bluuebunny/crossref_metadata_2025 huggingface dataset:
Contrasting roles of SPARC-related granuloma in bacterial containment and in the induction of anti–Salmonella typhimurium immunity
Authors: Rotta Gianluca , Matteoli Gianluca , Mazzini Elisa , Nuciforo Paolo , Colombo Mario P. , Rescigno Maria
Published: March 2008

The role of matricellular proteins in bacterial containment and in the induction of pathogen-specific adaptive immune responses is unknown. We studied the function of the matricellular protein secreted protein, acidic and rich in cysteine (SPARC/osteonectin) in the dissemination of locally injected Salmonella typhimurium and in the subsequent immune response. We show that SPARC was required for the development of organized acute inflammatory reactions with granuloma-like (GL) features and for the control of bacterial spreading to draining lymph nodes (DLNs). However, SPARC-related GL also inhibited dendritic cell (DC) migration to the DLNs and limited the development of adaptive immune response, thus conferring increased susceptibility to the pathogen. In SPARC-deficient mice, both DC migration and antigen-specific responses were restored against bacteria, leading to protective anti–S. typhimurium immunity. This highlights a new function of matricellular proteins in bacterial infection and suggests that initial containment of bacteria can have drawbacks.
Allergic pulmonary inflammation in mice is dependent on eosinophil-induced recruitment of effector T cells
Authors: Jacobsen Elizabeth A. , Ochkur Sergei I. , Pero Ralph S. , Taranova Anna G. , Protheroe Cheryl A. , Colbert Dana C. , Lee Nancy A. , Lee James J.
Published: March 2008

The current paradigm surrounding allergen-mediated T helper type 2 (Th2) immune responses in the lung suggests an almost hegemonic role for T cells. Our studies propose an alternative hypothesis implicating eosinophils in the regulation of pulmonary T cell responses. In particular, ovalbumin (OVA)-sensitized/challenged mice devoid of eosinophils (the transgenic line PHIL) have reduced airway levels of Th2 cytokines relative to the OVA-treated wild type that correlated with a reduced ability to recruit effector T cells to the lung. Adoptive transfer of Th2-polarized OVA-specific transgenic T cells (OT-II) alone into OVA-challenged PHIL recipient mice failed to restore Th2 cytokines, airway histopathologies, and, most importantly, the recruitment of pulmonary effector T cells. In contrast, the combined transfer of OT-II cells and eosinophils into PHIL mice resulted in the accumulation of effector T cells and a concomitant increase in both airway Th2 immune responses and histopathologies. Moreover, we show that eosinophils elicit the expression of the Th2 chemokines thymus- and activation-regulated chemokine/CCL17 and macrophage-derived chemokine/CCL22 in the lung after allergen challenge, and blockade of these chemokines inhibited the recruitment of effector T cells. In summary, the data suggest that pulmonary eosinophils are required for the localized recruitment of effector T cells.
A novel role for Lef-1, a central transcription mediator of Wnt signaling, in leukemogenesis
Authors: Petropoulos Konstantin , Arseni Natalia , Schessl Christina , Stadler Christiane R. , Rawat Vijay P.S. , Deshpande Aniruddha J. , Heilmeier Bernhard , Hiddemann Wolfgang , Quintanilla-Martinez Leticia , Bohlander Stefan K. , Feuring-Buske Michaela , Buske Christian
Published: March 2008

Canonical Wnt signaling is critically involved in normal hematopoietic development and the self-renewal process of hematopoietic stem cells (HSCs). Deregulation of this pathway has been linked to a large variety of cancers, including different subtypes of leukemia. Lef-1 is a major transcription factor of this pathway and plays a pivotal role in lymphoid differentiation as well as in granulopoiesis. Here, we demonstrate Lef-1 expression in murine HSCs as well as its expression in human leukemia. Mice transplanted with bone marrow retrovirally transduced to express Lef-1 or a constitutive active Lef-1 mutant showed a severe disturbance of normal hematopoietic differentiation and finally developed B lymphoblastic and acute myeloid leukemia (AML). Lef-1–induced AMLs were characterized by immunoglobulin (Ig) DH-JH rearrangements and a promiscuous expression of lymphoid and myeloid regulatory factors. Furthermore, single cell experiments and limiting dilution transplantation assays demonstrated that Lef-1–induced AML was propagated by a leukemic stem cell with lymphoid characteristics displaying Ig DH-JH rearrangements and a B220+ myeloid marker− immunophenotype. These data indicate a thus far unknown role of Lef-1 in the biology of acute leukemia, pointing to the necessity of balanced Lef-1 expression for an ordered hematopoietic development.
DNA-PKcs and Artemis function in the end-joining phase of immunoglobulin heavy chain class switch recombination
Authors: Franco Sonia , Murphy Michael M. , Li Gang , Borjeson Tiffany , Boboila Cristian , Alt Frederick W.
Published: March 2008

The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and Artemis are classical nonhomologous DNA end-joining (C-NHEJ) factors required for joining a subset of DNA double-strand breaks (DSB), particularly those requiring end processing. In mature B cells, activation-induced cytidine deaminase (AID) initiates class switch recombination (CSR) by introducing lesions into S regions upstream of two recombining CH exons, which are processed into DSBs and rejoined by C-NHEJ to complete CSR. The function of DNA-PKcs in CSR has been controversial with some reports but not others showing that DNA-PKcs–deficient mice are significantly impaired for CSR. Artemis-deficient B cells reportedly undergo CSR at normal levels. Overall, it is still not known whether there are any CSR-associated DSBs that require DNA-PKcs and/or Artemis to be joined. Here, we have used an immunoglobulin (Ig)H locus-specific fluorescent in situ hybridization assay to unequivocally demonstrate that both DNA-PKcs and, unexpectedly, Artemis are necessary for joining a subset of AID-dependent DSBs. In the absence of either factor, B cells activated for CSR frequently generate AID-dependent IgH locus chromosomal breaks and translocations. We also find that under specific activation conditions, DNA-PKcs−/− B cells with chromosomal breaks are eliminated or at least prevented from progressing to metaphase via a p53-dependent response.
A Room with a Viewpoint: Using Social Norms to Motivate Environmental Conservation in Hotels
Authors: Goldstein Noah J. , Cialdini Robert B. , Griskevicius Vladas
Published: March 2008

Two field experiments examined the effectiveness of signs requesting hotel guests' participation in an environmental conservation program. Appeals employing descriptive norms (e.g., “the majority of guests reuse their towels”) proved superior to a traditional appeal widely used by hotels that focused solely on environmental protection. Moreover, normative appeals were most effective when describing group behavior that occurred in the setting that most closely matched individuals' immediate situational circumstances (e.g., “the majority of guests in this room reuse their towels”), which we refer to as provincial norms. Theoretical and practical implications for managing proenvironmental efforts are discussed.
Robustified MANOVA with applications in detecting differentially expressed genes from oligonucleotide arrays
Authors: Xu Jin , Cui Xinping
Published: March 2008

Motivation: Oligonucleotide arrays such as Affymetrix GeneChips use multiple probes, or a probe set, to measure the abundance of mRNA of every gene of interest. Some analysis methods attempt to summarize the multiple observations into one single score before conducting further analysis such as detecting differentially expressed genes (DEG), clustering and classification. However, there is a risk of losing a significant amount of information and consequently reaching inaccurate or even incorrect conclusions during this data reduction.

Results: We developed a novel statistical method called robustified multivariate analysis of variance (MANOVA) based on the traditional MANOVA model and permutation test to detect DEG for both one-way and two-way cases. It can be extended to detect some special patterns of gene expression through profile analysis across k (≥2) populations. The method utilizes probe-level data and requires no assumptions about the distribution of the dataset. We also propose a method of estimating the null distribution using quantile normalization in contrast to the ‘pooling’ method (Section 3.1). Monte Carlo simulation and real data analysis are conducted to demonstrate the performance of the proposed method comparing with the ‘pooling’ method and the usual Analysis of Variance (ANOVA) test based on the summarized scores. It is found that the new method successfully detects DEG under desired false discovery rate and is more powerful than the competing method especially when the number of groups is small.

Availability: The package of robustified MANOVA can be downloaded from http://faculty.ucr.edu/~xpcui/software

Contact:  xinping.cui@ucr.edu; jxu@stat.ecnu.edu.cn
Intratumor heterogeneity of epidermal growth factor receptor mutations in lung cancer and its correlation to the response to gefitinib
Authors: Taniguchi Kazuya , Okami Jiro , Kodama Ken , Higashiyama Masahiko , Kato Kikuya
Published: March 2008

Somatic mutations introduced into the epidermal growth factor receptor (EGFR) gene in non‐small‐cell lung cancer (NSCLC) are important factors to determine therapeutic responses to gefitinib. The current diagnostic test measures the overall EGFR mutation status of the cancer tissue, and may ignore the presence of non‐mutated, gefitinib‐unresponsive cancer cells. Twenty‐one NSCLC patients with EGFR mutations were recruited for the study. All patients were treated with gefitinib after surgical treatment. Fifty to sixty areas of NSCLC tumors were sampled from each tissue, and their EGFR mutation states were determined by a primer extension assay. This assay discriminates between EGFR mutation‐positive and ‐negative cancer cells within a single tumor tissue. Fifteen tissues consisted only of cells with EGFR mutations, but the remaining six tissues contained both mutated and non‐mutated cells. Time to disease progression and overall survival after gefitinib treatment were significantly shorter in those patients with EGFR heterogeneity (P = 0.009 and P = 0.003, respectively). A considerable proportion of NSCLC contains a heterogeneous population of both EGFR mutated and non‐mutated cancer cells, resulting in a reduced response to gefitinib. The intratumor genetic heterogeneity of a target molecule such as EGFR would be an important factor to consider when treating patients with molecular target agents. (Cancer Sci 2008; 99: 929–935)
Application of the Sleeping Beauty transposon system to avian cells
Authors: Kong B.‐W. , Carlson D. F. , Fahrenkrug S. C. , Foster D. N.
Published: March 2008

We have for the first time assessed the ability of the Sleeping Beauty (SB) transposon system to enhance transgenesis in chicken and turkey cells. The efficiency of transgenesis with a transposon encoding an antibiotic resistance gene was dramatically enhanced 15‐ to 35‐fold when transposase was supplied by co‐transfection of immortalized chicken and turkey cells with a construct encoding SB. In contrast, transgenesis of primary chicken embryo fibroblast (CEF) cells was not significantly increased by providing transposase, suggesting that the benefits of transposon–transgenesis in primary avian cells will require the application of more efficient transfection methods, further enhanced SB transposase or an alternative transposon system.
Characterization of the porcine KIT ligand gene: expression analysis, genomic structure, polymorphism detection and association with coat colour traits
Authors: Hadjiconstantouras C. , Sargent C. A. , Skinner T. M. , Archibald A. L. , Haley C. S. , Plastow G. S.
Published: March 2008

Kit ligand (KITLG) is the ligand for the type III receptor tyrosine kinase KIT. Studies of the KIT/KITLG pathway in a number of mammalian species have shown that it is important for the development of stem cell populations in haematopoietic tissues, germ cells in reproductive organs and the embryonic migrating melanoblasts that give rise to melanocytes. Consequently, mutations in the pathway may result in a range of defects including anaemia, sterility and de‐pigmentation. The cDNA sequence of the porcine KITLG gene has been reported previously, and is an attractive candidate locus for moderating coat colour in pigs. In this paper we report the gene structure and physical mapping of the porcine gene. We also report the identification of polymorphisms in the gene, one of which was used to confirm linkage to chromosome 5. Preliminary RNA expression studies using a panel of tissues have shown that in addition to the known variant lacking exon 6, there is alternative splicing of exon 4. However, little evidence was found for the KITLG gene being linked to variation in colour in a Meishan × Large White cross.
HIC1 tumour suppressor gene is suppressed in acute myeloid leukaemia and induced during granulocytic differentiation
Authors: Britschgi Christian , Jenal Mathias , Rizzi Mattia , Mueller Beatrice U. , Torbett Bruce E. , Andres Anne‐Catherine , Tobler Andreas , Fey Martin F. , Tschan Mario P.
Published: March 2008

A hallmark of acute myeloid leukaemia (AML) is a block in differentiation caused by deregulated gene expression. The tumour suppressor Hypermethylated In Cancer 1 (HIC1) is a transcriptional repressor, which is epigenetically silenced in solid cancers. HIC1 mRNA expression was found to be low in 128 patient samples of AML and CD34+ progenitor cells when compared with terminally differentiated granulocytes. HIC1 mRNA was induced in a patient with t(15;17)‐positive acute promyelocytic leukaemia receiving all‐trans retinoic acid (ATRA) therapy. We therefore investigated whether HIC1 plays a role in granulocytic differentiation and whether loss of function of this gene might contribute to the differentiation block in AML. We evaluated HIC1 mRNA levels in HL‐60 and U‐937 cells upon ATRA‐induced differentiation and in CD34+ progenitor cells after granulocyte colony‐stimulating factor‐induced differentiation. In both models of granulocytic differentiation, we observed significant HIC1 induction. When HIC1 mRNA was suppressed in HL‐60 cells using stably expressed short hairpin RNA targeting HIC1, granulocytic differentiation was altered as assessed by CD11b expression. Bisulphite sequencing of GC‐rich regions (CpG islands) in the HIC1 promoter provided evidence that the observed suppression in HL‐60 cells was not because of promoter hypermethylation. Our findings indicate a role for the tumour suppressor gene HIC1 in granulocytic differentiation. Low expression of HIC1 may very well contribute to pathogenic events in leukaemogenesis.
Recessive congenital methaemoglobinaemia: cytochrome b5 reductase deficiency
Authors: Percy Melanie J. , Lappin Terry R.
Published: March 2008

Some 60 years ago, Quentin Gibson reported the first hereditary disorder involving an enzyme when he deduced that familial methaemoglobinaemia was caused by an enzymatic lesion associated with the glycolysis pathway in red blood cells. This disorder, now known as recessive congenital methaemoglobinaemia (RCM), is caused by NADH‐cytochrome b5 reductase (cb5r) deficiency. Two distinct clinical forms, types I and II, have been recognized, both characterized by cyanosis from birth. In type II, the cyanosis is accompanied by neurological impairment and reduced life expectancy. Cytochrome b5 reductase is composed of one FAD and one NADH binding domain linked by a hinge region. It is encoded by the CYB5R3 (previously known as DIA1) gene and more than 40 mutations have been described, some of which are common to both types of RCM. Mutations associated with type II tend to cause incorrect splicing, disruption of the active site or truncation of the protein. At present the description of the sequence variants of cb5r in the literature is confusing, due to the use of two conventions which differ by one codon position. Herein we propose a new system for nomenclature of cb5r based on recommendations of the Human Genome Variation Society. The development of a heterologous expression system has allowed the impact of naturally occurring variants of cb5r to be assessed and has provided insight into the function of cb5r.
Anti‐CD20 monoclonal antibody therapy in multiple myeloma
Authors: Kapoor Prashant , Greipp Patricia T. , Morice William G. , Rajkumar S. Vincent , Witzig Thomas E. , Greipp Philip R.
Published: March 2008

CD20 is a particularly appealing target that is expressed on the surface of almost all B cells, with no significant shedding, secretion or internalization. In contrast to the demonstrated efficacy of anti‐CD20 strategies in various B‐cell lymphoproliferative disorders, the role of such therapy in multiple myeloma is undetermined and controversial. The expression of CD20 by myeloma cells is heterogeneous, and can be detected only in 13–22% of patients. However, there is increasing interest in testing anti‐CD20 therapy in myeloma because of recent studies suggesting the existence of clonogenic CD20‐positive precursor B cells in the disease. This article reviews the rationale, preclinical and clinical activity of anti‐CD20 therapy in myeloma. Clinical trials show that anti‐CD20 therapy with rituximab elicits a partial response in approximately 10% of CD20+ patients with multiple myeloma. In addition, there is preliminary evidence of disease stabilization in 50–57% of CD20+ patients for a period of 10–27 months. Further large‐scale clinical trials are therefore needed to establish the role of this promising strategy in the treatment of myeloma.
Murine bone marrow derived stromal progenitor cells fail to prevent or treat acute graft‐versus‐host disease
Authors: Badillo Andrea T. , Peranteau William H. , Heaton Todd E. , Quinn Courtney , Flake Alan W.
Published: March 2008

Human and murine stromal progenitor cells (SPCs) can suppress alloresponse in vitro, suggesting that SPCs may have clinical application toward prevention or treatment of graft‐versus‐host disease (GVHD). However, th eresults of in vivo studies have been conflicting. This study utilized an established murine model of acute GVHD to assess the ability of bone marrow derived murine SPCs (mSPCs) to prevent or treat GVHD. GVHD was established by transplantation of B6 bone marrow and spleen cells into lethally irradiated (900 cGy) B6 × BALB/c F1 recipients. mSPCs were administered using various dose and timing protocols designed to either prevent or treat GVHD. After transplantation, mice were monitored daily for weight and survival. Differences in symptom severity were compared using a clinical GVHD scoring system. All GVHD control mice died of lethal GVHD. All groups treated with mSPCs for the prevention of GVHD went on to develop clinical GVHD with no alteration of the disease course or severity compared to controls. Administration of mSPC after the development of GVHD failed to improve the disease course. We conclude that in this model, the ability of SPCs to suppress alloresponse in vitro does not correlate with in vivo prevention or treatment of acute GVHD.
Epigenetic inactivation of suppressors of cytokine signalling in Philadelphia‐negative chronic myeloproliferative disorders
Authors: Capello Daniela , Deambrogi Clara , Rossi Davide , Lischetti Tiziana , Piranda Daniela , Cerri Michaela , Spina Valeria , Rasi Silvia , Gaidano Gianluca , Lunghi Monia
Published: March 2008

Ph‐negative chronic myeloproliferative disorders (CMPD) are characterized by constitutive Janus kinase‐signal transducer and activator of transcription (JAK‐STAT) activation. SOCS3, SOCS1 and PTPN6 (SHP1) are negative regulators of the JAK‐STAT pathway. We investigated epigenetic and genetic inactivation of SOCS3, SOCS1 and PTPN6 in 112 CMPD and 20 acute myeloid leukaemia (AML) post‐CMPD. SOCS3 methylation occurred at high frequency in both CMPD (46/112; 41·1%) and AML post‐CMPD (10/17; 58·8%) and was associated with transcriptional silencing. In contrast, methylation of SOCS1 and PTPN6 was observed in only a fraction of CMPD (15/112, 13·4% for SOCS1; and 8/112, 7·1% for PTPN6) and AML post‐CMPD (3/20, 15% for SOCS1; and 1/20, 5% for PTPN6). No somatic mutations of SOCS1 were found in CMPD. SOCS3, SOCS1 and PTPN6 methylation occurred in both JAK2V617F‐positive (35·1% for SOCS3; 14·9% for SOCS1; 8·1% for PTPN6) and JAK2V617F‐negative (57·1% for SOCS3; 14·3% for SOCS1; and 9·5% for PTPN6) CMPD. These data indicate that methylation of SOCS3 and, to a lesser extent, SOCS1 and PTPN6 is a frequent event in both JAK2V617F‐positive and ‐negative CMPD and may act as an alternative or complementary mechanism to JAK2 mutations, enhancing cytokine signal transduction. The frequent inactivation of SOCS3 is a novel finding in CMPD with potential implications for the molecular pathology of these disorders.
Prospective study of homocysteine and MTHFR 677TT genotype and risk for venous thrombosis in a general population – results from the HUNT 2 study
Authors: Næss Inger Anne , Christiansen Sverre C. , Romundstad Pål R. , Cannegieter Suzanne C. , Blom Henk J. , Rosendaal Frits R. , Hammerstrøm Jens
Published: March 2008

This case‐cohort designed study prospectively investigated whether elevated homocysteine levels measured in blood samples drawn before the event and methylenetetrahydrofolate reductase (MTHFR) gene polymorphism (MTHFR C677T) were associated with subsequent first venous thrombosis (VT) in a general population. Between August 1995 and June 1997, blood was collected from 66 140 people in the second Norwegian Health Study of Nord‐Trøndelag (HUNT2). During a seven‐year follow‐up, 505 VT cases were identified. 1458 age‐ and sex‐matched controls were selected from the original cohort. Serum total homocysteine (tHcy) and MTHFR genotype were measured in stored samples that were drawn a median of 33 months before the events. The overall odds ratio (OR) was 1·50 [95% confidence interval (CI) 0·97–2·30] for homocysteine levels above versus below the 95th percentile. There was no graded association with VT over quintiles of homocysteine. In men the OR was 2·17 (95% CI 1·20–3·91) for levels above versus below the 95th percentile, but no association was found in women (OR 1·00). Stratification by age, predisposing risk factors or time to event did not change these results. The MTHFR 677TT genotype was not related to risk for VT. In conclusion, elevated homocysteine levels in the general population predicted subsequent first VT in men but not in women.
Detection of elevated levels of tumour‐associated microRNAs in serum of patients with diffuse large B‐cell lymphoma
Authors: Lawrie Charles H. , Gal Shira , Dunlop Heather M. , Pushkaran Beena , Liggins Amanda P. , Pulford Karen , Banham Alison H. , Pezzella Francesco , Boultwood Jacqueline , Wainscoat James S. , Hatton Christian S. R. , Harris Adrian L.
Published: March 2008

Circulating nucleic acids have been shown to have potential as non‐invasive diagnostic markers in cancer. We therefore investigated whether microRNAs also have diagnostic utility by comparing levels of tumour‐associated MIRN155 (miR‐155), MIRN210 (miR‐210) and MIRN21 (miR‐21) in serum from diffuse large B‐cell lymphoma (DLBCL) patients (n = 60) with healthy controls (n = 43). Levels were higher in patient than control sera (P = 0·009, 0·02 and 0·04 respectively). Moreover, high MIRN21 expression was associated with relapse‐free survival (P = 0·05). This is the first description of circulating microRNAs and suggests that microRNAs have potential as non‐invasive diagnostic markers for DLBCL and possibly other cancers.
The evolving use of serum free light chain assays in haematology
Authors: Pratt Guy
Published: March 2008

Over 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

Increasing 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

In 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.
Expression studies of missense mutations p.D141Y, p.C275S located in the propeptide of von Willebrand factor in patients with type 3 von Willebrand disease
Authors: BARONCIANI L. , FEDERICI A. B. , COZZI G. , LA MARCA S. , PUNZO M. , RUBINI V. , CANCIANI M. T. , MANNUCCI P. M.
Published: March 2008

Summary Missense mutations are not considered a common cause of type 3 von Willebrand’s disease (VWD), the most severe defect of von Willebrand factor (VWF) characterized by undetectable levels of this protein in plasma and platelets. Nevertheless, several missense mutations have been identified in these patients. In this study, we report the cases of two Italian patients with type 3 VWD, both compound heterozygotes for different missense mutations and null alleles, p.D141Y/c.2016_2019del and p.C275S/p.W222X. We performed in vitro expression studies of the candidate missense mutations, both located in the D1 domain of VWF propeptide, to confirm their link with the disease and to understand the mechanisms of type 3 VWD responsible in these patients. Mutant and wild‐type (WT) expression vectors were used for transient transfection and co‐transfection studies in COS‐7 cells. Single construct transfections of both missense mutations showed a strongly reduced but detectable secretion of recombinant (r)VWFs (approximately 15% of WT), with essentially only dimers being visualized on multimeric analysis. As expected, expression of a single construct of either mutation with the WT, showed mildly reduced secretion (approximately 40% of WT) and a full set of multimers. These expression studies indicate that the two amino acids D141 and C275 are key residues in the tertiary structure of the VWF propeptide. Their replacement with a tyrosine and a serine, respectively, might compromise propeptide folding, affecting both its intracellular survival and its capacity to mediate multimerization. Co‐expression of hybrid rVWFs confirmed the recessive inheritance pattern of these missense mutations.
Irony, critique and ethnomethodology in the study of computer work: irreconcilable tensions?
Authors: Marcon Teresa , Gopal Abhijit
Published: March 2008

Abstract. To broaden discussion of critique in the field of information systems beyond current approaches, we look outside the core management discourse and examine the critical element in ethnomethodological research on computer‐based work environments. Our examination reveals a form of critique that is above all without irony, seeking always to be respectful of the competence of research subjects, and informed by an in‐depth understanding of participants' practices. We argue that ethnomethodology is an often unrecognised critical approach that attempts to speak from within a community of practice and deliver critical insights that are responsive to the kinds of practical problems of interest to practitioners.
Examining technology, structure and identity during an Enterprise System implementation
Authors: Alvarez Rosio
Published: March 2008

Abstract. This paper presents a longitudinal study of an Enterprise System (ES) implementation by critically examining the discursive context in which an ES implementation unfolds. The findings show that users strongly supported the ES in the earlier stage of implementation when the technology was an imaginary phenomenon. However, in later stages, when the technology is in use, user support was not consistent. In this phase, the ES produces loss of control and an inability to function as an arbiter of fairness (in allocating resources associated with the system), thereby directly challenging existing professional identities and roles. These outcomes, in turn, generate acts of resistance on the part of workers. Users reach inside the technology and reshape it by devising creative workarounds that produce a sense of reskilling to counter the deskilling produced by the loss of control and power. The analysis also shows that an ES is a complex social phenomenon that is intricately linked to and complicit in shaping organizational structure and identity. In particular, this study shows how technology, structure and identity are in a mutually constitutive relationship.
The implications of a critical agenda in gender and IS research
Authors: Howcroft Debra , Trauth Eileen M.
Published: March 2008

Abstract.  This paper explores the nature of the critical agenda and endeavours to advance the critical debate by considering a particular case in point: gender and information systems (IS) research. It does so by drawing upon Chua's classic framework of outlining philosophical assumptions underpinning research and also by building upon prior work of the authors on the interconnections amongst research topic, epistemology and methodology. Specifically, it presents an argument for the benefits of adopting a critical perspective when studying gender and IS research, illustrating the additional insights that can be generated. These benefits and insights can also be mined from other areas of IS research.
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

The 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

Phthalates 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

Methoxyacetic 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

Environmental 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

Environmental 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

To 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

Population 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.