HPV infection and immunochemical detection of cell-cycle markers in verrucous carcinoma of the penis

Penile verrucous carcinoma is a rare disease and little is known of its aetiology or pathogenesis. In this study we examined cell-cycle proteins expression and correlation with human papillomavirus infection in a series of 15 pure penile verrucous carcinomas from a single centre. Of 148 penile tumours, 15 (10%) were diagnosed as pure verrucous carcinomas. The expression of the cell-cycle-associated proteins p53, p21, RB, p16INK4A and Ki67 were examined by immunohistochemistry. Human papillomavirus infection was determined by polymerase chain reaction to identify a wide range of virus types. The expression of p16INK4A and Ki67 was significantly lower in verrucous carcinoma than in usual type squamous cell carcinoma, whereas the expression of p53, p21 and RB was not significantly different. p53 showed basal expression in contrast to usual type squamous cell carcinoma. Human papillomavirus infection was present in only 3 out of 13 verrucous carcinomas. Unique low-risk, high-risk and mixed viral infections were observed in each of the three cases. In conclusion, lower levels of p16INK4A and Ki67 expressions differentiate penile verrucous carcinoma from usual type squamous cell carcinoma. The low Ki67 index reflects the slow-growing nature of verrucous tumours. The low level of p16INK4A expression and human papillomavirus detection suggests that penile verrucous carcinoma pathogenesis is unrelated to human papillomavirus infection and the oncogenes and tumour suppressor genes classically altered by virus infection.Peer reviewedFinal Accepted Versio

A negative screen for mutations in calstabin 1 and 2 genes in patients with dilated cardiomyopathy

<p>Abstract</p> <p>Background</p> <p>Calstabins 1 and 2 bind to Ryanodine receptors regulating muscle excitation-contraction coupling. Mutations in Ryanodine receptors affecting their interaction with calstabins lead to different cardiac pathologies. Animal studies suggest the involvement of calstabins with dilated cardiomyopathy.</p> <p>Results</p> <p>We tested the hypothesis that calstabins mutations may cause dilated cardiomyopathy in humans screening 186 patients with idiopathic dilated cardiomyopathy for genetic alterations in calstabins 1 and 2 genes (<it>FKBP12 </it>and <it>FKBP12.6)</it>. No missense variant was found. Five no-coding variations were found but not related to the disease.</p> <p>Conclusions</p> <p>These data corroborate other studies suggesting that mutations in <it>FKBP12 </it>and <it>FKBP12.6 </it>genes are not commonly related to cardiac diseases.</p

Pilot evaluation of a walking school bus program in a low-income, urban community

<p>Abstract</p> <p>Background</p> <p>To evaluate the impact of a walking school bus (WSB) program on student transport in a low-income, urban neighborhood.</p> <p>Methods</p> <p>The design was a controlled, quasi-experimental trial with consecutive cross-sectional assessments. The setting was three urban, socioeconomically disadvantaged, public elementary schools (1 intervention vs. 2 controls) in Seattle, Washington, USA. Participants were ethnically diverse students in kindergarten-5^thgrade (aged 5–11 years). The intervention was a WSB program consisting of a part-time WSB coordinator and parent volunteers. Students' method of transportation to school was assessed by a classroom survey at baseline and one-year follow-up. The Pearson Chi-squared test compared students transported to school at the intervention versus control schools at each time point. Due to multiple testing, we calculated adjusted p-values using the Ryan-Holm stepdown Bonferroni procedure. McNemar's test was used to examine the change from baseline to 12-month follow-up for walking versus all other forms of school transport at the intervention or control schools.</p> <p>Results</p> <p>At baseline, the proportions of students (n = 653) walking to the intervention (20% +/- 2%) or control schools (15% +/- 2%) did not differ (<it>p </it>= 0.39). At 12-month follow up, higher proportions of students (n = 643, <it>p </it>= 0.001)) walked to the intervention (25% +/- 2%) versus the control schools (7% +/- 1%). No significant changes were noted in the proportion of students riding in a car or taking the school bus at baseline or 12-month follow up (all <it>p </it>> 0.05). Comparing baseline to 12-month follow up, the numbers of students who walked to the intervention school increased while the numbers of students who used the other forms of transport did not change (<it>p </it>< 0.0001). In contrast, the numbers of students who walked to the control schools decreased while the numbers of students who used the other forms of transport did not change (<it>p </it>< 0.0001).</p> <p>Conclusion</p> <p>A WSB program is a promising intervention among urban, low-income elementary school students that may promote favorable changes toward active transport to school.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov NCT00402701</p

Foliar δ15N values characterize soil N cycling and reflect nitrate or ammonium preference of plants along a temperate grassland gradient

The natural abundance of stable 15N isotopes in soils and plants is potentially a simple tool to assess ecosystem N dynamics. Several open questions remain, however, in particular regarding the mechanisms driving the variability of foliar δ15N values of non-N2 fixing plants within and across ecosystems. The goal of the work presented here was therefore to: (1) characterize the relationship between soil net mineralization and variability of foliar Δδ15N (δ15Nleaf − δ15Nsoil) values from 20 different plant species within and across 18 grassland sites; (2) to determine in situ if a plant’s preference for NO3− or NH4+ uptake explains variability in foliar Δδ15N among different plant species within an ecosystem; and (3) test if variability in foliar Δδ15N among species or functional group is consistent across 18 grassland sites. Δδ15N values of the 20 different plant species were positively related to soil net mineralization rates across the 18 sites. We found that within a site, foliar Δδ15N values increased with the species’ NO3− to NH4+ uptake ratios. Interestingly, the slope of this relationship differed in direction from previously published studies. Finally, the variability in foliar Δδ15N values among species was not consistent across 18 grassland sites but was significantly influenced by N mineralization rates and the abundance of a particular species in a site. Our findings improve the mechanistic understanding of the commonly observed variability in foliar Δδ15N among different plant species. In particular we were able to show that within a site, foliar δ15N values nicely reflect a plant’s N source but that the direction of the relationship between NO3− to NH4+ uptake and foliar Δδ15N values is not universal. Using a large set of data, our study highlights that foliar Δδ15N values are valuable tools to assess plant N uptake patterns and to characterize the soil N cycle across different ecosystems

Spatial Stereoresolution for Depth Corrugations May Be Set in Primary Visual Cortex

Stereo “3D” depth perception requires the visual system to extract binocular disparities between the two eyes' images. Several current models of this process, based on the known physiology of primary visual cortex (V1), do this by computing a piecewise-frontoparallel local cross-correlation between the left and right eye's images. The size of the “window” within which detectors examine the local cross-correlation corresponds to the receptive field size of V1 neurons. This basic model has successfully captured many aspects of human depth perception. In particular, it accounts for the low human stereoresolution for sinusoidal depth corrugations, suggesting that the limit on stereoresolution may be set in primary visual cortex. An important feature of the model, reflecting a key property of V1 neurons, is that the initial disparity encoding is performed by detectors tuned to locally uniform patches of disparity. Such detectors respond better to square-wave depth corrugations, since these are locally flat, than to sinusoidal corrugations which are slanted almost everywhere. Consequently, for any given window size, current models predict better performance for square-wave disparity corrugations than for sine-wave corrugations at high amplitudes. We have recently shown that this prediction is not borne out: humans perform no better with square-wave than with sine-wave corrugations, even at high amplitudes. The failure of this prediction raised the question of whether stereoresolution may actually be set at later stages of cortical processing, perhaps involving neurons tuned to disparity slant or curvature. Here we extend the local cross-correlation model to include existing physiological and psychophysical evidence indicating that larger disparities are detected by neurons with larger receptive fields (a size/disparity correlation). We show that this simple modification succeeds in reconciling the model with human results, confirming that stereoresolution for disparity gratings may indeed be limited by the size of receptive fields in primary visual cortex

Modelling human visual navigation using multi-view scene reconstruction

It is often assumed that humans generate a 3D reconstruction of the environment, either in egocentric or world-based coordinates, but the steps involved are unknown. Here, we propose two reconstruction-based models, evaluated using data from two tasks in immersive virtual reality. We model the observer’s prediction of landmark location based on standard photogrammetric methods and then combine location predictions to compute likelihood maps of navigation behaviour. In one model, each scene point is treated independently in the reconstruction; in the other, the pertinent variable is the spatial relationship between pairs of points. Participants viewed a simple environment from one location, were transported (virtually) to another part of the scene and were asked to navigate back. Error distributions varied substantially with changes in scene layout; we compared these directly with the likelihood maps to quantify the success of the models. We also measured error distributions when participants manipulated the location of a landmark to match the preceding interval, providing a direct test of the landmark-location stage of the navigation models. Models such as this, which start with scenes and end with a probabilistic prediction of behaviour, are likely to be increasingly useful for understanding 3D vision

The relationship between patient physiology, the systemic inflammatory response and survival in patients undergoing curative resection of colorectal cancer

&lt;p&gt;Background: It is increasingly recognised that host-related factors may be important in determining cancer outcome. The aim was to examine the relationship between patient physiology, the systemic inflammatory response and survival after colorectal cancer resection.&lt;/p&gt; &lt;p&gt;Methods: Patients undergoing potentially curative resection of colorectal cancer were identified from a prospectively maintained database. Patient physiology was assessed using the physiological and operative severity score for the enumeration of mortality and morbidity (POSSUM) criteria. The systemic inflammatory response was assessed using the modified Glasgow Prognostic Score (mGPS). Multivariate 5-year survival analysis was carried out with calculation of hazard ratios (HR).&lt;/p&gt; &lt;p&gt;Results: A total of 320 patients were included. During follow-up (median 74 months), there were 136 deaths: 83 colorectal cancer related and 53 non-cancer related. Independent predictors of cancer-specific survival were age (HR: 1.46, P&#60;0.01), Dukes stage (HR: 2.39, P&#60;0.001), mGPS (HR: 1.78, P&#60;0.001) and POSSUM physiology score (HR: 1.38, P=0.02). Predictors of overall survival were age (HR: 1.64, P&#60;0.001), smoking (HR: 1.52, P=0.02), Dukes stage (HR: 1.64, P&#60;0.001), mGPS (HR: 1.60, P&#60;0.001) and POSSUM physiology score (HR: 1.27, P=0.03). A relationship between mGPS and POSSUM physiology score was also established (P&#60;0.006).&lt;/p&gt; &lt;p&gt;Conclusion: The POSSUM physiology score and the systemic inflammatory response are strongly associated and both are independent predictors of cancer specific and overall survival in patients undergoing potentially curative resection of colorectal cancer.&lt;/p&gt

Certification of breast centres in Germany: proof of concept for a prototypical example of quality assurance in multidisciplinary cancer care

<p>Abstract</p> <p>Background</p> <p>The main study objectives were: to develop a set of requirements of comprehensive breast centres; to establish a nationwide voluntary certification programme for breast centres based on such requirements, a certified quality management system (QMS), and scheduled independent, external audits and periodic recertification; and to demonstrate the general acceptance of such a certification programme with a view to introducing similar certification programmes for other major cancers.</p> <p>Methods</p> <p>Breast centres introduced a QMS and voluntarily participated in an external certification procedure based on guideline-derived Requirements of Breast Centres specifically developed for the application procedure, all subsequent audits and recertification. All data (numbers of pending and successful applications, sites/centre, etc.) were collected by a newly founded, independent organisation for certification of cancer services delivery. Data analysis was descriptive.</p> <p>Results</p> <p>Requirements of Breast Centres were developed by the German Cancer Society (DKG), the German Society of Senology (DGS) and other relevant specialist medical societies in the form of a questionnaire comprising 185 essential items based on evidence-based guidelines and the European Society of Breast Cancer Specialists' (EUSOMA) requirements of specialist breast units. From late 2002 to mid 2008, the number of participating breast centres rose from 1 to 175. As of mid 2008, 77% of an estimated 50,000 new breast cancers in Germany were diagnosed and treated at certified breast centres, 78% of which were single-site centres.</p> <p>Conclusion</p> <p>Nationwide voluntary certification of breast centres is feasible and well accepted in Germany. Dual certification of breast centres that involves certification of breast services to guideline-derived requirements in conjunction with independent certification of a mandatory QMS can serve as a model for other multidisciplinary site-specific cancer centres.</p

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

The role of impulsivity in the aetiology of drug dependence: reward sensitivity versus automaticity

Journal ArticleResearch Support, Non-U.S. Gov'tCopyright © The Author(s) 2011.RATIONALE: Impulsivity has long been known as a risk factor for drug dependence, but the mechanisms underpinning this association are unclear. Impulsivity may confer hypersensitivity to drug reinforcement which establishes higher rates of instrumental drug-seeking and drug-taking behaviour, or may confer a propensity for automatic (non-intentional) control over drug-seeking/taking and thus intransigence to clinical intervention. METHOD: The current study sought to distinguish these two accounts by measuring Barratt Impulsivity and craving to smoke in 100 smokers prior to their completion of an instrumental concurrent choice task for tobacco (to measure the rate of drug-seeking) and an ad libitum smoking test (to measure the rate of drug-taking-number of puffs consumed). RESULTS: The results showed that impulsivity was not associated with higher rates of drug-seeking/taking, but individual differences in smoking uptake and craving were. Rather, nonplanning impulsivity moderated (decreased) the relationship between craving and drug-taking, but not drug-seeking. CONCLUSIONS: These data suggest that whereas the uptake of drug use is mediated by hypervaluation of the drug as an instrumental goal, the orthogonal trait nonplanning impulsivity confers a propensity for automatic control over well-practiced drug-taking behaviour.MR