Inducible cytochrome P450 activities in renal glomerular mesangial cells: biochemical basis for antagonistic interactions among nephrocarcinogenic polycyclic aromatic hydrocarbons

BACKGROUND: Benzo(a)pyrene (BaP), anthracene (ANTH) and chrysene (CHRY) are polynuclear aromatic hydrocarbons (PAHs) implicated in renal toxicity and carcinogenesis. These PAHs elicit cell type-specific effects that help predict toxicity outcomes in vitro and in vivo. While BaP and ANTH selectively injure glomerular mesangial cells, and CHRY targets cortico-tubular epithelial cells, binary or ternary mixtures of these hydrocarbons markedly reduce the overall cytotoxic potential of individual hydrocarbons. METHODS: To study the biochemical basis of these antagonistic interactions, renal glomerular mesangial cells were challenged with BaP alone (0.03 – 30 μM) or in the presence of ANTH (3 μM) or CHRY (3 μM) for 24 hr. Total RNA and protein will be harvested for Northern analysis and measurements of aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin-O-deethylase (EROD) activity, respectively, to evaluate cytochrome P450 mRNA and protein inducibility. Cellular hydrocarbon uptake and metabolic profiles of PAHs were analyzed by high performance liquid chromatography (HPLC). RESULTS: Combined hydrocarbon treatments did not influence the cellular uptake of individual hydrocarbons. ANTH or CHRY strongly repressed BaP-inducible cytochrome P450 mRNA and protein expression, and markedly inhibited oxidative BaP metabolism. CONCLUSION: These findings indicate that antagonistic interactions among nephrocarcinogenic PAHs involve altered expression of cytochrome P450s that modulate bioactivation profiles and nephrotoxic/ nephrocarcinogenic potential

Risk scoring models for trade credit in small and medium enterprises

Trade credit refers to providing goods and services on a deferred payment basis. Commercial credit management is a matter of great importance for most small and medium enterprises (SMEs), since it represents a significant portion of their assets. Commercial lending involves assuming some credit risk due to exposure to default. Thus, the management of trade credit and payment delays is strongly related to the liquidation and bankruptcy of enterprises. In this paper we study the relationship between trade credit management and the level of risk in SMEs. Despite its relevance for most SMEs, this problem has not been sufficiently analyzed in the existing literature. After a brief review of existing literature, we use a large database of enterprises to analyze data and propose a multivariate decision-tree model which aims at explaining the level of risk as a function of several variables, both of financial and non-financial nature. Decision trees replace the equation in parametric regression models with a set of rules. This feature is an important aid for the decision process of risk experts, as it allows them to reduce time and then the economic cost of their decisions

Glucosylsphingosine Is a Highly Sensitive and Specific Biomarker for Primary Diagnostic and Follow-Up Monitoring in Gaucher Disease in a Non-Jewish, Caucasian Cohort of Gaucher Disease Patients

Gaucher disease (GD) is the most common lysosomal storage disorder (LSD). Based on a deficient β-glucocerebrosidase it leads to an accumulation of glucosylceramide. Standard diagnostic procedures include measurement of enzyme activity, genetic testing as well as analysis of chitotriosidase and CCL18/PARC as biomarkers. Even though chitotriosidase is the most well-established biomarker in GD, it is not specific for GD. Furthermore, it may be false negative in a significant percentage of GD patients due to mutation. Additionally, chitotriosidase reflects the changes in the course of the disease belatedly. This further enhances the need for a reliable biomarker, especially for the monitoring of the disease and the impact of potential treatments.Here, we evaluated the sensitivity and specificity of the previously reported biomarker Glucosylsphingosine with regard to different control groups (healthy control vs. GD carriers vs. other LSDs).Only GD patients displayed elevated levels of Glucosylsphingosine higher than 12 ng/ml whereas the comparison controls groups revealed concentrations below the pathological cut-off, verifying the specificity of Glucosylsphingosine as a biomarker for GD. In addition, we evaluated the biomarker before and during enzyme replacement therapy (ERT) in 19 patients, demonstrating a decrease in Glucosylsphingosine over time with the most pronounced reduction within the first 6 months of ERT. Furthermore, our data reveals a correlation between the medical consequence of specific mutations and Glucosylsphingosine.In summary, Glucosylsphingosine is a very promising, reliable and specific biomarker for GD

Towards quantum computing with single atoms and optical cavities on atom chips

We report on recent developments in the integration of optical microresonators into atom chips and describe some fabrication and implementation challenges. We also review theoretical proposals for quantum computing with single atoms based on the observation of photons leaking through the cavity mirrors. The use of measurements to generate entanglement can result in simpler, more robust and scalable quantum computing architectures. Indeed, we show that quantum computing with atom-cavity systems is feasible even in the presence of relatively large spontaneous decay rates and finite photon detector efficiencies.Comment: 14 pages, 6 figure

Building the capacity to solve complex health challenges in Sub-Saharan Africa : CARTA’s multidisciplinary PhD training

Objectives: To develop a curriculum (Joint Advanced Seminars- JAS) that produced PhD fellows who understood that health is an outcome of multiple determinants within complex environments and that approaches from a range of disciplines is required to address health and development within the Consortium for Advanced Research Training in Africa. We sought to attract PhD fellows, supervisors and teaching faculty from a range of disciplines into the program. Methods: Multidisciplinary teams developed the JAS curriculum. CARTA PhD fellowships were open to academics in consortium member institutions, irrespective of primary discipline, interested in doing a PhD in public and population health. Supervisors and JAS faculty were recruited from CARTA institutions. We use routine JAS evaluation data (closed and open ended questions) collected from PhD fellows at every JAS, a survey of one CARTA cohort and an external evaluation of CARTA to assess the impact of the JAS curriculum on learning. Results: We describe our pedagogic approach arguing its centrality to an appreciation of multiple disciplines and illustrate how it promotes working in multidisciplinary ways. CARTA has attracted PhD fellows, supervisors and JAS teaching faculty from across a range of disciplines. Evaluations indicate PhD fellows have a greater appreciation of how disciplines other than their own are important to understand health and its determinants and an appreciation and capacity to employ mixed methods research. Conclusions: In the short-term, we have been effective in promoting an understanding of multidisciplinarity resulting in fellows using methods from beyond their discipline of origin. This curriculum has international application

Predicting ICU survival: A meta-level approach

<p>Abstract</p> <p>Background</p> <p>The performance of separate Intensive Care Unit (ICU) status scoring systems vis-à-vis prediction of outcome is not satisfactory. Computer-based predictive modeling techniques may yield good results but their performance has seldom been extensively compared to that of other mature or emerging predictive models. The objective of the present study was twofold: to propose a prototype meta-level predicting approach concerning Intensive Care Unit (ICU) survival and to evaluate the effectiveness of typical mining models in this context.</p> <p>Methods</p> <p>Data on 158 men and 46 women, were used retrospectively (75% of the patients survived). We used Glasgow Coma Scale (GCS), Acute Physiology And Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment (SOFA) and Injury Severity Score (ISS) values to structure a decision tree (DTM), a neural network (NNM) and a logistic regression (LRM) model and we evaluated the assessment indicators implementing Receiver Operating Characteristics (ROC) plot analysis.</p> <p>Results</p> <p>Our findings indicate that regarding the assessment of indicators' capacity there are specific discrete limits that should be taken into account. The Az score ± SE was 0.8773± 0.0376 for the DTM, 0.8061± 0.0427 for the NNM and 0.8204± 0.0376 for the LRM, suggesting that the proposed DTM achieved a near optimal Az score.</p> <p>Conclusion</p> <p>The predicting processes of ICU survival may go "one step forward", by using classic composite assessment indicators as variables.</p

Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors

Background Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (177Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. Methods We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either 177Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (177Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. Results At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 177Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. Conclusions Treatment with 177Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the 177Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11

The stellar halo of the Galaxy

Stellar halos may hold some of the best preserved fossils of the formation history of galaxies. They are a natural product of the merging processes that probably take place during the assembly of a galaxy, and hence may well be the most ubiquitous component of galaxies, independently of their Hubble type. This review focuses on our current understanding of the spatial structure, the kinematics and chemistry of halo stars in the Milky Way. In recent years, we have experienced a change in paradigm thanks to the discovery of large amounts of substructure, especially in the outer halo. I discuss the implications of the currently available observational constraints and fold them into several possible formation scenarios. Unraveling the formation of the Galactic halo will be possible in the near future through a combination of large wide field photometric and spectroscopic surveys, and especially in the era of Gaia.Comment: 46 pages, 16 figures. References updated and some minor changes. Full-resolution version available at http://www.astro.rug.nl/~ahelmi/stellar-halo-review.pd

Informing research priorities for immature sea turtles through expert elicitation

This is the final version. Available from Inter Research via the DOI in this record. Although sea turtles have received substantial focus worldwide, research on the immature life stages is still relatively limited. The latter is of particular importance, given that a large proportion of sea turtle populations comprises immature individuals. We set out to identify knowledge gaps and identify the main barriers hindering research in this field. We analyzed the perceptions of sea turtle experts through an online survey which gathered their opinions on the current state of affairs on immature sea turtle research, including species and regions in need of further study, priority research questions, and barriers that have interfered with the advancement of research. Our gap analysis indicates that studies on immature leatherback Dermochelys coriacea and hawksbill Eretmochelys imbricata turtles are lacking, as are studies on all species based in the Indian, South Pacific, and South Atlantic Oceans. Experts also perceived that studies in population ecology, namely on survivorship and demography, and habitat use/behavior, are needed to advance the state of knowledge on immature sea turtles. Our survey findings indicate the need for more interdisciplinary research, collaborative efforts (e.g. data-sharing, joint field activities), and improved communication among researchers, funding bodies, stakeholders, and decision-makers