Nanotoxicology: characterizing the scientific literature, 2000–2007

Understanding the toxicity of nanomaterials and nano-enabled products is important for human and environmental health and safety as well as public acceptance. Assessing the state of knowledge about nanotoxicology is an important step in promoting comprehensive understanding of the health and environmental implications of these new materials. To this end, we employed bibliometric techniques to characterize the prevalence and distribution of the current scientific literature. We found that the nano-toxicological literature is dispersed across a range of disciplines and sub-fields; focused on in vitro testing; often does not specify an exposure pathway; and tends to emphasize acute toxicity and mortality rather than chronic exposure and morbidity. Finally, there is very little research on consumer products, particularly on their environmental fate, and most research is on the toxicity of basic nanomaterials. The implications for toxicologists, regulators and social scientists studying nanotechnology and society are discussed

Lime stabilisation for earthworks: a UK perspective

Lime stabilisation is a versatile technique applied during earthworks operations. Modern soil recycling units are much more efficient at pulverising fill material and intermixing the added binder/water than machinery available 20 years ago. While supplier innovation adds flexibility to the site working method, specifications have not been sufficiently updated to permit optimal application. This review paper details the physico-chemical changes instigated through the lime-clay soil reaction, updating previous reviews. It aims to assist scientific debate, current practitioners and future specification changes. For example, the application of the minimum 24 h mellowing periods (mandatory to UK specifications) with high reactivity, quicklime powders is concluded to cause increased air voids in the compacted fill. Increased air voids are associated with reduced long-term strength and potential volume change from water ingress, which is of particular concern for sulfate swelling. Shorter mellowing periods and/or use of hydrated lime may lesson this issue; however, a 'one size fits all' approach is discouraged in preference to site-specific methodologies refined to suit the fill material and project requirements. The discussion also summarises working methods which may lower the risk of sulfate swell and defines areas requiring further practical research

Wnt4 and LAP2alpha as pacemakers of Thymic Epithelial Senescence

Age-associated thymic involution has considerable physiological impact by inhibiting de novo T-cell selection. This impaired T-cell production leads to weakened immune responses. Yet the molecular mechanisms of thymic stromal adipose involution are not clear. Age-related alterations also occur in the murine thymus providing an excellent model system. In the present work structural and molecular changes of the murine thymic stroma were investigated during aging. We show that thymic epithelial senescence correlates with significant destruction of epithelial network followed by adipose involution. We also show in purified thymic epithelial cells the age-related down-regulation of Wnt4 (and subsequently FoxN1), and the prominent increase in LAP2α expression. These senescence-related changes of gene expression are strikingly similar to those observed during mesenchymal to pre-adipocyte differentiation of fibroblast cells suggesting similar molecular background in epithelial cells. For molecular level proof-of-principle stable LAP2α and Wnt4-over-expressing thymic epithelial cell lines were established. LAP2α over-expression provoked a surge of PPARγ expression, a transcription factor expressed in pre-adipocytes. In contrast, additional Wnt4 decreased the mRNA level of ADRP, a target gene of PPARγ. Murine embryonic thymic lobes have also been transfected with LAP2α- or Wnt4-encoding lentiviral vectors. As expected LAP2α over-expression increased, while additional Wnt4 secretion suppressed PPARγ expression. Based on these pioneer experiments we propose that decreased Wnt activity and increased LAP2α expression provide the molecular basis during thymic senescence. We suggest that these molecular changes trigger thymic epithelial senescence accompanied by adipose involution. This process may either occur directly where epithelium can trans-differentiate into pre-adipocytes; or indirectly where first epithelial to mesenchymal transition (EMT) occurs followed by subsequent pre-adipocyte differentiation. The latter version fits better with literature data and is supported by the observed histological and molecular level changes

Recursive construction of perfect DNA molecules from imperfect oligonucleotides

Making faultless complex objects from potentially faulty building blocks is a fundamental challenge in computer engineering, nanotechnology and synthetic biology. Here, we show for the first time how recursion can be used to address this challenge and demonstrate a recursive procedure that constructs error-free DNA molecules and their libraries from error-prone oligonucleotides. Divide and Conquer (D&C), the quintessential recursive problem-solving technique, is applied in silico to divide the target DNA sequence into overlapping oligonucleotides short enough to be synthesized directly, albeit with errors; error-prone oligonucleotides are recursively combined in vitro, forming error-prone DNA molecules; error-free fragments of these molecules are then identified, extracted and used as new, typically longer and more accurate, inputs to another iteration of the recursive construction procedure; the entire process repeats until an error-free target molecule is formed. Our recursive construction procedure surpasses existing methods for de novo DNA synthesis in speed, precision, amenability to automation, ease of combining synthetic and natural DNA fragments, and ability to construct designer DNA libraries. It thus provides a novel and robust foundation for the design and construction of synthetic biological molecules and organisms

Primary care and health inequality : Difference-in-difference study comparing England and Ontario

BACKGROUND: It is not known whether equity-oriented primary care investment that seeks to scale up the delivery of effective care in disadvantaged communities can reduce health inequality within high-income settings that have pre-existing universal primary care systems. We provide some non-randomised controlled evidence by comparing health inequality trends between two similar jurisdictions-one of which implemented equity-oriented primary care investment in the mid-to-late 2000s as part of a cross-government strategy for reducing health inequality (England), and one which invested in primary care without any explicit equity objective (Ontario, Canada). METHODS: We analysed whole-population data on 32,482 neighbourhoods (with mean population size of approximately 1,500 people) in England, and 18,961 neighbourhoods (with mean population size of approximately 700 people) in Ontario. We examined trends in mortality amenable to healthcare by decile groups of neighbourhood deprivation within each jurisdiction. We used linear models to estimate absolute and relative gaps in amenable mortality between most and least deprived groups, considering the gradient between these extremes, and evaluated difference-in-difference comparisons between the two jurisdictions. RESULTS: Inequality trends were comparable in both jurisdictions from 2004-6 but diverged from 2007-11. Compared with Ontario, the absolute gap in amenable mortality in England fell between 2004-6 and 2007-11 by 19.8 per 100,000 population (95% CI: 4.8 to 34.9); and the relative gap in amenable mortality fell by 10 percentage points (95% CI: 1 to 19). The biggest divergence occurred in the most deprived decile group of neighbourhoods. DISCUSSION: In comparison to Ontario, England succeeded in reducing absolute socioeconomic gaps in mortality amenable to healthcare from 2007 to 2011, and preventing them from growing in relative terms. Equity-oriented primary care reform in England in the mid-to-late 2000s may have helped to reduce socioeconomic inequality in health, though other explanations for this divergence are possible and further research is needed on the specific causal mechanisms

Screening mammography beliefs and recommendations: a web-based survey of primary care physicians

<p>Abstract</p> <p>Background</p> <p>The appropriateness and cost-effectiveness of screening mammography (SM) for women younger than 50 and older than 74 years is debated in the clinical research community, among health care providers, and by the American public. This study explored primary care physicians' (PCPs) perceptions of the influence of clinical practice guidelines for SM; the recommendations for SM in response to hypothetical case scenarios; and the factors associated with perceived SM effectiveness and recommendations in the US from June to December 2009 before the United States Preventive Services Task Force (USPSTF) recently revised guidelines.</p> <p>Methods</p> <p>A nationally representative sample of 11,922 PCPs was surveyed using a web-based questionnaire. The response rate was 5.7% (684); (41%) 271 family physicians (FP), (36%) 232 general internal medicine physicians (IM), (23%) 150 obstetrician-gynaecologists (OBG), and (0.2%) 31 others. Cross-sectional analysis examined PCPs perceived effectiveness of SM, and recommendation for SM in response to hypothetical case scenarios. PCPs responses were measured using 4-5 point adjectival scales. Differences in perceived effectiveness and recommendations for SM were examined after adjusting for PCPs specialty, race/ethnicity, and the US region.</p> <p>Results</p> <p>Compared to IM and FP, OBG considered SM more effective in reducing breast cancer mortality among women aged 40-49 years (<it>p </it>= 0.003). Physicians consistently recommended mammography to women aged 50-69 years with no differences by specialty (<it>p </it>= 0.11). However, 94% of OBG "always recommended" SM to younger and 86% of older women compared to 81% and 67% for IM and 84% and 59% for FP respectively (<it>p = </it>< .001). In ordinal regression analysis, OBG specialty was a significant predictor for perceived higher SM effectiveness and recommendations for younger and older women. In evaluating hypothetical scenarios, overall PCPs would recommend SM for the 80 year woman with CHF with a significant variation by specialty (38% of OBG, 18% of FP, 17% of IM; <it>p </it>= < .001).</p> <p>Conclusions</p> <p>A majority of physicians, especially OBG, favour aggressive breast cancer screening for women from 40 through 79 years of age, including women with short life expectancy. Policy interventions should focus on educating providers to provide tailored recommendations for mammography based on individualized cancer risk, health status, and preferences.</p

The Distribution of Toxoplasma gondii Cysts in the Brain of a Mouse with Latent Toxoplasmosis: Implications for the Behavioral Manipulation Hypothesis

reportedly manipulates rodent behavior to enhance the likelihood of transmission to its definitive cat host. The proximate mechanisms underlying this adaptive manipulation remain largely unclear, though a growing body of evidence suggests that the parasite-entrained dysregulation of dopamine metabolism plays a central role. Paradoxically, the distribution of the parasite in the brain has received only scant attention. at six months of age and examined 18 weeks later. The cysts were distributed throughout the brain and selective tropism of the parasite toward a particular functional system was not observed. Importantly, the cysts were not preferentially associated with the dopaminergic system and absent from the hypothalamic defensive system. The striking interindividual differences in the total parasite load and cyst distribution indicate a probabilistic nature of brain infestation. Still, some brain regions were consistently more infected than others. These included the olfactory bulb, the entorhinal, somatosensory, motor and orbital, frontal association and visual cortices, and, importantly, the hippocampus and the amygdala. By contrast, a consistently low incidence of tissue cysts was recorded in the cerebellum, the pontine nuclei, the caudate putamen and virtually all compact masses of myelinated axons. Numerous perivascular and leptomeningeal infiltrations of inflammatory cells were observed, but they were not associated with intracellular cysts. distribution stems from uneven brain colonization during acute infection and explains numerous behavioral abnormalities observed in the chronically infected rodents. Thus, the parasite can effectively change behavioral phenotype of infected hosts despite the absence of well targeted tropism

A Study of the Influence of Sex on Genome Wide Methylation

Sex differences in methylation status have been observed in specific gene-disease studies and healthy methylation variation studies, but little work has been done to study the impact of sex on methylation at the genome wide locus-to-locus level or to determine methods for accounting for sex in genomic association studies. In this study we investigate the genomic sex effect on saliva DNA methylation of 197 subjects (54 females) using 20,493 CpG sites. Three methods, two-sample T-test, principle component analysis and independent component analysis, all successfully identify sex influences. The results show that sex not only influences the methylation of genes in the X chromosome but also in autosomes. 580 autosomal sites show strong differences between males and females. They are found to be highly involved in eight functional groups, including DNA transcription, RNA splicing, membrane, etc. Equally important is that we identify some methylation sites associated with not only sex, but also other phenotypes (age, smoking and drinking level, and cancer). Verification was done through an independent blood cell DNA methylation data (1298 CpG sites from a cancer panel array). The same genomic site-specific influence pattern and potential confounding effects with cancer were observed. The overlapping rate of identified sex affected genes between saliva and blood cell is 81% for X chromosome, and 8% for autosomes. Therefore, correction for sex is necessary. We propose a simple correction method based on independent component analysis, which is a data driven method and accommodates sample differences. Comparison before and after the correction suggests that the method is able to effectively remove the potentially confounding effects of sex, and leave other phenotypes untouched. As such, our method is able to disentangle the sex influence on a genome wide level, and paves the way to achieve more accurate association analyses in genome wide methylation studies

Hereditary alpha-1-antitrypsin deficiency and its clinical consequences

Alpha-1-antitrypsin deficiency (AATD) is a genetic disorder that manifests as pulmonary emphysema, liver cirrhosis and, rarely, as the skin disease panniculitis, and is characterized by low serum levels of AAT, the main protease inhibitor (PI) in human serum. The prevalence in Western Europe and in the USA is estimated at approximately 1 in 2,500 and 1 : 5,000 newborns, and is highly dependent on the Scandinavian descent within the population. The most common deficiency alleles in North Europe are PI Z and PI S, and the majority of individuals with severe AATD are PI type ZZ. The clinical manifestations may widely vary between patients, ranging from asymptomatic in some to fatal liver or lung disease in others. Type ZZ and SZ AATD are risk factors for the development of respiratory symptoms (dyspnoea, coughing), early onset emphysema, and airflow obstruction early in adult life. Environmental factors such as cigarette smoking, and dust exposure are additional risk factors and have been linked to an accelerated progression of this condition. Type ZZ AATD may also lead to the development of acute or chronic liver disease in childhood or adulthood: prolonged jaundice after birth with conjugated hyperbilirubinemia and abnormal liver enzymes are characteristic clinical signs. Cirrhotic liver failure may occur around age 50. In very rare cases, necrotizing panniculitis and secondary vasculitis may occur. AATD is caused by mutations in the SERPINA1 gene encoding AAT, and is inherited as an autosomal recessive trait. The diagnosis can be established by detection of low serum levels of AAT and isoelectric focusing. Differential diagnoses should exclude bleeding disorders or jaundice, viral infection, hemochromatosis, Wilson's disease and autoimmune hepatitis. For treatment of lung disease, intravenous alpha-1-antitrypsin augmentation therapy, annual flu vaccination and a pneumococcal vaccine every 5 years are recommended. Relief of breathlessness may be obtained with long-acting bronchodilators and inhaled corticosteroids. The end-stage liver and lung disease can be treated by organ transplantation. In AATD patients with cirrhosis, prognosis is generally grave