Comparison of Torque,Screw-in Force,and Shaping Ability of Glide Path Instruments in Continuous Rotation and Optimum Glide Path Motion

IntroductionThis study aimed to analyze torque/force generation and transportation in double-curved canals instrumented with 3 types of glide path files using optimum glide path (OGP) motion in comparison with continuous rotation.MethodsSixty simulated double-curved canals were prepared with #10/0.05 or #15/0.03 HyFlex EDM Glidepath files (Coltene/Whaledent, Altstätten, Switzerland) or a #13/0.04 prototype MANI Glidepath file (Tochigi, Japan) using OGP motion or continuous rotation (n = 10 each). Canals were sequentially prepared to 20 mm and 22 mm (full working length) using automated root canal instrumentation and a torque/force analyzing device. Transportation was calculated at 1–9 mm from the apex. Data were compared using 2-way analysis of variance followed by a post hoc simple main effect test with Bonferroni correction and a Kruskal-Wallis test (α = 5%).ResultsAll #10/0.05 instruments fractured. In the 22-mm preparation, the OGP motion resulted in lower clockwise torque and screw-in force than did continuous rotation (P < .05). In the 20-mm preparation, #15/0.03 instruments recorded a lower screw-in force for OGP motion than for continuous rotation (P < .05). Comparing the 2 preparation phases, OGP motion generated no significant differences; however, continuous rotation developed higher clockwise torque and screw-in force in the 22-mm preparation than in the 20-mm preparation (P < .05). There was no significant difference among the tested groups for transportation values.ConclusionsCompared with continuous rotation, OGP motion generated less screw-in force, lower clockwise torque, and similar transportation. The #15/0.03 HyFlex EDM instrument and the #13/0.04 prototype MANI instrument performed similarly well.     

The Reverse-Direction Method Links Mass Experimental Data to Human Diseases

Genome-wide analyses such as DNA microarray, RNA sequencing and RNA interference-based high-throughput screening are prevalent to decipher a biological process of interest, and provide a large quantity of data to be processed. An ultimate goal for researchers must be extrapolation of their data to human diseases. We have conducted functional genome-wide screenings to elucidate molecular mechanisms of the inflammation amplifier, a NFκB/STAT3-dependent machinery that potently drives recruitment of immune cells to promote inflammation. Using a public database of genome-wide association studies (GWAS), we recently reported the reverse-direction method by which our mass screening data were successfully linked to many human diseases. As an example, the epiregulin–epidermal growth factor receptor pathway was identified as a regulator of the inflammation amplifier, and associated with human diseases by GWAS. In fact, serum epiregulin levels were higher in patients with chronic inflammatory disorders. The reverse-direction method can be a useful tool to narrow mass data down to focus on human disease-related genes.     

Longitudinal Development of Mother–Infant Interaction During the First Year of Life Among Mothers with Substance Abuse and Psychiatric Problems and Their Infants

The quality of mother–infant interaction during the first year may be hampered by maternal substance abuse and co-existing non-optimal factors such as psychiatric problems and difficult relational experiences. In the present study three groups of women were recruited during pregnancy: One group with substance abuse problems from residential treatment centers (n = 28), a second group from psychiatric outpatient treatment centers (n = 22), and a third group from well-baby clinics (n = 30). Four maternal optimality indexes were assessed (substance abuse, psychiatric problems, relational experiences and SES). Mother–infant interaction was observed at 3 and 12 months. The substance abuse group showed the most disturbed mother–infant interaction at 12 months. Low maternal optimality as well as impairments in maternal affective involvement at 3 months influenced negatively both on infant and dyadic affective behavior in interaction at 12 months. Long-term interventions are needed to promote affective reciprocity among mother–baby pairs with low optimality.     

Target-mediated clearance and bio-distribution of a monoclonal antibody against the Kunitz–type protease inhibitor 2 domain of Tissue Factor Pathway Inhibitor

Introduction

A humanised monoclonal antibody, concizumab, that binds with high affinity to the Kunitz-type protease inhibitor (KPI) 2 domain of human tissue factor pathway inhibitor (TFPI) is in clinical development. It promotes coagulation by neutralising the inhibitory function of TFPI and may provide a subcutaneous prophylaxis option for patients with haemophilia. We aimed to study biodistribution and pharmacokinetics (PK) of concizumab.

Materials and Methods

Blockage of cellular TFPI by concizumab was measured by tissue factor/Factor VIIa-mediated Factor X activation on human EA.hy926 cells. Biodistribution of concizumab was analysed in rabbits by immunohistology, and the PK was measured in rabbits and rats.

Results and Conclusions

Concizumab bound to cell surface TFPI on EA.hy926 cells and neutralised TFPI inhibition of Factor X activation. The antibody cross-reacted with rabbit TFPI, but not with rat TFPI, allowing for comparative PK studies. PK data in rats described a log-linear profile typical for a non-binding antibody, whereas PK data in rabbits revealed a non-linear, dose-dependent profile, consistent with a target-mediated clearance mechanism. Immunohistology in rabbits during target-saturation showed localisation of the antibody on the endothelium of the microvasculature in several organs. We observed a marked co-localisation with endogenous rabbit TFPI, but a negligible sub-endothelial build-up. Concizumab binds and neutralises the inhibitory effect of cell surface-bound TFPI. The PK profile observed in rabbits is consistent with a TFPI-mediated drug disposition. Double immunofluorescence shows co-localisation of the antibody with TFPI on the endothelium of the microvasculature and points to this TFPI as a putative target involved in the clearance mechanism.     

Substrate topography and size determine the fate of human embryonic stem cells to neuronal or glial lineage

Efficient derivation of neural cells from human embryonic stem cells (hESCs) remains an unmet need for the treatment of neurological disorders. The limiting factors for current methods include being labor-intensive, time-consuming and expensive. In this study, we hypothesize that the substrate topography, with optimal geometry and dimension, can modulate the neural fate of hESCs and enhance the efficiency of differentiation. A multi-architectural chip (MARC) containing fields of topographies varying in geometry and dimension was developed to facilitate high-throughput analysis of topography-induced neural differentiation in vitro. The hESCs were subjected to “direct differentiation”, in which small clumps of undifferentiated hESCs were cultured directly without going through the stage of embryoid body formation, on the MARC with N2 and B27 supplements for 7 days. The gene and protein expression analysis indicated that the anisotropic patterns like gratings promoted neuronal differentiation of hESCs while the isotropic patterns like pillars and wells promoted the glial differentiation of hESCs. This study showed that optimal combination of topography and biochemical cues could shorten the differentiation period and allowed derivation of neurons bearing longer neurites that were aligned along the grating axis. The MARC platform would enable high-throughput screening of topographical substrates that could maximize the efficiency of neuronal differentiation from pluripotent stem cells.     

Case with metastatic cutaneous malignant melanoma that developed Vogt–Koyanagi–Harada-like uveitis following pembrolizumab treatment

Documenta Ophthalmologica - The study reports a case with metastatic cutaneous malignant melanoma that developed Vogt–Koyanagi–Harada-like uveitis during pembrolizumab treatment. The...