DUNDRUM-2: Prospective validation of a structured professional judgment instrument assessing priority for admission from the waiting list for a forensic mental health hospital

<p>Abstract</p> <p>Background</p> <p>The criteria for deciding who should be admitted first from a waiting list to a forensic secure hospital are not necessarily the same as those for assessing need. Criteria were drafted qualitatively and tested in a prospective 'real life' observational study over a 6-month period.</p> <p>Methods</p> <p>A researcher rated all those presented at the weekly referrals meeting using the DUNDRUM-1 triage security scale and the DUNDRUM-2 triage urgency scale. The key outcome measure was whether or not the individual was admitted.</p> <p>Results</p> <p>Inter-rater reliability and internal consistency for the DUNDRUM-2 were acceptable. The DUNDRUM-1 triage security score and the DUNDRUM-2 triage urgency score correlated r = 0.663. At the time of admission, after a mean of 23.9 (SD35.9) days on the waiting list, those admitted had higher scores on the DUNDRUM-2 triage urgency scale than those not admitted, with no significant difference between locations (remand or sentenced prisoners, less secure hospitals) at the time of admission. Those admitted also had higher DUNDRUM-1 triage security scores. At baseline the receiver operating characteristic area under the curve for a combined score was the best predictor of admission while at the time of admission the DUNDRUM-2 triage urgency score had the largest AUC (0.912, 95% CI 0.838 to 0.986).</p> <p>Conclusions</p> <p>The triage urgency items and scale add predictive power to the decision to admit. This is particularly true in maintaining equitability between those referred from different locations.</p

Absence of association between pyronaridine in vitro responses and polymorphisms in genes involved in quinoline resistance in Plasmodium falciparum

<p>Abstract</p> <p>Background</p> <p>The aim of the present work was to assess the <it>in vitro </it>cross-resistance of pyronaridine with other quinoline drugs, artesunate and several other commonly used anti-malarials and to evaluate whether decreased susceptibility to pyronaridine could be associated with genetic polymorphisms in genes involved in reduced quinoline susceptibility, such as <it>pfcrt</it>, <it>pfmdr1</it>, <it>pfmrp </it>and <it>pfnhe</it>.</p> <p>Methods</p> <p>The <it>in vitro </it>chemosusceptibility profiles of 23 strains of <it>Plasmodium falciparum </it>were analysed by the standard 42-hour ³H-hypoxanthine uptake inhibition method for pyronaridine, artesunate, chloroquine, monodesethylamodiaquine, quinine, mefloquine, lumefantrine, atovaquone, pyrimethamine and doxycycline. Genotypes were assessed for <it>pfcrt</it>, <it>pfmdr1</it>, <it>pfnhe-1 </it>and <it>pfmrp </it>genes.</p> <p>Results</p> <p>The IC₅₀values for pyronaridine ranged from 15 to 49 nM (geometric mean = 23.1 nM). A significant positive correlation was found between responses to pyronaridine and responses to artesunate (<it>r²</it>= 0.20; <it>P </it>= 0.0317) but too low to suggest cross-resistance. No significant correlation was found between pyronaridine IC₅₀and responses to other anti-malarials. Significant associations were not found between pyronaridine IC₅₀and polymorphisms in <it>pfcrt</it>, <it>pfmdr1</it>, <it>pfmrp </it>or <it>pfnhe-1</it>.</p> <p>Conclusion</p> <p>There was an absence of cross-resistance between pyronaridine and quinolines, and the IC₅₀values for pyronaridine were found to be unrelated to mutations in the transport protein genes <it>pfcrt</it>, <it>pfmdr1</it>, <it>pfmrp </it>or <it>pfnhe-1</it>, known to be involved in quinoline resistance. These results confirm the interest and the efficacy of the use of a combination of pyronaridine and artesunate in areas in which parasites are resistant to quinolines.</p

Lack of EGF receptor contributes to drug sensitivity of human germline cells

Germline mutations have been associated with generation of various types of tumour. In this study, we investigated genetic alteration of germline tumours that affect the drug sensitivity of cells. Although all germline tumour cells we tested were hypersensitive to DNA-damaging drugs, no significant alteration was observed in their DNA repair activity or the expression of DNA repair proteins. In contrast, germline tumours expressed very low level of epidermal growth factor receptor (EGFR) compared to drug-resistant ovarian cancer cells. An immunohistochemical analysis indicated that most of the primary germline tumours we tested expressed very low level of EGFR. In accordance with this, overexpression of EGFR in germline tumour cells showed an increase in drug resistance, suggesting that a lack of EGFR, at least in part, contributes to the drug sensitivity of germline tumours

A Wnt-Frz/Ror-Dsh Pathway Regulates Neurite Outgrowth in Caenorhabditis elegans

One of the challenges to understand the organization of the nervous system has been to determine how axon guidance molecules govern axon outgrowth. Through an unbiased genetic screen, we identified a conserved Wnt pathway which is crucial for anterior-posterior (A/P) outgrowth of neurites from RME head motor neurons in Caenorhabditis elegans. The pathway is composed of the Wnt ligand CWN-2, the Frizzled receptors CFZ-2 and MIG-1, the co-receptor CAM-1/Ror, and the downstream component Dishevelled/DSH-1. Among these, CWN-2 acts as a local attractive cue for neurite outgrowth, and its activity can be partially substituted with other Wnts, suggesting that spatial distribution plays a role in the functional specificity of Wnts. As a co-receptor, CAM-1 functions cell-autonomously in neurons and, together with CFZ-2 and MIG-1, transmits the Wnt signal to downstream effectors. Yeast two-hybrid screening identified DSH-1 as a binding partner for CAM-1, indicating that CAM-1 could facilitate CWN-2/Wnt signaling by its physical association with DSH-1. Our study reveals an important role of a Wnt-Frz/Ror-Dsh pathway in regulating neurite A/P outgrowth

Site-Directed Mutations and the Polymorphic Variant Ala160Thr in the Human Thromboxane Receptor Uncover a Structural Role for Transmembrane Helix 4

The human thromboxane A2 receptor (TP), belongs to the prostanoid subfamily of Class A GPCRs and mediates vasoconstriction and promotes thrombosis on binding to thromboxane (TXA2). In Class A GPCRs, transmembrane (TM) helix 4 appears to be a hot spot for non-synonymous single nucleotide polymorphic (nsSNP) variants. Interestingly, A160T is a novel nsSNP variant with unknown structure and function. Additionally, within this helix in TP, Ala1604.53 is highly conserved as is Gly1644.57. Here we target Ala1604.53 and Gly1644.57 in the TP for detailed structure-function analysis. Amino acid replacements with smaller residues, A160S and G164A mutants, were tolerated, while bulkier beta-branched replacements, A160T and A160V showed a significant decrease in receptor expression (Bmax). The nsSNP variant A160T displayed significant agonist-independent activity (constitutive activity). Guided by molecular modeling, a series of compensatory mutations were made on TM3, in order to accommodate the bulkier replacements on TM4. The A160V/F115A double mutant showed a moderate increase in expression level compared to either A160V or F115A single mutants. Thermal activity assays showed decrease in receptor stability in the order, wild type>A160S>A160V>A160T>G164A, with G164A being the least stable. Our study reveals that Ala1604.53 and Gly1644.57 in the TP play critical structural roles in packing of TM3 and TM4 helices. Naturally occurring mutations in conjunction with site-directed replacements can serve as powerful tools in assessing the importance of regional helix-helix interactions

Chemical–Genetic Profiling of Imidazo[1,2-a]pyridines and -Pyrimidines Reveals Target Pathways Conserved between Yeast and Human Cells

Small molecules have been shown to be potent and selective probes to understand cell physiology. Here, we show that imidazo[1,2-a]pyridines and imidazo[1,2-a]pyrimidines compose a class of compounds that target essential, conserved cellular processes. Using validated chemogenomic assays in Saccharomyces cerevisiae, we discovered that two closely related compounds, an imidazo[1,2-a]pyridine and -pyrimidine that differ by a single atom, have distinctly different mechanisms of action in vivo. 2-phenyl-3-nitroso-imidazo[1,2-a]pyridine was toxic to yeast strains with defects in electron transport and mitochondrial functions and caused mitochondrial fragmentation, suggesting that compound 13 acts by disrupting mitochondria. By contrast, 2-phenyl-3-nitroso-imidazo[1,2-a]pyrimidine acted as a DNA poison, causing damage to the nuclear DNA and inducing mutagenesis. We compared compound 15 to known chemotherapeutics and found resistance required intact DNA repair pathways. Thus, subtle changes in the structure of imidazo-pyridines and -pyrimidines dramatically alter both the intracellular targeting of these compounds and their effects in vivo. Of particular interest, these different modes of action were evident in experiments on human cells, suggesting that chemical–genetic profiles obtained in yeast are recapitulated in cultured cells, indicating that our observations in yeast can: (1) be leveraged to determine mechanism of action in mammalian cells and (2) suggest novel structure–activity relationships

Tools and techniques for solvent selection: green solvent selection guides

Driven by legislation and evolving attitudes towards environmental issues, establishing green solvents for extractions, separations, formulations and reaction chemistry has become an increasingly important area of research. Several general purpose solvent selection guides have now been published with the aim to reduce use of the most hazardous solvents. This review serves the purpose of explaining the role of these guides, highlighting their similarities and differences. How they can be used most effectively to enhance the greenness of chemical processes, particularly in laboratory organic synthesis and the pharmaceutical industry, is addressed in detail

True heterotopic bone in the paralyzed patient

In past years the clinical and radiologic presentation of true heterotopic bone in the paralyzed patient has been confused with osteomyelitis, neoplasm, trauma, and thrombophlebitis. We reviewed 376 paralyzed patients' roentgenographic files and found 78 patients with soft tissue ossification unassociated with infection, neoplasm, or underlying fractures, which we called true heterotopic bone. From this population the usual spectrum of radiologic findings is described, so that the radiologist may separate roentgenographically a group of patients from other types of ectopic ossification.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46816/1/256_2004_Article_BF00347167.pd

Pigmentation plasticity enhances crypsis in larval newts: Associated metabolic cost and background choice behaviour

In heterogeneous environments, the capacity for colour change can be a valuable adaptation enhancing crypsis against predators. Alternatively, organisms might achieve concealment by evolving preferences for backgrounds that match their visual traits, thus avoiding the costs of plasticity. Here we examined the degree of plasticity in pigmentation of newt larvae (Lissotriton boscai) in relation to predation risk. Furthermore, we tested for associated metabolic costs and pigmentation-dependent background choice behaviour. Newt larvae expressed substantial changes in pigmentation so that light, high-reflecting environment induced depigmentation whereas dark, low-reflecting environment induced pigmentation in just three days of exposure. Induced pigmentation was completely reversible upon switching microhabitats. Predator cues, however, did not enhance cryptic phenotypes, suggesting that environmental albedo induces changes in pigmentation improving concealment regardless of the perceived predation risk. Metabolic rate was higher in heavily pigmented individuals from dark environments, indicating a high energetic requirement of pigmentation that could impose a constraint to larval camouflage in dim habitats. Finally, we found partial evidence for larvae selecting backgrounds matching their induced phenotypes. However, in the presence of predator cues, larvae increased the time spent in light environments, which may reflect a escape response towards shallow waters rather than an attempt at increasing crypsisFinancial support was provided by the Spanish Ministry of Science and Innovation (MICINN), Grant CGL2012-40044 to IGM, and by the Universidad Autónoma de Madrid, Short Stay Grant to NPC. Additional financial support was provided by the MICINN, Grant CGL2015-68670-R to NP