76 research outputs found
The Provision of Thromboprophylaxis and the Prediction of Renal Recovery in Critically Ill Patients with Acute Kidney Injury
Children and the unborn child, Exposure and susceptibility to chemical substances â an evaluation:Report to the Danish Environmental Protection Agency
Association between Polymorphisms in Glutathione Peroxidase and Selenoprotein P Genes, Glutathione Peroxidase Activity, HRT Use and Breast Cancer Risk.
Breast cancer (BC) is one of the most common cancers in women. Evidence suggests that genetic variation in antioxidant enzymes could influence BC risk, but to date the relationship between selenoproteins and BC risk remains unclear. In this report, a study population including 975 Danish cases and 975 controls matched for age and hormone replacement therapy (HRT) use was genotyped for five functional single nucleotide polymorphisms (SNPs) in SEPP1, GPX1, GPX4 and the antioxidant enzyme SOD2 genes. The influence of genetic polymorphisms on breast cancer risk was assessed using conditional logistic regression. Additionally pre-diagnosis erythrocyte GPx (eGPx) activity was measured in a sub-group of the population. A 60% reduction in risk of developing overall BC and ductal BC was observed in women who were homozygous Thr carriers for SEPP1 rs3877899. Additionally, Leu carriers for GPX1 Pro198Leu polymorphism (rs1050450) were at âź2 fold increased risk of developing a non-ductal BC. Pre-diagnosis eGPx activity was found to depend on genotype for rs713041 (GPX4), rs3877899 (SEPP1), and rs1050450 (GPX1) and on HRT use. Moreover, depending on genotype and HRT use, eGPx activity was significantly lower in women who developed BC later in life compared with controls. Furthermore, GPx1 protein levels increased in human breast adenocarcinoma MCF7 cells exposed to β-estradiol and sodium selenite.In conclusion, our data provide evidence that SNPs in SEPP1 and GPX1 modulate risk of BC and that eGPx activity is modified by SNPs in SEPP1, GPX4 and GPX1 and by estrogens. Our data thus suggest a role of selenoproteins in BC development
Order in disorder:solution and solid-state studies of [(M2M5II)-M-III] wheels (M-III = Cr, Al; M-II = Ni, Zn)
A family of heterometallic Anderson-type âwheelsâ of general formula [MIII2MII5(hmp)12](ClO4)4 (where MIII = Cr or Al and MII = Ni or Zn giving [Cr2Ni5] (1), [Cr2Zn5] (2), [Al2Ni5] (3) and [Al2Zn5] (4); hmpH = 2-pyridinemethanol) have been synthesised solvothermally. The metallic skeleton common to all structures describes a centred hexagon with the MIII sites disordered around the outer wheel. The structural disorder has been characterised via single crystal X-ray crystallography, 1â3D 1H and 13C solution-state NMR spectroscopy of the diamagnetic analogue (4), and solid-state 27Al MAS NMR spectroscopy of compounds (3) and (4). Alongside ESI mass spectrometry, these techniques show that structure is retained in solution, and that the disorder is present in both the solution and solid-state. Solid-state dc susceptibility and magnetisation measurements on (2) and (3) reveal the CrâCr and NiâNi exchange interactions to be JCrâCr = â1 cmâ1 and JNiâNi,r = â5 cmâ1, JNiâNi,c = 10 cmâ1. Fixing these values allows us to extract JCrâNi,r = â1.2 cmâ1, JCrâNi,c = 2.6 cmâ1 for (1), the exchange between adjacent Ni and Cr ions on the ring is antiferromagnetic and between Cr ions on the ring and the central Ni ion is ferromagnetic.EKB thanks the EPSRC for funding (EP/N01331X/1, EP/P025986/1). UGN acknowledges funding
from the Villum Young Investigator (VKR022364) and the Danish Council for Independent Research â Natural Sciences (DFF â 7014-00198). ME thanks MINECO for funding (MAT2015-68204-R)Peer reviewe
Idiopathic pulmonary fibrosis - a systematic review on methodology for the collection of epidemiological data
Peer reviewe
Anti-inflammatory Components from Functional Foods for Obesity
Obesity, defined as excessive fat accumulation that may impair health, has been described throughout human history, but it has now reached epidemic proportions with the WHO estimating that 39% of the worldâs adults over 18 years of age were overweight or obese in 2016. Obesity is a chronic low-grade inflammatory state leading to organ damage with an increased risk of common diseases including cardiovascular and metabolic disease, non-alcoholic fatty liver disease, osteo-arthritis and some cancers. This inflammatory state may be influenced by adipose tissue hypoxia and changes in the gut microbiota. There has been an increasing focus on functional foods and nutraceuticals as treatment options for obesity as drug treatments are limited in efficacy. This chapter summarises the importance of anthocyanin-containing fruits and vegetables, coffee and its components, tropical fruit and food waste as sources of phytochemicals for obesity treatment. We emphasise that preclinical studies can form the basis for clinical trials to determine the effectiveness of these treatments in humans
The contingent ranking method--a feasible and valid method when eliciting preferences for health care?
The Contingent Ranking Method--a feasible and valid method when eliciting preferences for health care? The objective of the study was to determine the feasibility and validity of the contingent ranking method, when eliciting preferences and measuring willingness to pay for health care. A measurement experiment based on ranking data is reported. Marginal willingness to pay for alleviation of rheumatoid arthritis symptoms that may be the outcome of a treatment with a novel anti-rheumatic agent, cA2 (now called TNF-[alpha] blockade) was calculated. The estimated marginal willingness to pay value was 650 DKK ($93). With regard to the health status variables and income variable the signs of the coefficients were, as expected, positive. The contingent ranking method is a feasible and valid method for eliciting preferences and determining willingness to pay estimates.Contingent ranking method Conjoint analysis Willingness to pay TNF-[alpha] blockade
EDEN. Exploring novel endpoints, exposure, low-dose and mixture effects in humans, aquatic wildlife and laboratory animals. Final Report.
The EDEN project is an interdisciplinary effort conceived to address key issues that have hampered sound hazard and risk assessment for endocrine disrupting chemicals (EDCs)
in the European Union. It has adopted an approach that fully integrates human, wildlife, exposures, mechanisms and low-dose/mixture evaluations. The project was structured into four interlocking themes focusing on EDC mixture exposures, mechanisms of action and novel endpoints, effects on male reproductive health and the evaluation of low-dose and mixture effects of EDCs.
For the first time, the simultaneous occurrence of nearly 150 different EDCs in human and wildlife tissues was measured. These studies revealed that numerous EDCs occur
together in humans, yet differences in the levels of individual EDCs in specimens from boys with cryptorchidism and from women suffering from breast cancer and their
respective controls did not become apparent. It appears that the likelihood of developing any of the above conditions cannot be attributed to any individual chemical at relevant exposure levels. However, there are signs that simultaneous exposure to many different EDCs may play a cumulative role in these disease processes. This means that efforts to develop biomarkers of cumulative EDC exposure should be re-doubled. In contrast, symptoms of endocrine disruption in fish could be explained largely in terms of exposure to estrogenic chemicals, but the possible role of antiandrogenic chemicals in disrupting
sexual development in fish requires urgent attention. Fish caught in certain Dutch rivers exceeded the EU permissible levels for polychlorinated dioxins and furans.
Considerable progress has been made in establishing relevant modes of action of EDCs and in assessing new endpoints. The screening for EDCs, with its focus on steroid receptor interactions, has not kept up with the progress made in understanding rapid cellular signalling events that occur in the wake of receptor activation. In the interest of avoiding overlooking endocrine active agents it is necessary to expand screening tools to
capture rapid signalling events. Substantial progress has been also achieved in characterising the role of the aromatase system in fish as a target of EDCs and the
consequences of steroid synthesis disruption on sexual differentiation, reproduction as well as non-reproductive processes such as neurodifferentiation. Extensive investigations of the role of certain phthalates in disrupting male sexual development have revealed delays in germ cell differentiation and other molecular effects as key events underlying the induction of the testicular dysgenesis syndrome. The role of the InsL3 protein in
promoting male sexual development proved to be more complex than thought previously. Although the development and validation of an assay for the measurement of InsL3 blood levels was successful, the differences in blood InsL3 levels in normal and cryptorchid boys were too small to exploit InsL3 as a biomarker indicative of disruption of testis descent. The hypothalamic pituitary unit proved to be exquisitely sensitive to the effects of several EDCs, and the effects may account for precocious sexual development observed after early EDC exposure. EDEN has advanced the study of endocrine disruption in fish with activities including the development of microarrays for assessing endocrine disruption in zebrafish and establishing sensitive screening tools for endocrine
disruption in fish. The development of a transgenic fish model for the detection of EDC effects proved to be technically too demanding to be completed in time, but efforts continue to complete this project after conclusion of EDEN. An in vivo model in fish (the three-spined stickleback) for the detection of antiandrogenic EDC was developed as a complement to the Hershberger assay.
Male reproductive health in Denmark and Finland showed a worrying declining trend. For the first time, it could be established that the same is true for young men in Germany.
It is of concern that semen quality among young Germans is similar to the values found in young Danes, a group previously thought to show the lowest semen quality in Europe. Foetal exposure to smoking has been identified as one reason for these effects. Observations of a declining total natural conception rate among the young Danish cohorts imply that the current poor semen quality has an impact on the population fertility in the future â a situation which will be difficult to reverse in the short term. The current and projected widespread use of assisted reproductive technologies may be a sign of such an
emerging public health problem which also adds to the load of medical costs in young population. It is of vital importance to continue surveillance of semen quality and all efforts should be made to identify the factors that may cause harm in order to prevent further deterioration.
Extensive low-dose studies with EDCs have shown that the conventional estimation of no-observed-adverse-effect-levels (NOAEL), with their reliance on hypothesis testing
methods is inadequate for capturing low-dose effects of EDCs. Whenever possible, regression-based approaches with benchmark dose limits should replace NOAEL as the basis for establishing acceptable human exposure levels. A framework was developed to combine the strengths of both methodologies by making considerations of statistical
detection limits and statistical power the starting point of testing procedures. Implementation of this framework will require a significant change in toxicological
testing practice.
Determinants of additivity for EDC mixtures have been characterised and are now well understood for combinations of similarly acting EDCs. Experimental studies have produced evidence that EDCs of relatively low potency and at low exposure levels can still work together to produce significant combination effects when they are present in
sufficient numbers. The perceived low potency of many EDCs alone is uninformative in anticipating possible risks stemming from these chemicals. Where EDCs act in concert
with endogenous hormones, significant additional effects may result under certain circumstances. Uncertainty still exists in relation to the likelihood of synergistic mixture
effects, and concerted efforts should be made to fill this gap. Another source of uncertainty that will hamper sound EDC mixture risk assessment is incomplete knowledge about the identity of EDCs, their exposure levels and number. This issue can only be resolved through the development of dedicated exposure assessment strategies that take account of cumulative exposures. Despite these uncertainties, knowledge about determinants and factors that govern the joint action of similarly acting EDCs is now sufficiently advanced to come to pragmatic risk assessment approaches that take mixture effects into consideration. A modus operandi for EDC mixtures was developed which includes the use of dose addition (including the toxic equivalency factor approach) to arrive at a âmixture no-observed-adverse-effect-levelâ (MNOAEL) for endpoints relevant to endocrine disruption. These are then combined with a safety factor to arrive at estimates of tolerable human exposure. âData-poorâ situations may require estimation of
a crude MNOAEL by dividing individual NOAEL of certain prototype chemicals by the anticipated number of relevant similarly acting chemicals
Modifications of amino acids during ferulic acid-mediated, laccase-catalysed cross-linking of peptides
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