bluuebunny/crossref_metadata_2025_split huggingface dataset:
The evolving use of serum free light chain assays in haematology
Authors: Pratt Guy 
Published: March 2008

SummaryOver the last few years new immunoassays have emerged that allow the measurement of free immunoglobulin light chains (FLCs) in serum to a level of 2–4 mg/l and provide a much greater sensitivity than older methods, such as immunofixation, which is able to detect FLCs at a minimum concentration of 100–150 mg/l. The new FLC assay has enabled the detection of monoclonal protein in some patients with non‐secretory myeloma and amyloidosis that were previously undetectable. FLC measurements are quantitative, correlating with disease activity, and are an advance in monitoring light chain only multiple myeloma, AL amyloidosis, non‐secretory and oligo‐secretory multiple myeloma. Serum FLC concentrations also reflect the disease course in the majority of myeloma patients producing intact monoclonal immunoglobulin proteins and have been incorporated into the new response criteria. The rapid half life of λ and κ free light chains means that FLC assays may provide a more rapid indication of the response to treatment but their clinical utility in this setting needs further study. An abnormal FLC ratio has been shown to be a risk factor for progression of monoclonal gammopathy of undetermined significance, smouldering myeloma and solitary plasmacytoma of bone and is prognostic in multiple myeloma.
Phosphorus‐induced mobilization of colloids: model systems and soils
Authors: Ilg K. , Dominik P. , Kaupenjohann M. , Siemens J. 
Published: March 2008

SummaryIncreasing the phosphorus (P) saturation of sandy soils may cause an increase in the rate of transport of dissolved P to groundwater. We hypothesize that by increasing sorption of P, soil colloids such as iron (Fe) oxides are also mobilized, because the adsorption of P causes the surface charge to become more negative, which increases the repulsive forces between the colloids and the sand grains, and between the colloids in suspension. Goethite particles adsorbed to fine quartz sand and precipitated goethite coatings on coarse quartz sand were used as model systems to test this hypothesis. Soil samples from a Cambisol Bw horizon and a Gleysol Bg horizon were also investigated. We conducted a series of batch experiments with increasing concentrations of ortho‐P and inositol hexaphosphate (IHP). The adsorption of P and the dispersion of colloids were determined by measuring P, Fe, aluminium and carbon concentrations in supernatants before and after ultracentrifugation. Dispersed colloids were characterized according to their optical density, zeta potential and particle size. The addition of P caused mobilization of goethite and soil colloids when a critical P saturation, corresponding to a zeta potential of about −20 mV, was exceeded. To induce colloid mobilization in soils, one to two orders of magnitude larger equilibrium concentrations of dissolved P were necessary, compared with those required for the model systems. The adsorption of IHP reduced the zeta potential of colloids more effectively than the adsorption of ortho‐P per mol P. Environmentally significant concentrations of colloidal P (> 0.1 mg P litre−1) were released from soil samples at equilibrium concentrations of dissolved P < 0.1 mg P litre−1. We conclude that the sorption and accumulation of P in sandy subsoils that might occur as a result of excessive fertilization might induce the mobilization of colloids and colloidal P.
Enhancing the P trapping of pasture filter strips: successes and pitfalls in the use of water supply residue and polyacrylamide
Authors: Redding M. R. , Welten B. , Kear M. 
Published: March 2008

SummaryIn intensive pastoral systems the landscape at ground level is clad in dense, filtering vegetation – yet phosphorus losses in overland flow do occur, and pollution of surface waters is a serious consequence. The use of pre‐applied polyacrylamide (PAM) or chitosan to trap particulate phosphorus (PP) and P‐sorbing potable water treatment alum residue (PWTR) to enhance vegetative filtering effects is examined here using field and laboratory overland flow simulation (flows from 0.43 to 0.34 litres s−1 (m width)−1) and analysis.Fitted equations suggest that up to 40% of dissolved reactive P applied (0.75 mg P litre−1) in overland flow could be captured in a flow length of 2.1 m (1 kg PWTR m−2). Unfortunately, drying decreased PWTR effectiveness, though little of the P captured was readily desorbed. This effect did not appear to be the result of gibbsite formation. Compared with the other treatments, there was a strong treatment effect of pre‐applied PAM on the change in PP losses (P < 0.001) over time, though evidence suggests the PAM effect declined during a 44 minute flow period.We showed that the investigated two‐pronged approach to the enhancement of the effectiveness of P trapping by pasture had limitations. Laboratory sheet‐flow simulations suggest that a field‐stable P sorber with sorption characteristics similar to those of the un‐dried PWTR could be an effective retention enhancer for dissolved P. Pre‐applied PAM can have an effect on particulate‐P trapping but was rapidly dissolved and removed by flow.
Endocrine‐disrupting properties in vivo of widely used azole fungicides
Authors: Taxvig C. , Vinggaard A. M. , Hass U. , Axelstad M. , Metzdorff S. , Nellemann C. 
Published: March 2008

SummaryThe endocrine‐disrupting potential of four commonly used azole fungicides, propiconazole, tebuconazole, epoxiconazole and ketoconazole, were tested in two short‐term in vivo studies. Initially, the antiandrogenic effects of propiconazole and tebuconazole (50, 100 and 150 mg/kg body weight/day each) were examined in the Hershberger assay. In the second study, pregnant Wistar rats were dosed with propiconazole, tebuconazole, epoxiconazole or ketoconazole (50 mg/kg/day each) from gestational day (GD) 7 to GD 21. Caesarian sections were performed on dams at GD 21. Tebuconazole and propiconazole demonstrated no antiandrogenic effects at doses between 50 and 150 mg/kg body weight/day in the Hershberger assay. In the in utero exposure toxicity study, ketoconazole, a pharmaceutical to treat human fungal infections, decreased anogenital distance and reduced testicular testosterone levels, demonstrating a demasculinizing effect on male fetuses. Tebuconazole, epoxiconazole and ketoconazole induced a high‐frequency of post‐implantation loss, and both ketoconazole and epoxiconazole caused a marked increase in late and very late resorptions. Overall the results show that many of the commonly used azole fungicides act as endocrine disruptors in vivo, although the profile of action in vivo varies. As ketoconazole is known to implicate numerous endocrine‐disrupting effects in humans, the concern for the effects of the other tested azole fungicides in humans is growing.
Urinary phthalate metabolites and semen quality: a review of a potential biomarker of susceptibility
Authors: Hauser Russ 
Published: March 2008

SummaryPhthalates are a class of chemicals with widespread general population exposure. Some phthalates are reproductive and developmental toxicants in laboratory animals. Advances in the field of phthalate research in humans are dependent on the development and implementation of biomarkers to assess exposure and outcome, as well as potential markers that may be indicative of increased susceptibility. Recently, we incorporated a novel biomarker of potential ‘susceptibility’ into our study on the relationship of phthalates with semen quality and sperm DNA damage among men recruited from an infertility clinic. We measured urinary concentrations of three di(2‐ethylhexyl) phthalate (DEHP) metabolites, mono(2‐ethylhexyl) phthalate (MEHP) and two oxidative metabolites, mono‐(2‐ethyl‐5‐hydroxylhexyl) phthalate (MEHHP) and mono‐(2‐ethyl‐5‐oxohexyl) phthalate (MEOHP). We calculated the percent of DEHP excreted as the hydrolytic monoester (i.e., MEHP). We referred to this as %MEHP and considered it a phenotypic marker of the proportion of DEHP excreted in the urine as MEHP. In our sperm DNA study, we found novel results for the DEHP metabolites. Although MEHP was positively correlated with the oxidative metabolites, the association of sperm DNA damage with MEHP, as compared to MEHHP and MEOHP, were in opposite directions. We hypothesized that MEHP is the bioactive toxicant and further metabolism to MEHHP/MEOHP may lower internal burden of MEHP and thus be protective from sperm DNA damage. An alternative explanation may include that the relative percentage of DEHP excreted as MEHP was a surrogate for the function of phase I enzymes. Men with high %MEHP may have higher levels of sperm DNA damage because of poor metabolism (detoxification) of other genotoxic chemicals. Our hypothesis that %MEHP may represent a phenotypic marker of metabolism is novel but requires further exploration to confirm.
Toxicity of ethylene glycol monomethyl ether: impact on testicular gene expression
Authors: Bagchi Gargi , Waxman David J. 
Published: March 2008

SummaryMethoxyacetic acid (MAA), the active biological oxidation product of the industrial solvent ethylene glycol monomethyl ether (EGME), causes acute toxicity in several species including humans. MAA primarily affects tissues with rapidly dividing cells and high rates of energy metabolism, including testes, thymus and the fetus. Testicular toxicity, one of the most prominent consequences of EGME, and MAA, exposure, results from apoptosis of primary spermatocytes and is associated with changes in the expression of various genes and signalling pathways. This review of EGME metabolism and its organ‐specific toxicities emphasizes genes and signalling pathways that are modulated by EGME exposure and their relevance to the molecular mechanisms underlying EGME and MAA toxicity. Of particular importance are the genes that code for oxidative stress response factors, protein kinases, and nuclear hormone receptors. Nuclear receptors and protein kinases regulate multiple cellular processes and are critical for signalling events required for spermatogenesis. De‐regulation of their activity by EGME or MAA leads to inappropriate signalling in testicular cells. Oxidative stress in spermatocytes exposed to MAA triggers mitochondrial release of cytochrome C, activation of caspases and ultimately apoptosis. Detailed investigation of the molecular responses to MAA exposure may help elucidate the overall impact and extent of toxicity seen following EGME exposure. Finally, given the effects of EGME on multiple genes and signalling pathways in the testis, mixture studies combining EGME, or MAA, with other testicular toxicants may help identify toxicities that are aggravated by EGME exposure.
Thyroid disrupting chemicals: mechanisms and mixtures
Authors: Crofton Kevin M. 
Published: March 2008

SummaryEnvironmental contaminants are known to act as thyroid disrupting chemicals (TDCs). Broadly defined, TDCs are xenobiotics that alter the structure or function of the thyroid gland, alter regulatory enzymes associated with thyroid hormone (TH) homeostasis or change circulating or tissue concentrations of THs. For THs, homeostasis is defined as the normal range of THs and TSH in circulation and tissues. TDCs include a wide range chemical structures that act through a variety of mechanisms. Concern about TDCs has increased because of the critical role that thyroid hormones play in brain development. A major uncertainty regarding the endocrine disrupting potential of environmental xenobiotics is the potential for additive, antagonistic or synergistic effects following exposure to mixtures. In addition, there are a number of uncertainties in both interpretation and extrapolation of results from studies of TDC mixtures. Extrapolation of data from laboratory animals to humans is tempered by uncertainty in how the mechanism(s)‐of‐action of the TDCs may differ between species. The variety of mechanisms by which TDCs alter thyroid homeostasis also yields a difficulty in determining at what level of biological organization to cumulate effects. Should it be at the molecular level, which could be chemical class specific or at the level of a downstream consequence (e.g. circulating hormone levels, brain biochemistry and behaviour) which would be mechanism‐independent? To date, the limited data from TDC mixture studies suggest that dose addition is reasonably accurate in predicting the effects on serum T4 concentrations. Assessing the health risks of thyroid disruption by environmental xenobiotics will need to include an improved understanding of how divergent mechanisms alter THs and consequent adverse impacts on nervous system development.
Effects of endocrine disruptors on obesity
Authors: Newbold Retha R. , Padilla‐Banks Elizabeth , Jefferson Wendy N. , Heindel Jerrold J. 
Published: March 2008

SummaryEnvironmental chemicals with hormone‐like activity can disrupt the programming of endocrine signalling pathways that are established during perinatal life and result in adverse consequences that may not be apparent until much later in life. Increasing evidence implicates developmental exposure to environmental hormone mimics with a growing list of adverse health consequences in both males and females. Most recently, obesity has been proposed to be yet another adverse health effect of exposure to endocrine disrupting chemicals (EDCs) during critical stages of development. Obesity is quickly becoming a significant human health crisis because it is reaching epidemic proportions worldwide, and is associated with chronic illnesses such as diabetes and cardiovascular disease. In this review, we summarize the literature reporting an association of EDCs and the development of obesity, and further describe an animal model of exposure to diethylstilbestrol that has proven useful in studying mechanisms involved in abnormal programming of various oestrogen target tissues during differentiation. Together, these data suggest new targets (i.e. adipocyte differentiation and mechanisms involved in weight homeostasis) of abnormal programming by EDCs, and provide evidence that support the scientific term ‘the developmental origins of adult disease’. The emerging idea of an association of EDCs and obesity expands the focus on obesity from intervention and treatment to include prevention and avoidance of these chemical modifiers.
A mixture of seven antiandrogens induces reproductive malformations in rats
Authors: Rider Cynthia V. , Furr Johnathan , Wilson Vickie S. , Gray L. Earl 
Published: March 2008

SummaryTo date, regulatory agencies have not considered conducting cumulative risk assessments for mixtures of chemicals with diverse mechanisms of toxicity because it is assumed that the chemicals will act independently and the individual chemical doses are not additive. However, this assumption is not supported by new research addressing the joint effects of chemicals that disrupt reproductive tract development in the male rat by disrupting the androgen signalling pathway via diverse mechanisms of toxicity [i.e. androgen receptor (AR) antagonism in the reproductive tract vs. inhibition of androgen synthesis in the foetal testis]. In this study, pregnant rats were exposed to four dilutions of a mixture containing vinclozolin, procymidone, linuron, prochloraz, benzyl butyl phthalate, dibutyl phthalate and diethylhexyl phthalate during the period of sexual differentiation and male offspring were assessed for effects on hormone sensitive endpoints including: anogenital distance, infant areolae retention and reproductive tract tissue weights and malformations. The ratio of the chemicals in the mixture was based upon each chemical’s ED50 for inducing reproductive tract malformations (hypospadias or epididymal agenesis). The observed responses from the mixture were compared with predicted responses generated with a toxic equivalency approach and models of dose addition, response addition or integrated addition. As hypothesized, we found that the mixture of chemicals that alter the androgen signalling pathway via diverse mechanisms disrupted male rat reproductive tract differentiation and induced malformations in a cumulative, dose‐additive manner. The toxic equivalency and dose addition models provided the best fit to observed responses even though the chemicals do not act via a common cellular mechanism of action. The current regulatory framework for conducting cumulative risk assessments needs to consider the results, including those presented herein, which indicate that chemicals that disrupt foetal tissues during sexual differentiation act in a cumulative, dose‐additive manner irrespective of the specific cellular mechanism of toxicity.
Semen quality in sub‐fertile range for a significant proportion of young men from the general German population: a co‐ordinated, controlled study of 791 men from Hamburg and Leipzig
Authors: Paasch Uwe , Salzbrunn Andrea , Glander Hans Juergen , Plambeck Kai , Salzbrunn Harald , Grunewald Sonja , Stucke Julia , Skakkebæk Niels E. , Jørgensen Niels 
Published: March 2008

SummaryPopulation studies have shown that a high proportion of Nordic men may have so poor semen quality that they can be classified as sub‐fertile according to international standards. A question is whether the Nordic data are specific for the Nordic countries or they should be seen as an expression of a general trend in Europe. We therefore carried out a prospective study of semen quality of young men raised in the former East Germany (Leipzig) and West Germany (Hamburg). To enable inter‐regional comparisons, we utilized a common European research protocol previously used in studies in the Nordic‐Baltic region. Three hundred and thirty‐four young men representative of the general population from Hamburg, and 457 from Leipzig delivered semen samples, underwent physical examinations and provided information on life‐style and reproductive health parameters. The study period in Hamburg was February 2003 – July 2004, and in Leipzig July 2003 – April 2005. No significant differences were observed in sperm concentration (median 46, 42, and 44 million/mL for men from Hamburg, Leipzig and the combined Hamburg‐Leipzig group respectively) or total sperm count (154, 141 and 149 million), whereas the differences for morphologically normal spermatozoa (9.4 and 8.4%) and motile spermatozoa (67 and 81%) were significantly different. Previously published studies have shown reduced fertility with decreasing sperm concentrations below 40–55 millions/mL and normal sperm morphology below 9–19%. Thus, a large fraction of young German men seem to have impaired semen quality that may reduce their natural fertility. However, it remains to be investigated to what extent poor semen quality contributes to the low German fertility rates.
Diverse mechanisms of anti‐androgen action: impact on male rat reproductive tract development
Authors: Wilson Vickie S. , Blystone Chad R. , Hotchkiss Andrew K. , Rider Cynthia V. , Gray L. Earl 
Published: March 2008

SummaryScientists have identified environmental chemicals that display anti‐androgenic activity via multiple mechanisms of action. Early studies focused on pesticides acting as androgen receptor (AR) antagonists but it soon became apparent that was not the only endocrine mode by which compounds affected the androgen signalling pathway. Classes of chemicals currently known to interfere with the androgen signalling pathway include dicarboximide fungicides (e.g. vinclozolin), organochlorine‐based insecticides (e.g. p,p′‐DDT and ‐DDE), conazole fungicides (e.g. prochloraz), plasticizers (phthalates) and urea‐based herbicides (linuron). Phthalate esters (PEs) and vinclozolin appear to act primarily via a single mechanism of action, while others such as linuron and prochloraz, appear to display dual mechanisms of action. Exposure to PEs decreases mRNA expression of key steroidogenic enzymes and also the peptide hormone insulin‐like peptide 3 (insl3) from the foetal Leydig cells. Hence, both androgen‐ and inls3‐dependent tissues are affected. Vinclozolin and procymidone act solely through binding to the AR as antagonists thus blocking the action of androgen at the cellular level but do not affect foetal testosterone synthesis or insl3 gene expression. The compounds linuron and prochloraz are AR antagonists but also inhibit foetal testosterone synthesis, although unlike the PEs, mRNA expression of steroidogenic enzymes and insl3 are not affected. All the above chemicals disrupt androgen signalling in the foetal male rat and produce some malformations in common, but the precise profiles of effects in the offspring are pathognomonic for each mode of action. For example, the ‘phthalate syndrome’ vs. the ‘vinclozolin syndrome’ each displays a profile of effects which is clearly different. In summary, as more and more molecular studies with anti‐androgenic compounds are conducted, the number of mechanisms by which compounds can affect the androgen signalling pathway is likely to increase. Furthermore, the effects of mixtures of these compounds are just beginning to be explored.
Combined exposure to anti‐androgens causes markedly increased frequencies of hypospadias in the rat
Authors: Christiansen S. , Scholze M. , Axelstad M. , Boberg J. , Kortenkamp A. , Hass U. 
Published: March 2008

SummaryThe incidence of hypospadias is increasing in young boys, but it remains unclear whether human exposure to endocrine disrupting chemicals plays a role. Risk assessment is based on estimation of no‐observed‐adverse‐effect levels for single compounds, although humans are exposed to combinations of several anti‐androgenic chemicals. In a mixture (MIX) study with three androgen receptor antagonists, vinclozolin, flutamide and procymidone, rats were gavaged during gestation and lactation with several doses of a MIX of the three chemicals or the chemicals alone. External malformations of the male reproductive organs were assessed on PND 47 using a score from 0 to 3 (normal to marked) for hypospadias. Markedly increased frequencies were observed after exposure to a MIX of the three chemicals compared to administration of the three chemicals alone. Anogenital distance at PND 1, nipple retention at PND 13, and dysgenesis score at PND 16 were highly correlated with the occurrence of hypospadias, and MIX effects were seen at doses where each of the individual chemicals caused no observable effects. Therefore, the results indicate that doses of anti‐androgens, which appear to induce no hypospadias when judged on their own, may induce a very high frequency of hypospadias when they interact in concert with other anti‐androgens.