Interaction of HIV protease inhibitors with OATP1B1, 1B3, and 2B1

The effects of human immunodeficiency virus (HIV) protease inhibitors (PI) on the accumulation of the fluorescent bile salt analogue cholyl-glycylamido-fluorescein (CGamF) were determined in organic anion transporting polypeptide (OATP)-1B1 and -1B3-expressing Chinese hamster ovary (CHO) cells. In addition, interaction studies in Caco-2 monolayers, known only to express the OATP2B1 isoform, were conducted using the established OATP substrate estrone 3-sulfate (E3S), since no CGamF accumulation was observed in Caco-2 monolayers. CGamF appeared an excellent substrate for the OATP1B subfamily, with net accumulation clearance values of 7.8 and 142 microl min(-1) mg(-1) protein in OATP1B1 and OATP1B3-transfected cells, respectively. K(i)-values reflecting inhibition of CGamF accumulation by HIV PI correlated well between OATP1B1 and OATP1B3-expressing cells. Lopinavir was the most potent inhibitor (K(i) = 0.5-1.4 microM) of OATP1B-mediated CGamF accumulation compared with atazanavir, darunavir, ritonavir, and saquinavir (K(i) between 1.4 and 3.3 microM). Inhibitory profiles towards OATP2B1-mediated E3S accumulation were different with only indinavir, saquinavir, and ritonavir showing substantial effects. In conclusion, OATP1B3 appears to be a major transport mechanism mediating sodium-independent CGamF accumulation in human liver, and CGamF could be used as a probe substrate for in vitro drug interaction studies. The remarkably potent inhibition of OATP1B1 by lopinavir may explain some clinically relevant drug interactions between lopinavir and OATP1B substrates such as fexofenadine

Computer-Assisted Precision Surgery in the Ear

Chirurgische Eingriffe am Ohr stellen aufgrund der komplexen Anatomie und der Grössenverhältnisse der beteiligten anatomischen Strukturen eine Herausforderung für den HNO-Chirurgen dar. In diesem Beitrag wird ein Ansatz für die roboterbasierte Navigation zur Hörgeräteimplantation vorgestellt. Insbesondere wird auf die Möglichkeit des Fräsens von Implantatlagern im Felsenbein eingegangen. Je präziser ein Implantat im Schädel verankert werden kann, desto einfacher ist der chirurgischen Ablauf. Weiterhin, profitieren Patienten von verkürzten Operationszeiten und weniger schmerzhaften Eingriffen.Traditional surgical procedures involving the implantation of artificial hearing devices in the inner ear are challenging due to the size and complexity of anatomical structures within the temporal bone. To date, no stereotactic instrument guidance technology providing the necessary levels of accuracy is available. This work presents an approach to robot assisted implantation of hearing devices. Specifically, the robot system was used to milla cavity to for a direct acoustical stimulation implant. As the precision of such cavities increases, so also can future implant generations improve in terms of size, complexity and cost effectiveness. Additionally, patients themselves would profit from shorter procedure times and less painful interventions

Measurements of PM10 ions and trace gases with the online system MARGA at the research station Melpitz in Germany – A five-year study

An hourly quantification of inorganic water-soluble PM10 ions and corresponding trace gases was performed using the Monitor for AeRosols and Gases in ambient Air (MARGA) at the TROPOS research site in Melpitz, Germany. The data availability amounts to over 80% for the five-year measurement period from 2010 to 2014. Comparisons were performed for the evaluation of the MARGA, resulting in coefficients of determinations (slopes) of 0.91 (0.90) for the measurements against the SO2 gas monitor, 0.84 (0.88), 0.79 (1.39), 0.85 (1.20) for the ACSM NO3 −, SO4 2− and NH4 + measurements, respectively, and 0.85 (0.65), 0.88 (0.68), 0.91 (0.83), 0.86 (0.82) for the filter measurements of Cl−, NO3 −, SO4 2− and NH4 +, respectively. A HONO comparison with a batch denuder shows large scatter (R2 = 0.41). The MARGA HNO3 is underestimated compared to a batch and coated denuder with shorter inlets (slopes of 0.16 and 0.08, respectively). Less NH3 was observed in coated denuders for high ambient concentrations. Long-time measurements show clear daily and seasonal variabilities. Potential Source Contribution Function (PSCF) analysis indicates the emission area of particulate ions Cl−, NO3 −, SO4 2−, NH4 +, K+ and gaseous SO2 to lie in eastern European countries, predominantly in wintertime. Coarse mode sea salt particles are transported from the North Sea to Melpitz. The particles at Melpitz are nearly neutralised with a mean molar ratio of 0.90 for the five-year study. A slight increase of the neutralization ratio over the last three years indicates a stronger decrease of the anthropogenically emitted NO3 − and SO4 2− compared to NH4 +

Toward genome editing in X-linked RP-development of a mouse model with specific treatment relevant features

Genome editing represents a powerful tool to treat inherited disorders. Highly specific endonucleases induce a DNA double strand break near the mutant site, which is subsequently repaired by cellular DNA repair mechanisms that involve the presence of a wild type template DNA. In vivo applications of this strategy are still rare, in part due to the absence of appropriate animal models carrying human disease mutations and knowledge of the efficient targeting of endonucleases. Here we report the generation and characterization of a new mouse model for X-linked retinitis pigmentosa (XLRP) carrying a point mutation in the mutational hotspot exon ORF15 of the RPGR gene as well as a recognition site for the homing endonuclease I-SceI. Presence of the genomic modifications was verified at the RNA and protein levels. The mutant protein was observed at low levels. Optical coherence tomography studies revealed a slowly progressive retinal degeneration with photoreceptor loss starting at 9 months of age, paralleling the onset of functional deficits as seen in the electroretinogram. Early changes to the outer retinal bands can be used as biomarker during treatment applications. We further show for the first time efficient targeting using the I-SceI enzyme at the genomic locus in a proof of concept in photoreceptors following adeno-associated virus mediated gene transfer in vivo. Taken together, our studies not only provide a human-XLRP disease model but also act as a platform to design genome editing technology for retinal degenerative diseases using the currently available endonucleases