The FMCA-GM assays,high throughput non-clonogenic alternatives to CFU-GM in preclinical hematotoxicity testing

One of the most common dose limiting adverse effects in cancer treatment is myelotoxicity. The aim of this study was to develop an in vitro method for measuring potential myelotoxic properties of a drug candidate in a high throughput setting. Human CD34⁺ progenitor cells from umbilical cord blood were plated in 384-well microplates with drugs in liquid culture, supplemented with specific cytokines for the granulocytopoietic-macrophage lineage. After 7 or 14 days of proliferation and differentiation the cells were analyzed using the automated non-clonogenic fluorometric microculture cytotoxicity assay (FMCA). Two types of assays setups were evaluated, the FMCA-GM7 where cells were exposed to drugs directly after thawing and cytotoxicity measured on day 7 in contrast to the FMCA-GM14 where the cells were cultured 7 days prior to plating and drug exposure, with viability analysis on day 14 of differentiation. Drug sensitivity was similar in both assays and method validation was performed using 24 drugs with known myelotoxic profile (acyclovir, bortezomib, busulfan, carboplatin, chloramphenicol, chlorpromazine, cisplatin, cytarabine, clozapine, doxorubicin, erlotinib, etoposide, 5-fluorouracil, fludarabine, gefitinib, gemcitabine, hydroxyurea, imatinib, lomustine, melphalan, sorafenib, sunitinib, taxol and 6-thioguanine). The 50% inhibitory concentrations (IC₅₀) from the FMCA-GM7 and the FMCA-GM14 correlated highly (r = 0.83) and (r = 0.82), respectively, with IC₅₀ from the established clonogenic assay (CFU-GM), obtained from the literature. The current data suggests that the FMCA-GM could offer a simple and robust alternative to the CFU-GM assay in preclinical hematotoxicity studies.     

AhR and ARNT modulate ER signaling

The aryl hydrocarbon receptor (AhR), in complex with its binding partner ARNT, mediates the cellular response to xenobiotic compounds such as the environmental pollutant dioxin. In addition, the AhR has important regulatory roles in normal physiology. For instance, there is extensive data showing an intricate relationship between the AhR and estrogen receptor (ER) pathways.     

Lupus nephritis: the central role of nucleosomes revealed

Systemic lupus erythematosus (SLE) is an autoimmune syndrome characterized by autoantibodies to nuclear constituents. Some of these antibodies are diagnostically important, whereas others act as disease-modifying factors. One clinically important factor is autoantibodies against dsDNA and nucleosomes, which have overlapping diagnostic and nephritogenic impact in SLE. Although a scientific focus for 5 decades, the molecular and cellular origin of these antibodies, and why they are associated with lupus nephritis, is still not fully understood. A consensus has, however, evolved that antibodies to dsDNA and nucleosomes are central pathogenic factors in the development of lupus nephritis. In contrast, no agreement has been reached as to which glomerular structures are bound by nephritogenic anti-nucleosome antibodies in vivo. Mutually contradictory paradigms and models have evolved simply because we still lack precise and conclusive data to provide definitive insight into how autoantibodies induce lupus nephritis and which specificity is critical in the nephritic process(es). In this review, data demonstrating the central role of nucleosomes in inducing and binding potentially nephritogenic antibodies to DNA and nucleosomes are presented and discussed. These autoimmune-inducing processes are discussed in the context of Matzinger’s danger model (Matzinger P: Friendly and dangerous signals: is the tissue in control? Nat Immunol 2007, 8:11–13; Matzinger P: The danger model: a renewed sense of self. Science 2002, 296:301–305; Matzinger P: Tolerance, danger, and the extended family. Annu Rev Immunol 1994, 12:991–1045) and Medzhitov’s and Janeway’s (Medzhitov R, Janeway CA Jr: Decoding the patterns of self and nonself by the innate immune system. Science 2002, 296:298–300; Medzhitov R, Janeway CA Jr: How does the immune system distinguish self from nonself? Semin Immunol 2000, 12:185–188; Janeway CA Jr, Medzhitov R: Innate immune recognition. Annu Rev Immunol 2002, 20:197–216) distinction of noninfectious self (NIS) and infectious nonself (INS). The mechanisms leading to production of potentially nephritogenic anti-nucleosome antibodies and to overt lupus nephritis are interpreted in the context of these paradigms.     

Environmental implication of iodine in water,milk and other foods used in Saharawi refugees camps in Tindouf,Algeria

A cross-sectional survey among Saharawi refugees in four camps carried out in 2007 revealed enlarged thyroid volume and high urinary iodine concentration in women and school children. The purpose of this paper is to describe the content of iodine in food and water and explore whether any sources in the environment can explain the situation. Samples of water (n = 143), milk (n = 19) and salt (n = 89) were collected. Different wells supplied the camps with water and the median iodine concentration was 108 μg/L (range 55–545 μg/L) and significantly higher in two of the camps (El Aiune and Ausserd; 300 μg/L (range 55–545 μg/L)), compared to the two other camps (Smara; 87 μg/L (55–127 μg/L) and Dakla; 70 μg/L (55–96 μg/L)). In local goat milk the median iodine concentration was 370 μg/L (70–13,070 μg/L). The median content of iodine in salt was 6 μg/g (0–51 μg/g). Water and local milk were the most important sources of iodine for women. High levels of iodine in water seem to be one of the main sources of iodine that affects humans as well as animals.     

Care for Nurses Only? Medicine and the Perceiving Eye

In this paper I introduce a theoretical framework on care developed by the Norwegian nurse and philosopher Kari Martinsen, and I argue that this approach has relevance not only within nursing, but also within clinical medicine. I try to substantiate this claim by analysing some of the key concepts in this approach, and I illustrate the potential clinical relevance of this approach by applying it in relation to two care scenarios. Finally, I discuss some of the concerns that have been raised in relation to the aim of highlighting care in medicine.