301 research outputs found

    ALLN-177, oral enzyme therapy for hyperoxaluria

    Get PDF
    PURPOSE: To evaluate the potential of ALLN-177, an orally administered, oxalate-specific enzyme therapy to reduce urine oxalate (UOx) excretion in patients with secondary hyperoxaluria. METHODS: Sixteen male and female subjects with both hyperoxaluria and a kidney stone history were enrolled in an open-label study. Subjects continued their usual diets and therapies. During a 3-day baseline period, two 24-h (24-h) urines were collected, followed by a 4-day treatment period with ALLN-177 (7,500 units/meal, 3 × day) when three 24-h urines were collected. The primary endpoint was the change in mean 24-h UOx from baseline. Safety assessments and 24-h dietary recalls were performed throughout. RESULTS: The study enrolled 5 subjects with enteric hyperoxaluria and 11 with idiopathic hyperoxaluria. ALLN-177 was well tolerated. Overall mean (SD) UOx decreased from 77.7 (55.9) at baseline to 63.7 (40.1) mg/24 h while on ALLN-177 therapy, with the mean reduction of 14 mg/24 h, (95% CI - 23.71, - 4.13). The calcium oxalate-relative urinary supersaturation ratio in the overall population decreased from a mean of 11.3 (5.7) to 8.8 (3.8) (- 2.8; 95% CI - 4.9, - 0.79). This difference was driven by oxalate reduction alone, but not any other urinary parameters. Mean daily dietary oxalate, calcium, and fluid intake recorded by frequent diet recall did not differ by study periods. CONCLUSION: ALLN-177 reduced 24-h UOx excretion, and was well tolerated. The results of this pilot study provided justification for further investigation of ALLN-177 in patients with secondary hyperoxaluria

    Designing small molecule CXCR3 antagonists

    Full text link

    Comparison of triploid and diploid rainbow trout (Oncorhynchus mykiss) fine-scale movement, migration and catchability in lowland lakes of western Washington

    Get PDF
    Fisheries managers stock triploid (i.e., infertile, artifcially produced) rainbow trout Oncorhynchus mykiss in North American lakes to support sport fsheries while minimizing the risk of genetic introgression between hatchery and wild trout. In Washington State, the Washington Department of Fish and Wildlife (WDFW) allocates approximately US $3 million annually to stock hatchery-origin rainbow trout in>600 lakes, yet only about 10% of them are triploids. Many lakes in Washington State drain into waters that support wild anadromous steelhead O. mykiss that are listed as threatened under the U.S. Endangered Species Act. As a result, there is a strong interest in understanding the costs and benefts associated with stocking sterile, triploid rainbow trout as an alternative to traditional diploids. The objectives of this study were to compare triploid and diploid rainbow trout in terms of: (1) contribution to the sport fshery catch, (2) fne-scale movements within the study lakes, (3) rate of emigration from the lake, and (4) natural mortality. Our results demonstrated that triploid and diploid trout had similar day-night distribution patterns, but triploid trout exhibited a lower emigration rate from the lake and lower catch rates in some lakes. Overall, triploid rainbow trout represent a viable alternative to stocking of diploids, especially in lakes draining to rivers, because they are sterile, have comparable home ranges, and less often migrat

    Action research and democracy

    Get PDF
    This contribution explores the relationship between research and learning democracy. Action research is seen as being compatible with the orientation of educational and social work research towards social justice and democracy. Nevertheless, the history of action research is characterized by a tension between democracy and social engineering. In the social-engineering approach, action research is conceptualized as a process of innovation aimed at a specific Bildungsideal. In a democratic approach action research is seen as research based on cooperation between research and practice. However, the notion of democratic action research as opposed to social engineering action research needs to be theorized. So called democratic action research involving the implementation by the researcher of democracy as a model and as a preset goal, reduces cooperation and participation into instruments to reach this goal, and becomes a type of social engineering in itself. We argue that the relationship between action research and democracy is in the acknowledgment of the political dimension of participation: ‘a democratic relationship in which both sides exercise power and shared control over decision-making as well as interpretation’. This implies an open research design and methodology able to understand democracy as a learning process and an ongoing experiment

    Nanoliter high throughput quantitative PCR

    Get PDF
    Understanding biological complexity arising from patterns of gene expression requires accurate and precise measurement of RNA levels across large numbers of genes simultaneously. Real time PCR (RT-PCR) in a microtiter plate is the preferred method for quantitative transcriptional analysis but scaling RT-PCR to higher throughputs in this fluidic format is intrinsically limited by cost and logistic considerations. Hybridization microarrays measure the transcription of many thousands of genes simultaneously yet are limited by low sensitivity, dynamic range, accuracy and sample throughput. The hybrid approach described here combines the superior accuracy, precision and dynamic range of RT-PCR with the parallelism of a microarray in an array of 3072 real time, 33 nl polymerase chain reactions (RT-PCRs) the size of a microscope slide. RT-PCR is demonstrated with an accuracy and precision equivalent to the same assay in a 384-well microplate but in a 64-fold smaller reaction volume, a 24-fold higher analytical throughput and a workflow compatible with standard microplate protocols

    Predictions of CCR1 Chemokine Receptor Structure and BX 471 Antagonist Binding Followed by Experimental Validation

    Get PDF
    A major challenge in the application of structure-based drug design methods to proteins belonging to the superfamily of G protein-coupled receptors (GPCRs) is the paucity of structural information (1). The 19 chemokine receptors, belonging to the Class A family of GPCRs, are important drug targets not only for autoimmune diseases like multiple sclerosis but also for the blockade of human immunodeficiency virus type 1 entry (2). Using the MembStruk computational method (3), we predicted the three-dimensional structure of the human CCR1 receptor. In addition, we predicted the binding site of the small molecule CCR1 antagonist BX 471, which is currently in Phase II clinical trials (4). Based on the predicted antagonist binding site we designed 17 point mutants of CCR1 to validate the predictions. Subsequent competitive ligand binding and chemotaxis experiments with these mutants gave an excellent correlation to these predictions. In particular, we find that Tyr-113 and Tyr-114 on transmembrane domain 3 and Ile-259 on transmembrane 6 contribute significantly to the binding of BX 471. Finally, we used the predicted and validated structure of CCR1 in a virtual screening validation of the Maybridge data base, seeded with selective CCR1 antagonists. The screen identified 63% of CCR1 antagonists in the top 5% of the hits. Our results indicate that rational drug design for GPCR targets is a feasible approach
    corecore