Low penetrance susceptibility to glioma is caused by the TP53 variant rs78378222.

BACKGROUND: Most of the heritable risk of glioma is presently unaccounted for by mutations in known genes. In addition to rare inactivating germline mutations in TP53 causing glioma in the context of the Li-Fraumeni syndrome, polymorphic variation in TP53 may also contribute to the risk of developing glioma. METHODS: To comprehensively evaluate the impact of variation in TP53 on risk, we analysed 23 tagSNPs and imputed 2377 unobserved genotypes in four series totaling 4147 glioma cases and 7435 controls. RESULTS: The strongest validated association signal was shown by the imputed single-nucleotide polymorphism (SNP) rs78378222 (P=6.86 × 10(-24), minor allele frequency ~0.013). Confirmatory genotyping confirmed the high quality of the imputation. The association between rs78378222 and risk was seen for both glioblastoma multiforme (GBM) and non-GBM tumours. We comprehensively examined the relationship between rs78378222 and overall survival in two of the case series totaling 1699 individuals. Despite employing statistical tests sensitive to the detection of differences in early survival, no association was shown. CONCLUSION: Our data provided strong validation of rs78378222 as a risk factor for glioma but do not support the tenet that the polymorphism being a clinically useful prognostic marker. Acquired TP53 inactivation is a common feature of glioma. As rs78378222 changes the polyadenylation signal of TP53 leading to impaired 3'-end processing of TP53 mRNA, the SNP has strong plausibility for being directly functional contributing to the aetiological basis of glioma.

Dietary acrylamide intake and risk of breast cancer in the UK women's cohort.

BACKGROUND: No studies to date have demonstrated a clear association with breast cancer risk and dietary exposure to acrylamide. METHODS: A 217-item food frequency questionnaire was used to estimate dietary acrylamide intake in 33,731 women aged 35-69 years from the UK Women's Cohort Study followed up for a median of 11 years. RESULTS: In all, 1084 incident breast cancers occurred during follow-up. There was no evidence of an overall association between acrylamide intake and breast cancer (hazard ratio=1.08 per 10 µg day(-1), 95% CI: 0.98-1.18, P(trend)=0.1). There was a suggestion of a possible weak positive association between dietary acrylamide intake and premenopausal breast cancer after adjustment for potential confounders (hazard ratio=1.2, 95% CI: 1.0-1.3, P(trend)=0.008). There was no suggestion of any association for postmenopausal breast cancer (hazard ratio=1.0, 95% CI: 0.9-1.1, P(trend)=0.99). CONCLUSIONS: There is no evidence of an association between dietary acrylamide intake and breast cancer. A weak association may exist with premenopausal breast cancer, but requires further investigation.

Infectious exposure in the first year of life and risk of central nervous system tumors in children: analysis of day care, social contact, and overcrowding.

Little is known regarding the aetiology of central nervous system tumors in children. Recent studies have speculated on a potential infectious aetiology, but no clear associations have been found. This article uses parent reported questionnaire data from the UK Childhood Cancer Study (UKCCS), a population-based case-control study, to examine the relationship between the infectious exposure in the first year of life and the likelihood of developing a CNS tumor. The variables representing infectious exposure were social contact (including social contact with other infants and attendance at informal and formal day care), sharing a bedroom with another child, birth order, and exposure to a school-age child within the home. Children reported to have had no social contact with other infants in the first year of life displayed an increased risk of developing a CNS tumor when compared to those who had (OR 1.37, 95% CI 1.08-1.75). This effect was most prominent in the primitive neuroectodermal tumor/medulloblastoma subgroup (OR 1.78, 95% CI 1.12-2.83). Those who had attended informal (OR 0.86, 95% CI 0.68-1.09) or formal day care (OR 0.93, 95% CI 0.68-1.26) showed slightly non-statistically significant reduced risks when compared to those reporting social contact only. No association with any of the other variables was observed. Overall, the inconsistent findings by variable and tumor subtype suggest that an early exposure to infections is not strongly implicated in the aetiology of CNS tumors. However, the effect for social contact outside the home, particularly for PNET/medulloblastomas warrants further investigation.

Determinants of mobile phone output power in a multinational study: implications for exposure assessment.

OBJECTIVES: The output power of a mobile phone is directly related to its radiofrequency (RF) electromagnetic field strength, and may theoretically vary substantially in different networks and phone use circumstances due to power control technologies. To improve indices of RF exposure for epidemiological studies, we assessed determinants of mobile phone output power in a multinational study. METHODS: More than 500 volunteers in 12 countries used Global System for Mobile communications software-modified phones (GSM SMPs) for approximately 1 month each. The SMPs recorded date, time, and duration of each call, and the frequency band and output power at fixed sampling intervals throughout each call. Questionnaires provided information on the typical circumstances of an individual's phone use. Linear regression models were used to analyse the influence of possible explanatory variables on the average output power and the percentage call time at maximum power for each call. RESULTS: Measurements of over 60,000 phone calls showed that the average output power was approximately 50% of the maximum, and that output power varied by a factor of up to 2 to 3 between study centres and network operators. Maximum power was used during a considerable proportion of call time (39% on average). Output power decreased with increasing call duration, but showed little variation in relation to reported frequency of use while in a moving vehicle or inside buildings. Higher output powers for rural compared with urban use of the SMP were observed principally in Sweden where the study covered very sparsely populated areas. CONCLUSIONS: Average power levels are substantially higher than the minimum levels theoretically achievable in GSM networks. Exposure indices could be improved by accounting for average power levels of different telecommunications systems. There appears to be little value in gathering information on circumstances of phone use other than use in very sparsely populated regions.

Atopic dysfunction and risk of central nervous system tumours in children.

Risk factors for central nervous system (CNS) tumours in children remain largely unknown. Evidence of an inverse relationship between atopy and tumour development exists in adults but little is known about childhood tumours. This study aims to examine the risk of childhood CNS tumours given a history of eczema and asthma. Cases of children diagnosed with CNS tumours (n=575) and controls (n=6292) from the UK Childhood Cancer Study (UKCCS) were analysed using conditional logistic regression comparing reported histories of allergic disease. Asthma was statistically significantly and negatively associated with all CNS tumours (odds ratios, OR 0.75, confidence of interval, CI(95%): 0.58-0.97), though this was not observed for eczema (OR 0.94, CI(95%): 0.74-1.18). Individuals who had suffered both asthma and eczema showed the most significant reduction in risk (OR 0.48, CI(95%): 0.28-0.81). Analysis by tumour subtype showed the strongest effect for the medulloblastoma/PNET group. These results may have a biological explanation with raised immunosurveillance in atopic individuals protecting against the development of brain tumours. Alternative explanations might include bias, reverse causality or confounding.

An Ssn6-Tup1-dependent negative regulatory element controls sporulation-specific expression of DIT1 and DIT2 in Saccharomyces cerevisiae.

Sporulation of the yeast Saccharomyces cerevisiae is a process of cellular differentiation that occurs in MATa/MAT alpha diploid cells in response to starvation. The sporulation-specific genes DIT1 and DIT2, which are required for spore wall formation, are activated midway through the sporulation program, with maximal transcript accumulation occurring at the time of prospore enclosure. In this study, we have identified a negative regulatory element, termed NREDIT, that is located between the start sites of transcription of these divergently transcribed genes. This element, which prevents expression of the DIT1 and DIT2 genes during vegetative growth, reduces expression of a CYC1-lacZ reporter gene more than 1,000-fold and acts in an orientation- and position-independent manner. We found that the ability of NREDIT to turn of expression of the reporter gene and the chromosomal DIT1 and DIT2 genes in vegetative cells requires the Ssn6-Tup1 repression complex. Interestingly, NREDIT-mediated repression of the reporter gene is maintained during sporulation. Derepression during sporulation requires complex interactions among several cis-acting elements. These are present on an approximately 350-bp DNA fragment extending from NREDIT to the TATA box and an approximately 125-bp fragment spanning the TATA box of DIT1. Additionally, a region of NREDIT which is very similar in sequence to UASSPS4, an element that activates gene expression midway through sporulation, contributes both to vegetative repression and to sporulation-specific induction of DIT1. We propose a model to explain the requirement for multiple elements in overcoming NREDIT-mediated repression during sporulation.

NDT80 and the meiotic recombination checkpoint regulate expression of middle sporulation-specific genes in Saccharomyces cerevisiae.

Distinct classes of sporulation-specific genes are sequentially expressed during the process of spore formation in Saccharomyces cerevisiae. The transition from expression of early meiotic genes to expression of middle sporulation-specific genes occurs at about the time that cells exit from pachytene and form the meiosis I spindle. To identify genes encoding potential regulators of middle sporulation-specific gene expression, we screened for mutants that expressed early meiotic genes but failed to express middle sporulation-specific genes. We identified mutant alleles of RPD3, SIN3, and NDT80 in this screen. Rpd3p, a histone deacetylase, and Sin3p are global modulators of gene expression. Ndt80p promotes entry into the meiotic divisions. We found that entry into the meiotic divisions was not required for activation of middle sporulation genes; these genes were efficiently expressed in a clb1 clb3 clb4 strain, which fails to enter the meiotic divisions due to reduced Clb-dependent activation of Cdc28p kinase. In contrast, middle sporulation genes were not expressed in a dmc1 strain, which fails to enter the meiotic divisions because a defect in meiotic recombination leads to a RAD17-dependent checkpoint arrest. Expression of middle sporulation genes, as well as entry into the meiotic divisions, was restored to a dmc1 strain by mutation of RAD17. Our studies also revealed that NDT80 was a temporally distinct, pre-middle sporulation gene and that its expression was reduced, but not abolished, on mutation of DMC1, RPD3, SIN3, or NDT80 itself. In summary, our data indicate that Ndt80p is required for expression of middle sporulation genes and that the activity of Ndt80p is controlled by the meiotic recombination checkpoint. Thus, middle genes are expressed only on completion of meiotic recombination and subsequent generation of an active form of Ndt80p.

A 15-base-pair element activates the SPS4 gene midway through sporulation in Saccharomyces cerevisiae.

Sporulation of the yeast Saccharomyces cerevisiae represents a simple developmental process in which the events of meiosis and spore wall formation are accompanied by the sequential activation of temporally distinct classes of genes. In this study, we have examined expression of the SPS4 gene, which belongs to a group of genes that is activated midway through sporulation. We mapped the upstream boundary of the regulatory region of SPS4 by monitoring the effect of sequential deletions of 5'-flanking sequence on expression of plasmid-borne versions of SPS4 introduced into a MATa/MAT alpha delta sps4/delta sps4 strain. This analysis indicated that the 5' boundary of the regulatory region was within 50 bp of the putative TATA box of the gene. By testing various oligonucleotides that spanned this boundary and the downstream sequence for their ability to activate expression of a heterologous promoter, we found that a 15-bp sequence sufficed to act as a sporulation-specific upstream activation sequence. This 15-bp fragment, designated UASSPS4, activated expression of a CYC1-lacZ reporter gene midway through sporulation and was equally active in both orientations. Extending the UAS fragment to include the adjacent 14-bp enhanced its activity 10-fold. We show that expression of SPS4 is regulated in a manner distinct from that of early meiotic genes: mutation of UME6 did not lead to vegetative expression of SPS4, and sporulation-specific expression was delayed by mutation of IME2. In vivo and in vitro assays suggested that a factor present in vegetative cells bind to the UASSPS4 element. We speculate that during sporulation this factor is modified to serve as an activator of the SPS4 gene or, alternatively, that it recruits an activator to the promoter.

Assigning exposure to pesticides and solvents from self-reports collected by a computer assisted personal interview and expert assessment of job codes: the UK Adult Brain Tumour Study.

OBJECTIVES: To compare assignment of occupational pesticide and solvent exposure using self-reported data collected by a computer assisted personal interview (CAPI) with exposure based on expert assessment of job codes. To discuss the advantages and disadvantages of using a CAPI to collect individual occupational exposure data. METHODS: Between 2001 and 2004, 1495 participants were interviewed using a CAPI for a case-control study of adult brain tumours and acoustic neuromas. Two types of occupational data were collected: (1) a full history, including job title from which a job code was assigned from the Standard Occupational Classification; and (2) specific details on pesticide and solvent exposure reported by participants. Study members' experiences of using the CAPI were recorded and advantages and disadvantages summarised. RESULTS: Of 7192 jobs recorded, the prevalence of self-reported exposure was 1.3% for pesticides and 11.5% for solvents. Comparing this with exposure expertly assessed from job titles showed 53.6% and 45.8% concordance for pesticides and solvents respectively. Advantages of the CAPI include no data entry stage, automatic input validation, and a reduction in interviewer bias. Disadvantages include an adverse effect on study implementation as a consequence of resources required for programming and difficulties encountered with data management prior to analysis. CONCLUSIONS: Different methods of exposure assessment derive different exposure levels for pesticide and solvent exposure at work. Agreement between self-reported and expert assessment of exposure was greater for pesticides compared to solvents. The advantages of using a CAPI for the collection of complex data outweigh the disadvantages for interviewers and data quality but using such a method requires extra resources at the study outset.

Validation of short term recall of mobile phone use for the Interphone study.

AIM: To validate short term recall of mobile phone use within Interphone, an international collaborative case control study of tumours of the brain, acoustic nerve, and salivary glands related to mobile telephone use. METHODS: Mobile phone use of 672 volunteers in 11 countries was recorded by operators or through the use of software modified phones, and compared to use recalled six months later using the Interphone study questionnaire. Agreement between recalled and actual phone use was analysed using both categorical and continuous measures of number and duration of phone calls. RESULTS: Correlations between recalled and actual phone use were moderate to high (ranging from 0.5 to 0.8 across countries) and of the same order for number and duration of calls. The kappa statistic demonstrated fair to moderate agreement for both number and duration of calls (weighted kappa ranging from 0.20 to 0.60 across countries). On average, subjects underestimated the number of calls per month (geometric mean ratio of recalled to actual = 0.92, 95% CI 0.85 to 0.99), whereas duration of calls was overestimated (geometric mean ratio = 1.42, 95% CI 1.29 to 1.56). The ratio of recalled to actual use increased with level of use, showing underestimation in light users and overestimation in heavy users. There was substantial heterogeneity in this ratio between countries. Inter-individual variation was also large, and increased with level of use. CONCLUSIONS: Volunteer subjects recalled their recent phone use with moderate systematic error and substantial random error. This large random error can be expected to reduce the power of the Interphone study to detect an increase in risk of brain, acoustic nerve, and parotid gland tumours with increasing mobile phone use, if one exists.

Protective effect of liposome-associated alpha-tocopherol against paraquat-induced acute lung toxicity.

The present study was undertaken to investigate whether alpha-tocopherol, entrapped in liposomes and delivered directly to the lung, could protect against paraquat-induced lung damage in the rat. Plain liposomes (composed of dipalmitoylphosphatidylcholine, DPPC) or DPPC/alpha-tocopherol liposomes were administered intratracheally to animals 24 hr prior to an intraperitoneal injection of paraquat (20 mg/kg); rats were killed 24 or 48 hr after paraquat treatment. Results of this study showed that lungs of animals treated with paraquat were damaged extensively as evidenced by an increase in lung weight and a significant reduction in lung angiotensin-converting enzyme (ACE) activity and cytochrome P450 concentration. Furthermore, paraquat treatment resulted in a significant decrease in reduced glutathione (GSH) concentrations and a marked elevation in microsomal lipid peroxidation levels as measured by the formation of diene conjugates. Pretreatment of rats with DPPC liposomes alone did not alter significantly the paraquat-induced changes of all parameters examined. On the other hand, pretreatment of rats with DPPC/alpha-tocopherol liposomes 24 hr prior to paraquat challenge resulted in a significant increase in pulmonary alpha-tocopherol concentrations and antagonized paraquat-induced changes in lipid peroxidation, GSH/GSSG ratio, lung ACE activity and cytochrome P450 concentrations. Results of this study suggested that alpha-tocopherol, delivered directly to the lung in a liposomal formulation 24 hr prior to paraquat administration, confers protection against paraquat-induced lung damage.

Dynamics of polymerization in polyacrylamide gel (PAG) dosimeters: (II) modeling oxygen diffusion.

Oxygen contamination of a polyacrylamide gel (PAG) dosimeter can have a significant detrimental effect upon the performance characteristics of the gel as a dosimeter. Oxygen contamination can occur during preparation, but can also arise from the diffusion of atmospheric oxygen through vessel walls. Even 'trace' amounts of oxygen present in any gaseous space (usually nitrogen filled) between the surface of the PAG and the vessel seal can have a detectable effect. This paper describes a method used to quantify the detrimental effects of a range of oxygen concentrations upon the performance of the PAG. The results of diffusion studies for air and pure oxygen diffusing into the PAG over time are presented and coupled with a novel method of calculating oxygen concentrations in the PAG. Results obtained suggest that the diffusion is Fickian. The coefficient of diffusion D has been calculated to be (8+/-2) x 10(-6) cm2 s(-1) for oxygen diffusing into PAG stored at 4 degrees C, under the assumption that the diffusion mechanism is independent of the concentration of the diffusing species. In addition, a quantitative relation has been established between the transverse relaxation rate R2 of the PAG and the concentration of oxygen present. The implications of these findings for polymer gel dosimetry are discussed.

Pulmonary uptake of liposome-associated alpha-tocopherol following intratracheal instillation in rats.

This study examined the uptake and subcellular distribution of alpha-tocopherol in the lung following intratracheal instillation of liposome-associated alpha-tocopherol in rats. The liposomal suspension was composed of dipalmitoylphosphatidylcholine (DPPC) and alpha-tocopherol (molar ratio 7:3), labelled with [3H]alpha-tocopherol and [14C]cholesterol. Following intratracheal administration of the liposomal preparation (2 mg alpha-tocopherol/animal), the recovery of [3H]alpha-tocopherol in the lung was maximal (87% of initial dose) 1 h after treatment; thereafter, alpha-tocopherol levels remained relatively high (no less than 73% of initial dose) for the rest of the 72-h experimental period. This treatment effect/resulted in a 16-fold increase in pulmonary total alpha-tocopherol concentration 72 h post-instillation. No radioactivity was detected in the blood, liver, kidney, pancreas, spleen and heart of animals during the 72-h experimental period. [3H]alpha-Tocopherol was recovered largely from cytosolic (45%) and nuclear (36%) fractions of lung and to a lesser extent, from microsomal (11%) and mitochondrial (9%) fractions. Chromatographic analysis of the subcellular fractions revealed that [3H]alpha-tocopherol was co-eluted with 14C-labelled liposomal lipids. Our in-vitro study, involving the incubation of Fe(3+)-ADP (a pro-oxidant) with mitochondrial or microsomal fractions isolated from lung tissues of animals treated with liposome-associated alpha-tocopherol, provided evidence that alpha-tocopherol levels present in the membranes of these subcellular fractions were sufficient to protect against oxidant-induced lipid peroxidation.(ABSTRACT TRUNCATED AT 250 WORDS)

Visual integration difficulties in a 9-year-old girl with Turner syndrome: parallel verbal disabilities?

Turner syndrome (TS) is a genetic disorder in females that arises from the loss of X chromosome material. Affected individuals demonstrate a characteristic neuropsychological profile of strengths in verbal processing and weaknesses in visuospatial processing, consistent with the Nonverbal Learning Disabilities syndrome. Previous research has described a wide range of visuospatial deficits in TS; however, their verbal abilities are less extensively studied. The present paper describes the processing difficulties of a 9-year-old girl with TS who demonstrated problems in integrating details of a complex visual display and using organizational terms to describe visual scenes or events. Her specific cognitive disabilities were thought to underlie some of the social and behavioral problems she was currently experiencing. Her pattern of results is consonant with the neuropsychological pattern that others have attributed to right hemisphere dysfunction and/or white matter abnormality.

Vestibular schwannoma in an only hearing ear.

A vestibular schwannoma in an only hearing ear is a difficult management problem. A case is presented of a patient who had a Nucleus-22 channel device implanted into a nonfunctioning ear and auditory rehabilitation prior to resection of a large vestibular schwannoma in the contralateral ear.

Recall of past use of mobile phone handsets.

Previous studies investigating health effects of mobile phones have based their estimation of exposure on self-reported levels of phone use. This UK validation study assesses the accuracy of reported voice calls made from mobile handsets. Data collected by postal questionnaire from 93 volunteers was compared to records obtained prospectively over 6 months from four network operators. Agreement was measured for outgoing calls using the kappa statistic, log-linear modelling, Spearman correlation coefficient and graphical methods. Agreement for number of calls gained moderate classification (kappa = 0.39) with better agreement for duration (kappa = 0.50). Log-linear modelling produced similar results. The Spearman correlation coefficient was 0.48 for number of calls and 0.60 for duration. Graphical agreement methods demonstrated patterns of over-reporting call numbers (by a factor of 1.7) and duration (by a factor of 2.8). These results suggest that self-reported mobile phone use may not fully represent patterns of actual use. This has implications for calculating exposures from questionnaire data.

The assessment of student nurses.

This paper starts from the personal view that there are a number of issues related to the process of assessment which require investigation. It is suggested that a model of the assessment process might help clarify the present situation. The Brunswik lens model is explained and then expanded and adapted to facilitate its application to the assessment of student nurses in the clinical environment. Finally an 'armchair' evaluation of the model is undertaken with suggestions being offered for future investigation strategies.

Professional judgement and nurse education.

This paper discusses some issues related to the difficulties faced by the professionals who are required to assess a student nurse's competence to practice.

Deoxynivalenol exposure assessment in a cohort of pregnant women from Bradford, UK.

Deoxynivalenol (DON) is a ubiquitous contaminant of cereal crops in temperate regions of the world. It causes growth faltering and immune suppression in animals. Limited information is available on DON exposure in UK subpopulations. The objective of this study was to provide DON exposure assessment in a subset of pregnant women scheduled for an elective caesarean in a large multi-ethnic mother/infant birth cohort from Bradford, UK. Women aged 16-44 years (n = 85) provided a urine sample for DON analysis in the last trimester of pregnancy, and concurrently completed a food-frequency questionnaire (FFQ). The urinary DON biomarker was detected in all measured samples (geometric mean (GM) = 10.3 ng DON mg(-1) creatinine, range = 0.5-116.7 ng mg(-1)). Levels were higher in women classified as South Asian in origin (GM: 15.2 ng mg(-1); 95% CI = 10.7-21.5 ng mg(-1)) compared with non-South Asians (GM = 8.6 ng mg(-1); 95% CI = 6.6-11.8 ng mg(-1)), p = 0.02). Estimated DON intake from FFQ data and typical levels of DON contamination of food suggest that this was mainly due to higher levels of exposure from bread, particularly daily intake of DON from chapattis in South Asians (estimated mean = 2.4 µg day(-1); 95% CI = 1.2, 3.7 µg day(-1)) compared with non-South Asians (estimated mean = 0.2 µg day(-1); 95% CI = 0-0.4 µg day(-1)), p < 0.001. This is the first biomarker demonstration of DON exposure in pregnant women, and several urinary DON levels were the highest ever recorded in any study. A larger survey within this birth cohort is warranted to investigate any potential risk to mothers and their babies, from DON exposure during pregnancy.