Defining the in vivo mechanism of air pollutant toxicity using murine stress response biomarkers.

Air pollution can cause a wide range of serious human diseases. For the informed instigation of interventions which prevent these outcomes there is an urgent need to develop robust in vivo biomarkers which provide insights into mechanisms of toxicity and relate pollutants to specific adverse outcomes. We exemplify for a first time the application of in vivo stress response reporters in establishing mechanisms of air pollution toxicity and the application of this knowledge in epidemiological studies. We first demonstrated the utility of reporter mice to understand toxicity mechanisms of air pollutants using diesel exhaust particles compounds. We observed that nitro-PAHs induced Hmox1 and CYP1a1 reporters in a time- and dose-dependent, cell- and tissue-specific manner. Using in vivo genetic and pharmacological approaches we confirmed that the NRF2 pathway mediated this Hmox1-reporter induction stress reporter activity. We then correlated the activation of stress-reporter models (oxidative stress/inflammation, DNA damage and Ah receptor -AhR- activity) with responses in primary human nasal cells exposed to chemicals present in particulate matter (PM; PM2.5-SRM2975, PM10-SRM1648b) or fresh roadside PM10. To exemplify their use in clinical studies, Pneumococcal adhesion was assessed in exposed primary human nasal epithelial cells (HPNEpC). The combined use of HPNEpC and in vivo reporters demonstrated that London roadside PM10 particles induced pneumococcal infection in HPNEpC mediated by oxidative stress responses. The combined use of in vivo reporter models with human data thus provides a robust approach to define the relationship between air pollutant exposure and health risks. Moreover, these models can be used in epidemiological studies to hazard ranking environmental pollutants by considering the complexity of mechanisms of toxicity. These data will facilitate the relationship between toxic potential and the level of pollutant exposure in populations to be established and potentially extremely valuable tools for intervention studies for disease prevention

Health literacy, health status, and healthcare utilization of Taiwanese adults: results from a national survey

Abstract Background Low health literacy is considered a worldwide health threat. The purpose of this study is to assess the prevalence and socio-demographic covariates of low health literacy in Taiwanese adults and to investigate the relationships between health literacy and health status and health care utilization. Methods A national survey of 1493 adults was conducted in 2008. Health literacy was measured using the Mandarin Health Literacy Scale. Health status was measured based on self-rated physical and mental health. Health care utilization was measured based on self-reported outpatient clinic visits, emergency room visits, and hospitalizations. Results Approximately thirty percent of adults were found to have low (inadequate or marginal) health literacy. They tended to be older, have fewer years of schooling, lower household income, and reside in less populated areas. Inadequate health literacy was associated with poorer mental health (OR, 0.57; 95% CI, 0.35-0.91). No association was found between health literacy and health care utilization even after adjusting for other covariates. Conclusions Low (inadequate and marginal) health literacy is prevalent in Taiwan. High prevalence of low health literacy is not necessarily indicative of the need for interventions. Systematic efforts to evaluate the impact of low health literacy on health outcomes in other countries would help to illuminate features of health care delivery and financing systems that may mitigate the adverse health effects of low health literacy.http://deepblue.lib.umich.edu/bitstream/2027.42/78252/1/1471-2458-10-614.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78252/2/1471-2458-10-614.pdfPeer Reviewe

Phase I study of TP300 in patients with advanced solid tumors with pharmacokinetic, pharmacogenetic and pharmacodynamic analyses

Background: A Phase I dose escalation first in man study assessed maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and recommended Phase II dose of TP300, a water soluble prodrug of the Topo-1 inhibitor TP3076, and active metabolite, TP3011. <p/>Methods: Eligible patients with refractory advanced solid tumors, adequate performance status, haematologic, renal, and hepatic function. TP300 was given as a 1-hour i.v. infusion 3-weekly and pharmacokinetic (PK) profiles of TP300, TP3076 and TP3011 were analysed. Polymorphisms in CYP2D6, AOX1 and UGT1A1 were studied and DNA strand-breaks measured in peripheral blood mononuclear cells (PBMCs). <p/>Results: 32 patients received TP300 at 1, 2, 4, 6, 8, 10, 12 mg/m2. MTD was 10 mg/m2; DLTs at 12 (2/4 patients) and 10 mg/m2 (3/12) included thrombocytopenia and febrile neutropenia; diarrhea was uncommon. Six patients (five had received irinotecan), had stable disease for 1.5-5 months. TP3076 showed dose proportionality in AUC and Cmax from 1--10 mg/m2. Genetic polymorphisms had no apparent influence on exposure. DNA strand-breaks were detected after TP300 infusion. <p/>Conclusions: TP300 had predictable hematologic toxicity, and diarrhea was uncommon. AUC at MTD is substantially greater than for SN38. TP3076 and TP3011 are equi-potent with SN38, suggesting a PK advantage

Contact Manifolds, Contact Instantons, and Twistor Geometry

Recently, Kallen and Zabzine computed the partition function of a twisted supersymmetric Yang-Mills theory on the five-dimensional sphere using localisation techniques. Key to their construction is a five-dimensional generalisation of the instanton equation to which they refer as the contact instanton equation. Subject of this article is the twistor construction of this equation when formulated on K-contact manifolds and the discussion of its integrability properties. We also present certain extensions to higher dimensions and supersymmetric generalisations.Comment: v3: 28 pages, clarifications and references added, version to appear in JHE

Spin qubits with electrically gated polyoxometalate molecules

Spin qubits offer one of the most promising routes to the implementation of quantum computers. Very recent results in semiconductor quantum dots show that electrically-controlled gating schemes are particularly well-suited for the realization of a universal set of quantum logical gates. Scalability to a larger number of qubits, however, remains an issue for such semiconductor quantum dots. In contrast, a chemical bottom-up approach allows one to produce identical units in which localized spins represent the qubits. Molecular magnetism has produced a wide range of systems with tailored properties, but molecules permitting electrical gating have been lacking. Here we propose to use the polyoxometalate [PMo12O40(VO)2]q-, where two localized spins-1/2 can be coupled through the electrons of the central core. Via electrical manipulation of the molecular redox potential, the charge of the core can be changed. With this setup, two-qubit gates and qubit readout can be implemented.Comment: 9 pages, 6 figures, to appear in Nature Nanotechnolog

Sample Size under Inverse Negative Binomial Group Testing for Accuracy in Parameter Estimation

Background:The group testing method has been proposed for the detection and estimation of genetically modified plants (adventitious presence of unwanted transgenic plants, AP). For binary response variables (presence or absence), group testing is efficient when the prevalence is low, so that estimation, detection, and sample size methods have been developed under the binomial model. However, when the event is rare (low prevalence Methodology/Principal Findings: This research proposes three sample size procedures (two computational and one analytic) for estimating prevalence using group testing under inverse (negative) binomial sampling. These methods provide the required number of positive pools (rm), given a pool size (k), for estimating the proportion of AP plants using the Dorfman model and inverse (negative) binomial sampling. We give real and simulated examples to show how to apply these methods and the proposed sample-size formula. The Monte Carlo method was used to study the coverage and level of assurance achieved by the proposed sample sizes. An R program to create other scenarios is given in Appendix S2. Conclusions: The three methods ensure precision in the estimated proportion of AP because they guarantee that the width (W) of the confidence interval (CI) will be equal to, or narrower than, the desired width (v), with a probability of c. With the Monte Carlo study we found that the computational Wald procedure (method 2) produces the more precise sample size (with coverage and assurance levels very close to nominal values) and that the samples size based on the Clopper-Pearson CI (method 1) is conservative (overestimates the sample size); the analytic Wald sample size method we developed (method 3) sometimes underestimated the optimum number of pools

The influence of the atmospheric boundary layer on nocturnal layers of noctuids and other moths migrating over southern Britain

Insects migrating at high altitude over southern Britain have been continuously monitored by automatically-operating, vertical-looking radars over a period of several years. During some occasions in the summer months, the migrants were observed to form well-defined layer concentrations, typically at heights of 200-400 m, in the stable night-time atmosphere. Under these conditions, insects are likely to have control over their vertical movements and are selecting flight heights which are favourable for long-range migration. We therefore investigated the factors influencing the formation of these insect layers by comparing radar measurements of the vertical distribution of insect density with meteorological profiles generated by the UK Met. Office’s Unified Model (UM). Radar-derived measurements of mass and displacement speed, along with data from Rothamsted Insect Survey light traps provided information on the identity of the migrants. We present here three case studies where noctuid and pyralid moths contributed substantially to the observed layers. The major meteorological factors influencing the layer concentrations appeared to be: (a) the altitude of the warmest air, (b) heights corresponding to temperature preferences or thresholds for sustained migration and (c), on nights when air temperatures are relatively high, wind-speed maxima associated with the nocturnal jet. Back-trajectories indicated that layer duration may have been determined by the distance to the coast. Overall, the unique combination of meteorological data from the UM and insect data from entomological radar described here show considerable promise for systematic studies of high-altitude insect layering

Bootstrap, Bayesian probability and maximum likelihood mapping: exploring new tools for comparative genome analyses

BACKGROUND: Horizontal gene transfer (HGT) played an important role in shaping microbial genomes. In addition to genes under sporadic selection, HGT also affects housekeeping genes and those involved in information processing, even ribosomal RNA encoding genes. Here we describe tools that provide an assessment and graphic illustration of the mosaic nature of microbial genomes. RESULTS: We adapted the Maximum Likelihood (ML) mapping to the analyses of all detected quartets of orthologous genes found in four genomes. We have automated the assembly and analyses of these quartets of orthologs given the selection of four genomes. We compared the ML-mapping approach to more rigorous Bayesian probability and Bootstrap mapping techniques. The latter two approaches appear to be more conservative than the ML-mapping approach, but qualitatively all three approaches give equivalent results. All three tools were tested on mitochondrial genomes, which presumably were inherited as a single linkage group. CONCLUSIONS: In some instances of interphylum relationships we find nearly equal numbers of quartets strongly supporting the three possible topologies. In contrast, our analyses of genome quartets containing the cyanobacterium Synechocystis sp. indicate that a large part of the cyanobacterial genome is related to that of low GC Gram positives. Other groups that had been suggested as sister groups to the cyanobacteria contain many fewer genes that group with the Synechocystis orthologs. Interdomain comparisons of genome quartets containing the archaeon Halobacterium sp. revealed that Halobacterium sp. shares more genes with Bacteria that live in the same environment than with Bacteria that are more closely related based on rRNA phylogeny . Many of these genes encode proteins involved in substrate transport and metabolism and in information storage and processing. The performed analyses demonstrate that relationships among prokaryotes cannot be accurately depicted by or inferred from the tree-like evolution of a core of rarely transferred genes; rather prokaryotic genomes are mosaics in which different parts have different evolutionary histories. Probability mapping is a valuable tool to explore the mosaic nature of genomes

Adolescent brain maturation and cortical folding: evidence for reductions in gyrification

Evidence from anatomical and functional imaging studies have highlighted major modifications of cortical circuits during adolescence. These include reductions of gray matter (GM), increases in the myelination of cortico-cortical connections and changes in the architecture of large-scale cortical networks. It is currently unclear, however, how the ongoing developmental processes impact upon the folding of the cerebral cortex and how changes in gyrification relate to maturation of GM/WM-volume, thickness and surface area. In the current study, we acquired high-resolution (3 Tesla) magnetic resonance imaging (MRI) data from 79 healthy subjects (34 males and 45 females) between the ages of 12 and 23 years and performed whole brain analysis of cortical folding patterns with the gyrification index (GI). In addition to GI-values, we obtained estimates of cortical thickness, surface area, GM and white matter (WM) volume which permitted correlations with changes in gyrification. Our data show pronounced and widespread reductions in GI-values during adolescence in several cortical regions which include precentral, temporal and frontal areas. Decreases in gyrification overlap only partially with changes in the thickness, volume and surface of GM and were characterized overall by a linear developmental trajectory. Our data suggest that the observed reductions in GI-values represent an additional, important modification of the cerebral cortex during late brain maturation which may be related to cognitive development

Developing a placebo-controlled trial in surgery:issues of design, acceptability and feasibility

BACKGROUND: Surgical placebos are controversial. This in-depth study explored the design, acceptability, and feasibility issues relevant to designing a surgical placebo-controlled trial for the evaluation of the clinical and cost effectiveness of arthroscopic lavage for the management of people with osteoarthritis of the knee in the UK. METHODS: Two surgeon focus groups at a UK national meeting for orthopaedic surgeons and one regional surgeon focus group (41 surgeons); plenary discussion at a UK national meeting for orthopaedic anaesthetists (130 anaesthetists); three focus groups with anaesthetists (one national, two regional; 58 anaesthetists); two focus groups with members of the patient organisation Arthritis Care (7 participants); telephone interviews with people on consultant waiting lists from two UK regional centres (15 participants); interviews with Chairs of UK ethics committees (6 individuals); postal surveys of members of the British Association of Surgeons of the Knee (382 surgeons) and members of the British Society of Orthopaedic Anaesthetists (398 anaesthetists); two centre pilot (49 patients assessed). RESULTS: There was widespread acceptance that evaluation of arthroscopic lavage had to be conducted with a placebo control if scientific rigour was not to be compromised. The choice of placebo surgical procedure (three small incisions) proved easier than the method of anaesthesia (general anaesthesia). General anaesthesia, while an excellent mimic, was more intrusive and raised concerns among some stakeholders and caused extensive discussion with local decision-makers when seeking formal approval for the pilot.Patients were willing to participate in a pilot with a placebo arm; although some patients when allocated to surgery became apprehensive about the possibility of receiving placebo, and withdrew. Placebo surgery was undertaken successfully. CONCLUSIONS: Our study illustrated the opposing and often strongly held opinions about surgical placebos, the ethical issues underpinning this controversy, and the challenges that exist even when ethics committee approval has been granted. It showed that a placebo-controlled trial could be conducted in principle, albeit with difficulty. It also highlighted that not only does a placebo-controlled trial in surgery have to be ethically and scientifically acceptable but that it also must be a feasible course of action. The place of placebo-controlled surgical trials more generally is likely to be limited and require specific circumstances to be met. Suggested criteria are presented. TRIAL REGISTRATION NUMBER: The trial was assigned ISRCTN02328576 through http://controlled-trials.com/ in June 2006. The first patient was randomised to the pilot in July 2007