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Primary Screen (primary + screen)
Selected AbstractsBimatoprost, a novel efficacious ocular hypotensive drug now recognized as a member of a new class of agents called prostamidesDRUG DEVELOPMENT RESEARCH, Issue 4 2007Robert M. Burk Pursuit of a new FP-agonist prodrug led to the identification of an interesting series of neutral C1-substituted prostaglandin F2, analogues. Although these initial analogues were devoid of any inherent pharmacological activity at the FP-receptor, two compounds AGN-190910 and AGN-191129, were found to have pronounced effects in lowering intraocular pressure (IOP) in normotensive dogs and monkeys. The cat iris sphincter assay was quickly developed as a primary screen for these analogues, leading to rapid identification of AGN-192024 (17-phenyl PGF2, ethyl amide, bimatoprost). While bimatoprost is structurally similar to naturally occurring mammalian hormones of the prostanoid family, surprisingly it demonstrates no significant activity at any of the known prostanoid receptors. Furthermore, results of considerable additional pharmacological studies provide evidence that it may indeed act through a unique receptor yet to be identified. The effect of Bimatoprost on lowering IOP has also been found to be unique in comparison to prostanoids. Bimatoprost reduces human IOP by increasing aqueous humor outflow through a dual mechanism of action where it improves both pressure-dependent and pressure-independent outflow pathways. First introduced to the market in 2002, bimatoprost is currently the most potent single therapy available for control of ocular hypertension. Drug Dev Res 68:147,155, 2007. ©2007 Wiley-Liss, Inc. [source] Metabolic phenotyping of mouse mutants in the German Mouse ClinicINTEGRATIVE ZOOLOGY (ELECTRONIC), Issue 3 2006Ralf ELVERT Abstract The German Mouse Clinic was established as a phenotyping center to provide the scientific community with systematic standardized phenotyping of mouse models from various genetic backgrounds. We found metabolic phenotypes in nine out of 20 mutant lines screened in a primary screen. Based on these findings, the mutants were analyzed in secondary and tertiary screens. Mice of a sample mutant line, isolated from the ENU-screen at the National Research Center for Environment and Health in Munich, were found to have lower body weight, consume less food, but have higher ratios of metabolized energy per unit body weight compared with their wild-type littermates. Basal metabolic rate and heat production were simultaneously increased by 16,18%, whereas body fat content was reduced by 11,16%. The combination of various parameters of energy consumption, expenditure and energy storage illustrate the metabolic demands of the sample mutant mouse line and demonstrate the utility of the powerful phenotyping tool used at the German Mouse Clinic. [source] Evaluation of a rapid diagnostic field test kit for identification of Phytophthora species, including P. ramorum and P. kernoviae at the point of inspectionPLANT PATHOLOGY, Issue 5 2007C. R. Lane Plant health regulations to prevent the introduction and spread of Phytophthora ramorum and P. kernoviae require rapid, cost effective diagnostic methods for screening large numbers of plant samples at the time of inspection. Current on-site techniques require expensive equipment, considerable expertise and are not suited for plant health inspectors. Therefore, an extensive evaluation of a commercially available lateral flow device (LFD) for Phytophthora species was performed involving four separate trials and 634 samples. The assay proved simple to use, provided results in a few minutes and on every occasion a control line reacted positively confirming the validity of the test. LFD results were compared with those from testing a parallel sample, using laboratory methods (isolation and real-time PCR). The diagnostic sensitivity of the LFD (87·6%) compared favourably with the standard laboratory methods although the diagnostic specificity was not as stringent (82·9%). There were a small number (n = 28) of false negatives, but for statutory purposes where all positive samples must be identified to species level by laboratory testing, overall efficiency was 95·6% as compared with visual assessment of symptoms of between 20-30% for P. ramorum and P. kernoviae. This work demonstrates the value of the LFD for diagnosing Phytophthora species at the time of inspection and as a useful primary screen for selecting samples for laboratory testing to determine the species identification. [source] A genome-screen experiment to detect quantitative trait loci affecting resistance to facial eczema disease in sheepANIMAL GENETICS, Issue 1 2009S. H. Phua Summary Facial eczema (FE) is a secondary photosensitization disease arising from liver cirrhosis caused by the mycotoxin sporidesmin. The disease affects sheep, cattle, deer and goats, and costs the New Zealand sheep industry alone an estimated NZ$63M annually. A long-term sustainable solution to this century-old FE problem is to breed for disease-resistant animals by marker-assisted selection. As a step towards finding a diagnostic DNA test for FE sensitivity, we have conducted a genome-scan experiment to screen for quantitative trait loci (QTL) affecting this trait in Romney sheep. Four F1 sires, obtained from reciprocal matings of FE resistant and susceptible selection-line animals, were used to generate four outcross families. The resulting half-sib progeny were artificially challenged with sporidesmin to phenotype their FE traits measured in terms of their serum levels of liver-specific enzymes, namely gamma-glutamyl transferase and glutamate dehydrogenase. In a primary screen using selective genotyping on extreme progeny of each family, a total of 244 DNA markers uniformly distributed over all 26 ovine autosomes (with an autosomal genome coverage of 79,91%) were tested for linkage to the FE traits. Data were analysed using Haley,Knott regression. The primary screen detected one significant and one suggestive QTL on chromosomes 3 and 8 respectively. Both the significant and suggestive QTL were followed up in a secondary screen where all progeny were genotyped and analysed; the QTL on chromosome 3 was significant in this analysis. [source] 4142: The Sanger Mouse Genetics Programme: high throughput characterisation of knockout miceACTA OPHTHALMOLOGICA, Issue 2010AK GERDIN Purpose The Sanger Mouse Genetics Programme (MGP) aims to make a significant impact on our understanding of the function of genes and their role in disease by generating, characterising and archiving in the order of 200 lines of knockout mice per year, including 40 lines as part of the EUMODIC consortium. The phenotyping screens employed include a wide range of assays relevant to key disease areas including diabetes, obesity, hearing and vision disorders, immune disorders, pain and motor function. The data generated by the primary screen will help to further the understanding of the interplay of genes and disease and will provide an insight into the various underlying biological pathways. All phenotyping data and biological resources generated by the programme are openly available to the scientific community. Methods Eye morphology is routinely assessed using the Slit Lamp and Ophthalmoscope and images are collected when abnormalities are identified. Expression profiling via the lacZ reporter gene is performed for each mutant line in adults and at E14.5. Results To date, the eye screen has been performed on over 180 mutant lines. Here we report examples of novel eye-related abnormalities identified by the eye morphology, embryonic lethality and/or expression screens performed by the Sanger MGP. We will present how to identify a potentially interesting mouse mutant on our database and discuss the impact our knock-out mouse models might have on your research. [source] 4143: The German Mouse Clinic: recent findings from the Eye ScreenACTA OPHTHALMOLOGICA, Issue 2010O PUK Purpose The purpose of this study was the large-scale screening of different mouse mutant lines in order to detect novel models for eye disorders. Methods The eyes of the mouse mutants were analyzed by slit lamp biomicroscopy, funduscopy, laser interference biometry, optokinetic drum, and histology. Results In the past 12 months, 46 mouse mutant lines were investigated in the primary Eye Screen of the German Mouse Clinic (GMC). These included Csemp1 and Aey69 that exhibited irregular eye development. All tested mice of the mutant line Csemp1 unexpectedly showed white fundus flecks and significantly reduced axial eye lengths. Moreover, we additionally found strong opacities in a least a portion of the Csemp1 mutant lenses. Aey69 mice are severely microphthalmic due to a yet undefined ENU-induced mutation. The rudimentary eyes completely lack ocular structures as iris or lens. Further significant irregularities in fat metabolism, immunology, and behaviour were detected in the GMC-wide primary screen. Linkage studies mapped the mutated site on chromosome 3 within a 0.78 Mb spanning region between the flanking microsatellite markers D3Mit188 and D3Mit76. Among the 34 positional candidate genes, Tnrc4 (elav-like family member 3) and Selenbp1 (selenium binding protein 1) are expressed in the eye. Sequencing studies in order to detect the causative mutation of Aey69 are in process. Conclusion Two novel mouse models for microphthalmia were detected in the primary Eye Screen of the GMC. These mutant lines will provide further insights into molecular mechanisms behind this kind of eye disease. [source] | |||||||||||||