RTT-led IGRT for cervix cancer; training, implementation and validation.

INTRODUCTION: IGRT in cervical cancer treatment delivery is complex due to significant target and organs at risk (OAR) motion. Implementing image assessment of soft-tissue target and OAR position to improve accuracy is recommended. We report the development and refinement of a training and competency programme (TCP), leading to on-line Radiation Therapist (RTT) led soft-tissue assessment, evaluated by a prospective audit. METHODS AND MATERIALS: The TCP comprised didactic lectures and practical sessions, supported by a comprehensive workbook. The content was decided by a team comprised of Clinical Oncologists, RTTs, and Physicists. On completion of training, RTT soft-tissue review proficiency (after bony anatomy registration) was assessed against a clinician gold-standard from a database of 20 cervical cancer CBCT images. Reviews were graded pass or fail based on PTV coverage assessment and decision taken in concordance with the gold-standard. Parity was set at ≥80% agreement.The initial TCP (stage one) focussed on offline verification and decision making. Sixteen RTTs completed this stage, four achieved ≥80%. This was not sufficient to support clinical implementation.The TCP was redesigned, more stringent review guidelines and greater anatomy teaching was added. TCP stage two focussed on online verification and decision making supported by a decision flowchart. Twenty-one RTTs completed this TCP, all achieved ≥80%. This supported clinical implementation of RTT-led soft-tissue review under prospective audit conditions.The prospective audit was conducted between March 2017 and August 2017. Daily online review was performed by two trained RTTs. Online review and decision making proficiency was evaluated by a clinician. RESULTS: Thirteen patients were included in the audit. Daily online RTT-led IGRT was achieved for all 343 fractions. Two-hundred CBCT images were reviewed offline by the clinician; the mean number of reviews per patient was 15. 192/200 (96%) RTT image reviews were in agreement with clinician review, presenting excellent concordance. DISCUSSION AND CONCLUSION: Multidisciplinary involvement in training development, redesign of the TCP and inclusion of summative competency assessment were important factors to support RTT skill development. Consequently, RTT-led cervical cancer soft-tissue IGRT was clinically implemented in the hospital.

Physical activity guidelines and cardiovascular risk in children: a cross sectional analysis to determine whether 60 minutes is enough.

BACKGROUND: Physical activity reduces cardiovascular mortality and morbidity. The World Health Organisation (WHO) recommends children engage in 60 min daily moderate-to-vigorous physical activity (MVPA). The effect of compliance with this recommendation on childhood cardiovascular risk has not been empirically tested. To evaluate whether achieving recommendations results in reduced composite-cardiovascular risk score (CCVR) in children, and to examine if vigorous PA (VPA) has independent risk-reduction effects. METHODS: PA was measured using accelerometry in 182 children (9-11 years). Subjects were grouped according to achievement of 60 min daily MVPA (active) or not (inactive). CCVR was calculated (sum of z-scores: DXA body fat %, blood pressure, VO2peak, flow mediated dilation, left ventricular diastolic function; CVR score ≥ 1SD indicated 'higher risk'). The cohort was further split into quintiles for VPA and odds ratios (OR) calculated for each quintile. RESULTS: Active children (92 (53 boys)) undertook more MVPA (38 ± 11 min, P < 0.001), had greater VO2peak (4.5 ± 0.8 ml/kg/min P < 0.001), and lower fat % (3.9 ± 1.1 %, P < 0.001) than inactive. No difference were observed between active and inactive for CCVR or OR (P > 0.05). CCVR in the lowest VPA quintile was significantly greater than the highest quintile (3.9 ± 0.6, P < 0.05), and the OR was 4.7 times higher. CONCLUSION: Achievement of current guidelines has positive effects on body composition and cardiorespiratory fitness, but not CCVR. Vigorous physical activity appears to have beneficial effects on CVD risk, independent of moderate PA, implying a more prescriptive approach may be needed for future VPA guidelines.

Assessment of biochemical liver markers, physical activity, fitness and body mass index for a cardiometabolic risk model in childhood.

AIM: The aim of this study was to investigate clustered cardiometabolic risk scores in healthy 10- to 12-year-olds using anthropometric characteristics, measurements of cardiorespiratory fitness (CRF) and physical activity and blood markers of metabolic disease. We also evaluated how including markers of liver cell injury would affect the clustered cardiometabolic risk assessment model. METHODS: This cross-sectional study focused on 99 children aged 10-12 years. The main outcome included assessing participants with increased and low cardiometabolic risk factors using a clustered risk score model that incorporated markers implicated in metabolic syndrome pathogenesis. Two clustered risk scores were calculated, one incorporating markers of liver cell injury. RESULTS: Children classified as 'increased risk' exhibited significantly lower CRF and higher body mass index Z-scores than their 'low-risk' peers. No significant differences in physical activity were observed. This trend remained unchanged when markers of liver injury were included in the clustered risk assessment model. CONCLUSION: The clustered risk score model is a scientifically robust method of cardiometabolic risk assessment, which reiterates the importance of weight reduction and CRF promotion in childhood. Our study did not show a significant contribution of liver injury markers, and further research is needed to evaluate their effect on cardiometabolic risk stratification in childhood.

Effects of 6 months glucagon-like peptide-1 receptor agonist treatment on endothelial function in type 2 diabetes mellitus patients.

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are used for treatment in type 2 diabetes mellitus (T2DM). Little is known about their cardiovascular (CV) impact. We sought to determine the effects of chronic treatment on vascular function in T2DM. Brachial artery endothelial-dependent flow-mediated dilation (FMD) and endothelial-independent glyceryl trinitrate (GTN) function and carotid intima-medial thickness (cIMT) were assessed in 11 severely obese T2DMs (4 females, 7 males: 55 ± 8 years, diabetes duration 8.3 ± 4.7 years mean ± s.d.) before and after 6 months GLP-1 RA. Body weight (5.3 ± 1.2 kg; p < 0.05) and magnetic resonance imaging determined total and subcutaneous fat, but not visceral fat, decreased. Glycaemic control improved. There were no significant changes in FMD, GTN and cIMT (-1.1 ± 0.4%, 0.3 ± 3.0% and 0.00 ± 0.04 mm, respectively). Despite significant improvements in body composition and glycaemic control, 6 months GLP-1 RA treatment did not modulate vascular function. Alternative strategies may therefore be needed to reduce the burden of CV risk in severely obese patients with long-standing T2DM.

Impact of exercise training on endothelial function and body composition in young people: a study of mono- and di-zygotic twins.

Flow mediated dilation (FMD) is a surrogate marker of arterial function which can be improved by exercise training. To date, no study has assessed the magnitude of FMD changes in response to exercise training between groups of mono- (MZ) and di-zygotic (DZ) twins. The purpose of this study was therefore to compare FMD in MZ- and DZ twins before and after identical exercise training interventions. At baseline, FMD was assessed using high resolution Duplex ultrasound in 12 twin pairs (6 MZ pairs 13.5 ± 0.8 years, 6 DZ pairs 13.4 ± 0.8 years). Twins completed 8 weeks of exercise training (65-85% HR(max)), consisting of three 45-min sessions per week. Change (Δ) scores were entered into twin versus twin intraclass correlation analyses by group. Change in %body fat (r = 0.63, P = 0.05) was significantly correlated in the MZ, but not the DZ group (r = 0.31, P = 0.23). Change in FMD was also highly correlated in MZ (r = 0.74, P = 0.02) but not in the DZ group (r = 0.37, P = 0.18). Heritability of ΔFMD was estimated at 0.74. Exercise induced changes in FMD were similar within sets of monozygotic twins but not dizygotic twins. These data suggest that a significant portion of the arterial function response to exercise training may be genetically determined.

Randomised controlled trial of thermostatic mixer valves in reducing bath hot tap water temperature in families with young children in social housing.

OBJECTIVES: To assess the effectiveness of thermostatic mixing valves (TMVs) in reducing bath hot tap water temperature, assess acceptability of TMVs to families and impact on bath time safety practices. DESIGN: Pragmatic parallel arm randomised controlled trial. SETTING: A social housing organisation in Glasgow, Scotland, UK. PARTICIPANTS: 124 families with at least one child under 5 years. INTERVENTION: A TMV fitted by a qualified plumber and educational leaflets before and at the time of TMV fitting. MAIN OUTCOME MEASURES: Bath hot tap water temperature at 3-month and 12-month post-intervention or randomisation, acceptability, problems with TMVs and bath time safety practices. RESULTS: Intervention arm families had a significantly lower bath hot water temperature at 3-month and 12-month follow-up than families in the control arm (3 months: intervention arm median 45.0°C, control arm median 56.0°C, difference between medians, -11.0, 95% CI -14.3 to -7.7); 12 months: intervention arm median 46.0°C, control arm median 55.0°C, difference between medians -9.0, 95% CI -11.8 to -6.2) They were significantly more likely to be happy or very happy with their bath hot water temperature (RR 1.43, 95% CI 1.05 to 1.93), significantly less likely to report the temperature as being too hot (RR 0.33, 95% CI 0.16 to 0.68) and significantly less likely to report checking the temperature of every bath (RR 0.84, 95% CI 0.73 to 0.97). Seven (15%) intervention arm families reported problems with their TMV. CONCLUSIONS: TMVs and accompanying educational leaflets are effective at reducing bath hot tap water temperatures in the short and longer term and are acceptable to families. Housing providers should consider fitting TMVs in their properties and legislators should consider mandating their use in refurbishments as well as in new builds.

The impact of exercise training on the diameter dilator response to forearm ischaemia in healthy men.

AIM: Recent studies found differences between groups in the rate of diameter increase following the flow-mediated dilation (FMD). Whilst exercise training alters the magnitude of the FMD, little is known about the impact of exercise training on the rate of diameter increase. The aim of this study is to examine post-cuff deflation changes in brachial artery diameter following 5 min forearm ischaemia every 2 weeks across 8-weeks of a handgrip exercise training regimen. METHODS: Post-deflation changes in brachial artery diameter following 5-min of ischaemia were examined before, after and every 2-weeks across an 8-week handgrip training programme in healthy young men (n = 11) using echo-Doppler. RESULTS: The magnitude of dilation increased at week 2-4-6, but returned towards baseline values at week 8 (anova: P = 8.001). The time-to-peak diameter (42 ± 15s) demonstrated a significant prolongation at week 4 (77 ± 32s), but returned towards baseline values at weeks 6 and 8 (anova: P < 0.001). The rate of diameter increase did not differ across the intervention. CONCLUSION: Exercise training in healthy subjects is initially characterized by a larger dilation. Since the rate of dilation did not change, a longer time-to-peak dilation was necessary to achieve the increase in magnitude of dilation. As exercise training continues, the timing and magnitude of the peak diameter response returns to near baseline levels.

Duplex scanning is no substitute for surgical expertise in identifying the saphenopopliteal junction: results following short saphenous vein surgery.

OBJECTIVES: Short saphenous vein (SSV) surgery carries a high risk of failure to identify the saphenopopliteal junction (SPJ). We assessed the impact of surgical expertise on anatomical outcome from SSV surgery and the role of preoperative duplex SPJ marking in improving outcome for vascular and non-vascular specialists. METHODS: A retrospective analysis identified patients (30 limbs) who had undergone SSV surgery. These were recalled for duplex scanning of the SPJ. In a prospective study, 187 limbs had preoperative duplex marking of SPJ and postoperative duplex to assess outcome. Grade of operating surgeon was recorded in both retrospective and prospective analysis. RESULTS: In both retrospective and prospective analysis, vascular specialists were significantly more likely than non-vascular specialists to correctly identify the SPJ (P < 0.0001). Preoperative SPJ marking did not improve outcome for the vascular specialist or the non-vascular specialist. CONCLUSION: Preoperative SPJ marking is no substitute for surgical expertise. Competence in SSV surgery should be assessed prior to surgeons proceeding to independent practice.

Does brachial artery flow-mediated dilation scale to anthropometric characteristics?

Flow-mediated dilation (FMD) assesses the health of the vascular endothelium. Despite widespread adoption of scaling practices in cardiac research, scaling for body size or composition has not been used for FMD. The present study investigated the relationships between brachial FMD and body composition in 129 children aged 9-10 (75 female symbol, 54 male symbol), and 50 men aged 16-49. Body composition variables (total, lean, fat mass in the whole body, arm, forearm) were assessed by dual-energy X-ray absorptiometry, FMD was measured in the brachial artery using high-resolution ultrasound. FMD was scaled using simple ratios (y/x) and allometric approaches (y/x ( b )) after log-log least squares linear regression produced allometric exponents (b). Size independence was confirmed via bivariate correlations (x:y/x; x:y/x ( b )). No relationships were evident between FMD and body composition variables in adults. Small correlations existed between FMD and measures of segmental fat mass in children (r = -0.18 to -0.19, p < 0.05), there were no significant relationships between FMD and measures of lean or total mass in children. For all significant relationships, b-exponents were different from 1 (CIs -0.36 to 0.07), suggesting ratio scaling approaches were flawed. This was confirmed when ratio scaling produced negative residual size correlations, whereas allometric scaling produced size-independent indices. Correlations between FMD and body composition were weak in children and insignificant in adults. As the results of this study are limited to the populations examined, our findings do not support the adoption of scaling procedures to correct FMD.

Does conduit artery diameter vary according to the anthropometric characteristics of children or men?

Arterial measurements are commonly undertaken to assess acute and chronic adaptations to exercise. Despite the widespread adoption of scaling practices in cardiac research, the relevance of scaling for body size and/or composition has not been addressed for arterial measures. We therefore investigated the relationships between brachial artery diameter and body composition in 129 children aged 9 to 10 yr (75 girls and 54 boys), and 50 men aged 16-49 yr. Body composition variables (total, lean, and fat mass in the whole body, arm, and forearm) were assessed by dual-energy X-ray absorptiometry, and brachial artery diameter was measured using high-resolution ultrasound. Bivariate correlations were performed, and arterial diameter was then scaled using simple ratios (y/x) and allometric approaches after log-log least squares linear regression and production of allometric exponents (b) and construction of power function ratios (y/xb). Size independence was checked via bivariate correlations (x:y/x; x:y/xb). As a result, significant correlations existed between brachial artery diameter and measures of body mass and lean mass in both cohorts (r=0.21-0.48, P<0.05). There were no significant relationships between diameter and fat mass. All b exponents were significantly different from 1 (0.08-0.50), suggesting that simple ratio scaling approaches were likely to be flawed. This was confirmed when ratio scaling produced negative residual size correlations, whereas allometric scaling produced size-independent indexes (r=0.00 to 0.03, P>0.05). In conclusion, when between- or within-group comparisons are performed under circumstances where it is important to control for differences in body size or composition, allometric scaling of artery diameter should be adopted rather than ratio scaling. Our data also suggest that scaling for lean or total mass may be more appropriate than scaling for indexes of fat mass.

Relationships between measures of fitness, physical activity, body composition and vascular function in children.

BACKGROUND: The prevalence of obesity and physical inactivity in Western countries has increased rapidly. Both are modifiable risk factors for cardiovascular disease. Atherosclerosis begins in childhood and endothelial dysfunction is its earliest detectable manifestation. METHODS: We assessed flow-mediated dilation (FMD) in 129 children (75 female; 10.3+0.3 yrs; 54 male; 10.4; 0.3 yrs). FMD was normalised for differences in the eliciting shear rate stimulus between subjects (SR(AUC)). Fitness was assessed as peak oxygen uptake during an incremental treadmill exercise test (V O(2)peak). Body composition was measured using a dual-energy X-ray absorptiometry (DEXA) scan. Physical activity (PA) was assessed using Actigraph accelerometers. The cohort was split into tertiles according to FMD% and also FMD% corrected for SR(AUC) to gain insight into the determinants of vascular function. RESULTS: Across the cohort, significant correlations were observed between FMD%/SR(AUC) and DEXA percentage fat (r=-0.23, p=0.009) and percentage lean mass (r=0.21, p=0.008), and also with PA performed at moderate-to-high intensity (r=0.363, p=0.001). For children in the lowest FMD%/SR(AUC) tertile, a stronger relationship with all PA measures was observed, particularly with high intensity PA (r=0.572, P=0.003). Regression analysis revealed that high intensity PA was the only predictor of impaired FMD%/SR(AUC). CONCLUSIONS: These data suggest that traditional risk factors for CHD in adult populations impact upon vascular function in young people. Furthermore, it appears that individuals with impaired FMD may benefit from performing high intensity PA, whereas no relationships exist between FMD and lower intensities of PA or between PA and FMD in those subjects who possess preserved vascular function a priori.

Anti-inflammatory effect of augmented nitric oxide production in chronic lung infection.

Chronic infection of the lungs with Pseudomonas aeruginosa complicates many long-term lung diseases including cystic fibrosis, bronchiectasis, chronic obstructive lung disease, and mechanical ventilation. In acute inflammatory lung diseases, increased nitric oxide synthase (NOS-2) expression leads to excess nitric oxide (NO) production, resulting in the production of reactive nitrogen intermediates, which contribute to tissue damage. In contrast, the contribution of NO to pulmonary damage in chronic Pseudomonas infection of the lung has not been directly examined and is unclear. Although NOS-2 expression is increased in this condition, NO production is not abnormally elevated. It was hypothesized that chronic infection of the airways does not cause increased NO production but, in contrast, leads to inappropriately low NO concentrations that are pro-inflammatory. A rodent model of chronic airway infection was used to examine the effects on lung damage of augmenting or inhibiting NO production after airway infection with P. aeruginosa was well established. Three days post-infection, L-arginine, which augments NO production, or L-NAME, an inhibitor of NO production, was administered in drinking water. Lung damage was assessed 12 days later. L-arginine treatment reduced tissue damage, inhibited neutrophil recruitment, and reduced the pro-inflammatory cytokine interleukin (IL)-1beta. Treatment with L-NAME caused loss of alveolar walls, greater vascular damage, and increased levels of the pro-inflammatory cytokine IL-6. Thus, in chronic airway infection, inhibition of NO production worsened lung damage, whereas augmenting NO ameliorated this damage. This is the first demonstration that augmenting endogenous NO production in chronic infective lung disease caused by P. aeruginosa is anti-inflammatory. Given that infection with this organism complicates many chronic lung diseases, most notoriously cystic fibrosis, these findings have important clinical implications.

Discrimination between ricin and sulphur mustard toxicity in vitro using Raman spectroscopy.

A Raman spectroscopy cell-based biosensor has been proposed for rapid detection of toxic agents, identification of the type of toxin and prediction of the concentration used. This technology allows the monitoring of the biochemical properties of living cells over long periods of time by measuring the Raman spectra of the cells non-invasively, rapidly and without use of labels (Notingher et al. 2004 doi:10.1016/j.bios.2004.04.008). Here we show that this technology can be used to distinguish between changes induced in A549 lung cells by the toxin ricin and the chemical warfare agent sulphur mustard. A multivariate model based on principal component analysis (PCA) and linear discriminant analysis (LDA) was used for the analysis of the Raman spectra of the cells. The leave-one-out cross-validation of the PCA-LDA model showed that the damaged cells can be detected with high sensitivity (98.9%) and high specificity (87.7%). High accuracy in identifying the toxic agent was also found: 88.6% for sulphur mustard and 71.4% for ricin. The prediction errors were observed mostly for the ricin treated cells and the cells exposed to the lower concentration of sulphur mustard, as they induced similar biochemical changes, as indicated by cytotoxicity assays. The concentrations of sulphur mustard used were also identified with high accuracy: 93% for 200 microM and 500 microM, and 100% for 1,000 microM. Thus, biological Raman microspectroscopy and PCA-LDA analysis not only distinguishes between viable and damaged cells, but can also discriminate between toxic challenges based on the cellular biochemical and structural changes induced by these agents and the eventual mode of cell death.

Medullary thyroid carcinoma: a rare presentation as a hypervascular tumour.

Sporadic medullary thyroid carcinoma (MTC) usually presents with a thyroid mass, cervical lymphadenopathy or other local cervical symptoms. Often the diagnosis is unsuspected pre-operatively. We report a unique case of a mixed follicular medullary thyroid carcinoma presenting as a tumour with extreme vascularity. The management of hypervascular thyroid tumours is discussed together with current controversies regarding persistent hypercalcitoninaemia.

Age and sex effects on the pharmacokinetics of linezolid.

OBJECTIVE: To evaluate the possible effects of age and sex on the pharmacokinetics of linezolid in healthy volunteers. METHODS: A single 600-mg dose of linezolid was administered orally to young (18-40 years) and elderly (> or =65 years) healthy males and females. Blood and urine samples were collected until 48 h after dosing and assayed for linezolid concentrations using a validated high-performance liquid chromatography method. Pharmacokinetic parameters were assessed using noncompartmental methods. Comparisons of the pharmacokinetic parameters for each age and sex group were performed using a two-way analysis of variance model. Pairwise comparisons were done using least-square means analysis. RESULTS: Peak plasma drug concentrations occurred within 1.5 h after linezolid administration for males and females in both age groups. However, the maximum concentration achieved differed significantly between males and females. There was no significant difference between males and females or young and elderly for mean apparent elimination rate constant or half-life. There was no difference in mean apparent oral clearance (CLPO) between the young and elderly; however, there was a significant difference between males and females. Mean CLPO for females was approximately 37% less than mean CLPO for males when not corrected for body weight. Correcting for differences in weight reduced this difference to approximately 20%. Overall, females had a slightly lower volume of distribution than males, but this was not affected by the age of subjects. CONCLUSIONS: A dose adjustment based on age and sex is not warranted due to the wide range of linezolid concentrations that are well tolerated and the relative small difference in linezolid disposition between males and females.

vhnf1, the MODY5 and familial GCKD-associated gene, regulates regional specification of the zebrafish gut, pronephros, and hindbrain.

Mutations in the homeobox gene vHnf1 are associated with human diseases MODY5 (maturity-onset diabetes of the young, type V) and familial GCKD (glomerulocystic kidney disease). In an insertional mutagenesis screen in zebrafish, we isolated mutant alleles of vhnf1. Phenotypes of these mutants include formation of kidney cysts, underdevelopment of the pancreas and the liver, and reduction in size of the otic vesicles. We show that these abnormalities arise from patterning defects during development. We further provide evidence that vhnf1 regulates the expression of key patterning genes for these organs. vhnf1 is required for the proper expression of pdx1 and shh (sonic hedgehog) in the gut endoderm, pax2 and wt1 in the pronephric primordial, and valentino (val) in the hindbrain. Complementary to the loss-of-function phenotypes, overexpression of vhnf1 induces expansion of the val expression domain in the hindbrain. We propose that vhnf1 controls development of multiple organs through regulating regional specification of organ primordia. The similarity between vhnf1-associated fish phenotypes and human symptoms suggests a correlation between developmental functions of vhnf1 and the molecular etiology of MODY5 and GCKD.

Linezolid absolute bioavailability and the effect of food on oral bioavailability.

Linezolid is a novel oxazolidinone antibiotic that has a spectrum of activity encompassing a variety of Gram-positive bacteria. The objectives of this study were twofold: (1) to compare the absorption of linezolid tablets given immediately following a high-fat meal with the absorption of tablets administered while fasting, and (2) to assess the bioavailability of a 375-mg oral dose given while fasting relative to a 375-mg dose of linezolid sterile solution given intravenously. Venous blood samples were taken over the 48 h following the single dose administration of both the oral and intravenous (IV) treatment. Samples were subsequently frozen for the determination of linezolid concentrations by HPLC. The only statistically significant difference between the fasted and the fed treatment was in peak plasma concentration, with the mean C(max) for fasted subjects being 23% greater than that for subjects after consumption of a high-fat meal. Comparable AUC(0-infinity) values were measured under both conditions, indicating that the overall extent of absorption is the same. Therefore, the difference in C(max), while statistically significant, should not affect the therapeutic efficacy of linezolid when it is administered with food. There were no statistically significant differences in AUC(0-infinity), CL or half-life between the fasted oral treatment and the intravenous treatment. As expected, C(max) was statistically different between the two treatments. However, the mean absolute bioavailability (F) of the tablet, using the IV sterile solution as the reference treatment, was 103% (+/-20%).

Methylation of the FSHD syndrome-linked subtelomeric repeat in normal and FSHD cell cultures and tissues.

Facioscapulohumeral muscular dystrophy (FSHD) has an unusual molecular etiology. In a putatively heterochromatic subtelomeric region of each chromosome 4 homologue (4q35), unaffected individuals have 11 to about 95 tandem copies of a complex 3.3-kb repeat (D4Z4). Most FSHD patients have less than 10 copies at one allelic 4q35. This has been proposed to lead to the loss of heterochromatinization and, thereby, inappropriate gene expression by position effects, explaining the dominant nature of FSHD and the role of a decreased number of copies of D4Z4 at 4q35 but not at 10q26. Consistent with the proposed heterochromatinization of this repeat, by Southern blot analysis, we found that SmaI, MluI, SacII, and EagI sites in D4Z4 are highly methylated in normal and FSHD cell lines and somatic tissues, including skeletal muscle. Like repeated DNA sequences in the juxtacentromeric heterochromatin of chromosomes 1, 9, and 16, D4Z4 was hypomethylated at numerous CpGs in sperm and in cell lines from patients with an unrelated DNA methyltransferase deficiency syndrome (ICF; immunodeficiency, centromeric region instability, facial anomalies) in contrast to its hypermethylation in non-ICF postnatal somatic tissues. Our data on FSHD samples suggest that the disease-associated 4q35 D4Z4 repeats, which constitute a small percentage of the total D4Z4 repeats, are not generally hypomethylated relative to the other repeats of this sequence. However, in individuals not affected with FSHD, the hypermethylation of tandem, high-copy-number D4Z4 repeats might help stabilize heterochromatinization at allelic 4q35 regions just as hypermethylation elsewhere in the genome has been linked to chromatin compaction.

Group variability judgments: investigating the context-dependence of stereotypicality and dispersal judgments.

This study explores the context-dependent nature of perceptions of group variability by examining how ingroup and outgroup ratings are affected by asking participants (N = 237) to rate these groups either on their own or together. In key respects, it replicates the design utilized by Haslam, Oakes, Turner, and McGarty (1995). However, several features of the present study's design were distinctive and intended to address methodological issues raised in the original. First, an alternative to the Katz-Braly procedure was adopted such that the measure of 'stereotypicality' referred to the applicability of both stereotypic and counter-stereotypic attributes. Second, a measure of 'dispersion' was also employed. The data show that ingroup stereotypicality was, as predicted, affected by a manipulation of context, while outgroup stereotypicality was not. No effects of context on the dispersion measures were obtained for either the ratings of the ingroup or the outgroup. The relationship between stereotypicality and dispersal measures of variability is discussed.

Regulation of phenobarbital-mediated induction of CYP102 (cytochrome P450(BM-3)) in Bacillus megaterium by phytochemicals from soy and green tea.

Cytochrome P450 102 (CYP102 or Cytochrome P450(BM)(-)(3)) is induced in Bacillus megaterium by barbiturates, perioxisome proliferators, estrogen, and nonsteroidal antiinflammatory drugs. We have previously demonstrated that a CYP102 construct (BMC 143) coupled with a luciferase reporter gene can be used to identify the inducers of CYP102. We now describe the effect of added phytochemicals on the induction of CYP102 by phenobarbital (PB) in B. megaterium. The isoflavones genistein, biochanin A, coumestrol, and equol, the green tea flavanoid epicatechin, and the fungal toxin zearalenone inhibit the induction of CYP102 by PB in a dose-dependent manner. However, the isoflavone daidzein, the phytoalexin glyceollin, and catechin, an epimer of epicatechin, failed to exhibit a similar inhibitory effect on PB-mediated CYP102 induction.