Defects of renal tubular homeostasis and cystogenesis in the Pkhd1 knockout.

Loss of PKHD1-gene function causes autosomal recessive polycystic kidney disease (ARPKD) characterized by bilateral severely enlarged kidneys and congenital liver fibrosis requiring kidney replacement therapy most frequently during childhood. Studies using renal tissue from ARPKD patients suggest cyst promotion by suppressed hippo activity and enhanced Src/STAT3-signaling. We address renal homeostasis in female Pkhd1-knockout mice, aged 3 to 9 months, and observe features in common with late-onset ARPKD. Pkhd1-knockout animals show significant increase in kidney and liver weight with preserved organ function. Kidney cyst formation of the S3 segment is accompanied by macrophage recruitment and fibrotic remodeling. Cystic epithelia display increased proliferation, high levels of nuclear YAP/TAZ, and enhanced apoptosis. Y705-phosphorylated STAT3 is strongly enhanced in nuclei of cyst-lining epithelia. In this Pkhd1-deficiency model, stressed cystic epithelia expose the altered signaling pattern and disease-related mechanisms deemed relevant to human ARPKD, and thus may allow identification of therapeutic targets of this disease.

Paving the way to a bioresorbable technology: Development of the absorb BRS program.

Bioresorbable scaffolds (BRS) combine attributes of the preceding generations of percutaneous coronary intervention (PCI) devices with new technologies to result in a novel therapy promoted as being the fourth generation of PCI. By providing mechanical support and drug elution to suppress restenosis, BRS initially function similarly to drug eluting stents. Thereafter, through their degradation, BRS undergo a decline in radial strength, allowing a gradual transition of mechanical function from the scaffold back to the artery in order to provide long term effectiveness similar to balloon angioplasty. The principles of operation of BRS, whether of polymeric or metallic composition, follow three phases of functionality reflective of differing physiological requirements over time: revascularization, restoration, and resorption. In this review, these three fundamental performance phases and the metrics for the nonclinical evaluation of BRS, including both bench and preclinical testing, are discussed. © 2016 Wiley Periodicals, Inc.

Accuracy of CT-based thickness measurement of thin structures: modeling of limited spatial resolution in all three dimensions.

Measurement of the width of thin structures such as the cortical shell of the vertebral body or femoral neck with computed tomography (CT) is limited by the spatial resolution of the CT system. Limited spatial resolution exists both within the CT image plane and perpendicular to it and can be described by the in-plane point spread function (PSF) and the across-plane slice sensitivity profile (SSP), respectively. The goal of this study was to confirm that errors of thickness measurement of thin structures critically depend on the spatial positioning of the object and the spatial resolution limitations of CT in all three dimensions, and to assess the size of the errors themselves. We compared computer models that incorporated both effects to experimentally assessed cortical thicknesses of the European Spine Phantom. Analysis included varying CT slice width, the orientation of measurement and angle beta of misalignment of longitudinal scanner and phantom axes. Agreement of models with measurements was good in all configurations with an overall error of 0.17 mm. This showed that PSF and SSP are adequate system characteristics to predict deviation of measured values from true widths. Errors between measurements and true cortical thickness values delta(true) averaged to 1.5 mm were strongly positively correlated with slice width d and beta. When the across-plane partial volume effect was eliminated, limited in-plane resolution still accounted for overestimation of delta(true) by 0.68 (137%), 0.27 (27%), and 0.06 mm (4%) for delta(true)=0.5, 1.0, and 1.5 mm, respectively. For delta(true) of 1.0 mm and above, it was shown that although the absolute cortical thickness values might not be accurately measurable, relative differences between two values are reflected in measurement. Implications for cortical thickness measurement are that the spinal cortical shell is too thin, whereas accurate assessment at locations of the femoral neck exhibiting a thicker cortical shell of both difference and absolute values should be possible with CT even for larger misalignment angles, especially when a smaller CT slice width is chosen.