A multicenter assessment of single-cell models aligned to standard measures of cell health for prediction of acute hepatotoxicity.

Assessing the potential of a new drug to cause drug-induced liver injury (DILI) is a challenge for the pharmaceutical industry. We therefore determined whether cell models currently used in safety assessment (HepG2, HepaRG, Upcyte and primary human hepatocytes in conjunction with basic but commonly used endpoints) are actually able to distinguish between novel chemical entities (NCEs) with respect to their potential to cause DILI. A panel of thirteen compounds (nine DILI implicated and four non-DILI implicated in man) were selected for our study, which was conducted, for the first time, across multiple laboratories. None of the cell models could distinguish faithfully between DILI and non-DILI compounds. Only when nominal in vitro concentrations were adjusted for in vivo exposure levels were primary human hepatocytes (PHH) found to be the most accurate cell model, closely followed by HepG2. From a practical perspective, this study revealed significant inter-laboratory variation in the response of PHH, HepG2 and Upcyte cells, but not HepaRG cells. This variation was also observed to be compound dependent. Interestingly, differences between donors (hepatocytes), clones (HepG2) and the effect of cryopreservation (HepaRG and hepatocytes) were less important than differences between the cell models per se. In summary, these results demonstrate that basic cell health endpoints will not predict hepatotoxic risk in simple hepatic cells in the absence of pharmacokinetic data and that a multicenter assessment of more sophisticated signals of molecular initiating events is required to determine whether these cells can be incorporated in early safety assessment

Simple amides and amines for the synergistic recovery of rhodium from hydrochloric acid by solvent extraction

The separation and isolation of many of the platinum group metals (PGMs) is currently achieved commercially using solvent extraction processes. The extraction of rhodium is problematic however, as a variety of complexes of the form [RhCln(H2O)6-n](n−3)− are found in hydrochloric acid, making it difficult to design a reagent that can extract all the rhodium. In this work, the synergistic combination of a primary amine (2-ethylhexylamine, LA) with a primary amide (3,5,5-trimethylhexanamide, L1) is shown to extract over 85 % of rhodium from 4 M hydrochloric acid. Two rhodium complexes are shown to reside in the organic phase, the ion-pair [HLA]3[RhCl6] and the amide complex [HLA]2[RhCl5(L1)]; in the latter complex, the amide is tautomerized to its enol form and coordinated to the rhodium centre through the nitrogen atom. This insight highlights the need for ligands that target specific metal complexes in the aqueous phase and provides an efficient synergistic solution for the solvent extraction of rhodium

Texture variations suppress suprathreshold brightness and colour variations

Discriminating material changes from illumination changes is a key function of early vision. Luminance cues are ambiguous in this regard, but can be disambiguated by co-incident changes in colour and texture. Thus, colour and texture are likely to be given greater prominence than luminance for object segmentation, and better segmentation should in turn produce stronger grouping. We sought to measure the relative strengths of combined luminance, colour and texture contrast using a suprathreshhold, psychophysical grouping task. Stimuli comprised diagonal grids of circular patches bordered by a thin black line and contained combinations of luminance decrements with either violet, red, or texture increments. There were two tasks. In the Separate task the different cues were presented separately in a two-interval design, and participants indicated which interval contained the stronger orientation structure. In the Combined task the cues were combined to produce competing orientation structure in a single image. Participants had to indicate which orientation, and therefore which cue was dominant. Thus we established the relative grouping strength of each cue pair presented separately, and compared this to their relative grouping strength when combined. In this way we observed suprathreshold interactions between cues and were able to assess cue dominance at ecologically relevant signal levels. Participants required significantly more luminance and colour compared to texture contrast in the Combined compared to Separate conditions (contrast ratios differed by about 0.1 log units), showing that suprathreshold texture dominates colour and luminance when the different cues are presented in combination

Combined adenocarcinoid and mucinous cystadenoma of the appendix: a case report

<p>Abstract</p> <p>Introduction</p> <p>Adenocarcinoid of the appendix is a rare malignant tumour with features of both adenocarcinoma and carcinoid, showing both epithelial and endocrine differentiation. Mucinous cystadenoma is the commonest of the benign neoplasms of the appendix, with an incidence of 0.6% in appendicectomy specimens. We report a rare combination of these tumours and discuss the latest treatment options. To the best of our knowledge, only six cases have been reported in the literature to date.</p> <p>Case presentation</p> <p>A 71-year-old Caucasian man presented to our department with a right iliac fossa mass associated with pain. Laparoscopy revealed an adenocarcinoid of the appendix in combination with mucinous cystadenoma. He underwent a radical right hemicolectomy with clear margins and lymph nodes.</p> <p>Conclusion</p> <p>Adenocarcinoids account for 2% of primary appendiceal malignancies. Most tumours are less than 2 cm in diameter and 20% of them metastasize to the ovaries. The mean age for presentation is 59 years and the 5-year survival rate ranges from 60% to 84%. Right hemicolectomy is generally advised if any of the following features are present: tumours greater than 2 cm, involvement of resection margins, greater than 2 mitoses/10 high-power fields on histology, extension of tumour beyond serosa. Chemotherapy mostly with 5-Fluorouracil and Leucovorin is advised for remnant disease after surgery. Cytoreductive surgery with intraperitoneal chemotherapy can offer improved survival for advanced peritoneal dissemination.</p

Aerobic capacity, activity levels and daily energy expenditure in male and female adolescents of the kenyan nandi sub-group

The relative importance of genetic and socio-cultural influences contributing to the success of east Africans in endurance athletics remains unknown in part because the pre-training phenotype of this population remains incompletely assessed. Here cardiopulmonary fitness, physical activity levels, distance travelled to school and daily energy expenditure in 15 habitually active male (13.9±1.6 years) and 15 habitually active female (13.9±1.2) adolescents from a rural Nandi primary school are assessed. Aerobic capacity ([Formula: see text]) was evaluated during two maximal discontinuous incremental exercise tests; physical activity using accelerometry combined with a global positioning system; and energy expenditure using the doubly labelled water method. The [Formula: see text] of the male and female adolescents were 73.9±5.7 ml(.) kg(-1.) min(-1) and 61.5±6.3 ml(.) kg(-1.) min(-1), respectively. Total time spent in sedentary, light, moderate and vigorous physical activities per day was 406±63 min (50% of total monitored time), 244±56 min (30%), 75±18 min (9%) and 82±30 min (10%). Average total daily distance travelled to and from school was 7.5±3.0 km (0.8-13.4 km). Mean daily energy expenditure, activity-induced energy expenditure and physical activity level was 12.2±3.4 MJ(.) day(-1), 5.4±3.0 MJ(.) day(-1) and 2.2±0.6. 70.6% of the variation in [Formula: see text] was explained by sex (partial R(2) = 54.7%) and body mass index (partial R(2) = 15.9%). Energy expenditure and physical activity variables did not predict variation in [Formula: see text] once sex had been accounted for. The highly active and energy-demanding lifestyle of rural Kenyan adolescents may account for their exceptional aerobic fitness and collectively prime them for later training and athletic success

Ecological factors related to the widespread distribution of sylvatic Rhodnius ecuadoriensis populations in southern Ecuador

<p>Abstract</p> <p>Background</p> <p>Chagas disease transmission risk is a function of the presence of triatomines in domestic habitats. <it>Rhodnius ecuadoriensis </it>is one of the main vectors implicated in transmission of <it>Trypanosoma cruzi </it>in Ecuador. This triatomine species is present in domestic, peridomestic and sylvatic habitats in the country. To determine the distribution of sylvatic populations of <it>R. ecuadoriensis </it>and the factors related to this distribution, triatomine searches were conducted between 2005 and 2009 in southern Ecuador.</p> <p>Methods</p> <p>Manual triatomine searches were conducted by skilled bug collectors in 23 communities. Sylvatic searched sites were selected by a) directed sampling, where microhabitats were selected by the searchers and b) random sampling, where sampling points where randomly generated. Domiciliary triatomine searches were conducted using the one man-hour method. Natural trypanosome infection was determined by microscopic examination and PCR. Generalized linear models were used to test the effect of environmental factors on the presence of sylvatic triatomines.</p> <p>Results</p> <p>In total, 1,923 sylvatic individuals were collected representing a sampling effort of 751 man-hours. Collected sylvatic triatomines were associated with mammal and bird nests. The 1,219 sampled nests presented an infestation index of 11.9%, a crowding of 13 bugs per infested nest, and a colonization of 80% of the nests. Triatomine abundance was significantly higher in squirrel (<it>Sciurus stramineus</it>) nests located above five meters from ground level and close to the houses. In addition, 8.5% of the 820 examined houses in the same localities were infested with triatomines. There was a significant correlation between <it>R. ecuadoriensis </it>infestation rates found in sylvatic and synanthropic environments within communities (<it>p </it>= 0.012). Parasitological analysis revealed that 64.7% and 15.7% of the sylvatic bugs examined (n = 300) were infected with <it>Trypanosoma cruzi </it>and <it>T. rangeli </it>respectively, and 8% of the bugs presented mixed infections.</p> <p>Conclusions</p> <p>The wide distribution of sylvatic <it>R. ecuadoriensis </it>populations may jeopardize the effectiveness of control campaigns conducted to eliminate domestic populations of this species. Also, the high <it>T. cruzi </it>infection rates found in sylvatic <it>R. ecuadoriensis </it>populations in southern Ecuador could constitute a risk for house re-infestation and persistent long-term Chagas disease transmission in the region.</p

Benznidazole biotransformation and multiple targets in <i>Trypanosoma</i> cruzi revealed by metabolomics

&lt;b&gt;Background&lt;/b&gt;&lt;p&gt;&lt;/p&gt; The first line treatment for Chagas disease, a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi, involves administration of benznidazole (Bzn). Bzn is a 2-nitroimidazole pro-drug which requires nitroreduction to become active, although its mode of action is not fully understood. In the present work we used a non-targeted MS-based metabolomics approach to study the metabolic response of T. cruzi to Bzn.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methodology/Principal findings&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Parasites treated with Bzn were minimally altered compared to untreated trypanosomes, although the redox active thiols trypanothione, homotrypanothione and cysteine were significantly diminished in abundance post-treatment. In addition, multiple Bzn-derived metabolites were detected after treatment. These metabolites included reduction products, fragments and covalent adducts of reduced Bzn linked to each of the major low molecular weight thiols: trypanothione, glutathione, γ-glutamylcysteine, glutathionylspermidine, cysteine and ovothiol A. Bzn products known to be generated in vitro by the unusual trypanosomal nitroreductase, TcNTRI, were found within the parasites, but low molecular weight adducts of glyoxal, a proposed toxic end-product of NTRI Bzn metabolism, were not detected.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions/significance&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Our data is indicative of a major role of the thiol binding capacity of Bzn reduction products in the mechanism of Bzn toxicity against T. cruzi

Factors Affecting Infestation by Triatoma infestans in a Rural Area of the Humid Chaco in Argentina: A Multi-Model Inference Approach

Vector-borne transmission of Chagas disease remains a major public health problem in parts of Latin America. Triatoma infestans is the main vector in the countries located in the South American Cone, particularly in the Gran Chaco ecoregion where residual insecticide control has achieved only a moderate, irregular impact. To contribute to improved control strategies, we analyzed the factors associated with the presence and abundance of T. infestans in 327 inhabited houses in a well-defined rural area with no recent vector control interventions in the humid Argentine Chaco. Bugs were found mainly in domiciles, kitchens, storerooms, and chicken coops and nests, particularly where adequate refuge and animal hosts (humans, dogs, cats or poultry) were available. Domiciles constructed from mud were the most often infested, but brick-and-cement domiciles, even in good conditions, were also found infested. Availability of refuge and hosts for T. infestans are key targets for vector control. Ten-fold variations in domestic infestation observed across neighboring villages, and differences in the relevant factors for T. infestans presence with respect to other areas of the Gran Chaco region suggest that host management, building techniques and insecticide use need to be tailored to the local environment, socio-economic characteristics, and climatic conditions