selective apoptosis of endothelial cells was detected in vivo in sections of Colon 38 tumours in mice within 30 min of administration of 5,6-Dimethylxanthenone-4-acetic acid (25 mg kg−1). TUNEL staining intensified with time and after 3 h, necrosis of adjacent tumour tissue was observed. Apoptosis of central vessels in splenic white pulp was also detected in tumour-bearing mice but not in mice without tumours. Apoptosis was not observed in liver tissue. No apoptosis was observed with the inactive analogue 8-methylxanthenone-4-acetic acid. Positive TUNEL staining of tumour vascular endothelium was evident in one patient in a Phase I clinical trial, from a breast tumour biopsy taken 3 and 24 h after infusion of 5,6-Dimethylxanthenone-4-acetic acid (3.1 mg m−2). Tumour necrosis and the production of tumour tumour necrosis factor were not observed. No apoptotic staining was seen in tumour biopsies taken from two other patients (doses of 3.7 and 4.9 mg m−2). We conclude that 5,6-Dimethylxanthenone-4-acetic acid can induce vascular endothelial cell apoptosis in some murine and human tumours. The action is rapid and appears to be independent of tumour necrosis factor induction

Population-based incidence and 5-year survival for hospital-admitted traumatic brain and spinal cord injury, Western Australia, 2003-2008

This study aimed at analysing first-time hospitalisations for traumatic brain injury (TBI) and spinal cord injury (SCI) in Western Australia (WA), in terms of socio-demographic profile, cause of injury, relative risks and survival, using tabular and regression analyses of linked hospital discharge and mortality census files and comparing results with published standardised mortality rates (SMRs) for TBI. Participants were all 9,114 first hospital admissions for TBI or SCI from 7/2003 to 6/2008, linked to mortality census data through 12/2008, and the main outcome measures were number of cases by cause, SMRs in hospital and post-discharge by year through year 5. Road crashes accounted for 34 % of hospitalised TBI and 52 % of hospitalised SCI. 8,460 live TBI discharges experienced 580 deaths during 24,494 person-years of follow-up. The life-table expectation of deaths in the cohort was 164. Post-discharge SMRs were 7.66 in year 1, 3.86 in year 2 and averaged 2.31 in years 3 through 5. 317 live SCI discharges experienced 18 deaths during 929 years of follow-up. Post-discharge SMRs were 7.36 in year 1 and a fluctuating average of 2.13 in years 2 through 5. Use of data from model systems does not appear to yield biased SMRs. Similarly no systematic variation was observed between all-age studies and the more numerous studies that focused on those aged 14 to 16 and older. Based on two studies, SMRs for TBI, however, may be higher in year 2 post-discharge in Australia than elsewhere. That possibility and its cause warrant exploration. Expanding public TBI/SCI compensation in WA from road crash to all causes might triple TBI compensation and double SCI compensation

Organisational barriers to the facilitation of overseas volunteering and training placements in the NHS

Background Undertaking a period of voluntary work or a professional placement overseas has long been a feature of medical training in the UK. There are now a number of high profile National Health Service (NHS) initiatives aimed at increasing access to such opportunities for staff at all levels. We present findings from a qualitative study involving a range of NHS staff and other stakeholders which explored barriers to participation in these activities. Methods A grounded theory methodology was drawn upon to conduct thematic based analysis. Our data included in-depth, semi-structured interviews with a range of returned volunteers, non-volunteers and other stakeholders (n=51) who were, or had been, employed by the NHS. Results There are significant barriers to placement and volunteering activity stemming from structural and organisational shortcomings within the NHS. Difficulties in filling clinical roles has a significant impact on the ability of staff to plan and undertake independent placements. There is currently no clearly defined pathway within the NHS by which the majority of grades can apply for, or organise, a period of overseas voluntary or professional placement activity. There were divergent views on the relevance and usefulness of overseas professional placements. Conclusions We argue that in the context of current UK policy initiatives aimed at facilitating overseas volunteer and professional placement activity, urgent attention needs to be given to the structural and organisational framework within which such initiatives will be required to work

Do Meio- and Macrobenthic Nematodes Differ in Community Composition and Body Weight Trends with Depth?

Nematodes occur regularly in macrobenthic samples but are rarely identified from them and are thus considered exclusively a part of the meiobenthos. Our study compares the generic composition of nematode communities and their individual body weight trends with water depth in macrobenthic (>250/300 µm) samples from the deep Arctic (Canada Basin), Gulf of Mexico (GOM) and the Bermuda slope with meiobenthic samples (<45 µm) from GOM. The dry weight per individual (µg) of all macrobenthic nematodes combined showed an increasing trend with increasing water depth, while the dry weight per individual of the meiobenthic GOM nematodes showed a trend to decrease with increasing depth. Multivariate analyses showed that the macrobenthic nematode community in the GOM was more similar to the macrobenthic nematodes of the Canada Basin than to the GOM meiobenthic nematodes. In particular, the genera Enoploides, Crenopharynx, Micoletzkyia, Phanodermella were dominant in the macrobenthos and accounted for most of the difference. Relative abundance of non-selective deposit feeders (1B) significantly decreased with depth in macrobenthos but remained dominant in the meiobenthic community. The occurrence of a distinct assemblage of bigger nematodes of high dry weight per individual in the macrobenthos suggests the need to include nematodes in macrobenthic studies

Randomised phase II study of ASA404 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer

ASA404 (5,6-dimethylxanthenone-4-acetic acid or DMXAA) is a small-molecule tumour-vascular disrupting agent (Tumour-VDA). This randomised phase II study evaluated ASA404 plus standard therapy of carboplatin and paclitaxel in patients with histologically confirmed stage IIIb or IV non-small cell lung cancer (NSCLC) not previously treated with chemotherapy. Patients were randomised to receive ⩽6 cycles of carboplatin area under the plasma concentration–time curve 6 mg ml−1 min and paclitaxel 175 mg m−2 (CP, n=36) or standard therapy plus ASA404 1200 mg m−2 (ASA404-CP, n=37). There was little change in the systemic exposure of either total or free carboplatin or paclitaxel on addition of ASA404. Safety profiles were similar and manageable in both groups, with most adverse effects attributed to standard therapy. Tumour response rate (31 vs 22%), median time to tumour progression (5.4 vs 4.4 months) and median survival (14.0 vs 8.8 months, hazard ratio 0.73, 95% CI 0.39, 1.38) were improved in the ASA404 combination group compared with the standard therapy group. In conclusion, this study establishes the feasibility of combining ASA404 with carboplatin and paclitaxel in patients with previously untreated, advanced NSCLC, demonstrating a manageable safety profile and lack of adverse pharmacokinetic interactions. The results indicate that there may be a benefit associated with ASA404, but this needs to be evaluated in a larger trial