Systematic evaluation of particle loss during handling in the percutaneous transluminal angioplasty for eight different drug-coated balloons

Paclitaxel drug coated balloons (DCBs) should provide optimal drug transfer exclusively to the target tissue. The aim of this study was to evaluate the particle loss by handling during angioplasty. A robotic arm was developed for systematic and reproducible drug abrasion experiments. The contact force on eight different commercially available DCB types was gradually increased, and high-resolution microscopic images of the deflated and inflated balloons were recorded. Three types of DCBs were classified: no abrasion of the drug in both statuses (deflated and inflated), significant abrasion only in the inflated status, and significant abrasion in both statuses. Quantitative measurements via image processing confirmed the qualitative classification and showed changes of the drug area between 2.25 and 45.73% (13.28 ± 14.29%) in the deflated status, and between 1.66 and 40.41% (21.43 ± 16.48%) in the inflated status. The structures and compositions of the DCBs are different, some are significantly more susceptible to drug loss. Particle loss by handling during angioplasty leads to different paclitaxel doses in the target regions for same DCB types. Susceptibility to involuntary drug loss may cause side effects, such as varying effective paclitaxel doses, which may explain variations in studies regarding the therapeutic outcome

An integrated ultrasound curriculum (iUSC) for medical students: 4-year experience

A review of the development and implementation of a 4-year medical student integrated ultrasound curriculum is presented. Multiple teaching and assessment modalities are discussed as well as results from testing and student surveys. Lessons learned while establishing the curriculum are summarized. It is concluded that ultrasound is a well received, valuable teaching tool across all 4 years of medical school, and students learn ultrasound well, and they feel their ultrasound experience enhances their medical education

Lipid Alterations in Experimental Murine Colitis: Role of Ceramide and Imipramine for Matrix Metalloproteinase-1 Expression

BACKGROUND:Dietary lipids or pharmacologic modulation of lipid metabolism are potential therapeutic strategies in inflammatory bowel disease (IBD). Therefore, we analysed alterations of bioactive lipids in experimental models of colitis and examined the functional consequence of the second messenger ceramide in inflammatory pathways leading to tissue destruction. METHODOLOGY/PRINCIPAL FINDINGS:Chronic colitis was induced by dextran-sulphate-sodium (DSS) or transfer of CD4(+)CD62L(+) cells into RAG1(-/-)-mice. Lipid content of isolated murine intestinal epithelial cells (IEC) was analysed by tandem mass spectrometry. Concentrations of MMP-1 in supernatants of Caco-2-IEC and human intestinal fibroblasts from patients with ulcerative colitis were determined by ELISA. Imipramine was used for pharmacologic inhibition of acid sphingomyelinase (ASM). Ceramide increased by 71% in chronic DSS-induced colitis and by 159% in the transfer model of colitis. Lysophosphatidylcholine (LPC) decreased by 22% in both models. No changes were detected for phosphatidylcholine. Generation of ceramide by exogenous SMase increased MMP-1-protein production of Caco-2-IEC up to 7-fold. Inhibition of ASM completely abolished the induction of MMP-1 by TNF or IL-1beta in Caco-2-IEC and human intestinal fibroblasts. CONCLUSIONS/SIGNIFICANCE:Mucosal inflammation leads to accumulation of ceramide and decrease of LPC in the intestinal epithelium. One aspect of ceramide generation is an increase of MMP-1. Induction of MMP-1 by TNF or IL-1beta is completely blocked by inhibition of ASM with imipramine. Therefore, inhibition of ASM may offer a treatment strategy to reduce MMP-1 expression and tissue destruction in inflammatory conditions

Identification of Novel Functional Inhibitors of Acid Sphingomyelinase

We describe a hitherto unknown feature for 27 small drug-like molecules, namely functional inhibition of acid sphingomyelinase (ASM). These entities named FIASMAs (Functional Inhibitors of Acid SphingoMyelinAse), therefore, can be potentially used to treat diseases associated with enhanced activity of ASM, such as Alzheimer's disease, major depression, radiation- and chemotherapy-induced apoptosis and endotoxic shock syndrome. Residual activity of ASM measured in the presence of 10 µM drug concentration shows a bimodal distribution; thus the tested drugs can be classified into two groups with lower and higher inhibitory activity. All FIASMAs share distinct physicochemical properties in showing lipophilic and weakly basic properties. Hierarchical clustering of Tanimoto coefficients revealed that FIASMAs occur among drugs of various chemical scaffolds. Moreover, FIASMAs more frequently violate Lipinski's Rule-of-Five than compounds without effect on ASM. Inhibition of ASM appears to be associated with good permeability across the blood-brain barrier. In the present investigation, we developed a novel structure-property-activity relationship by using a random forest-based binary classification learner. Virtual screening revealed that only six out of 768 (0.78%) compounds of natural products functionally inhibit ASM, whereas this inhibitory activity occurs in 135 out of 2028 (6.66%) drugs licensed for medical use in humans

Nematic order-disorder state transition in a liquid crystal analogue formed by oriented and migrating amoeboid cells

In cell culture, liquid crystal analogues are formed by elongated, migrating, and interacting amoeboid cells. An apolar nematic liquid crystal analogue is formed by different cell types like human melanocytes ($=$pigment cells of the skin), human fibroblasts ($=$connective tissue cells), human osteoblasts ($=$bone cells), human adipocytes ($=$fat cells), etc. The nematic analogue is quite well described by i) a stochastic machine equation responsible for cell orientation and ii) a self-organized extracellular guiding signal, $E_2$, which is proportional to the orientational order parameter as well as to the cell density. The investigations were mainly made with melanocytes. The transition to an isotropic state analogue can be accomplished either by changing the strength of interaction (e.g. variation of the cell density) or by influencing the cellular machinery by an externally applied signal: i) An isotropic gaseous state analogue is observed at low cell density ($\rho < 110melanocytes/mm^2$) and a nematic liquid crystal state analogue at higher cell density. ii) The nematic state analogue disappears if the bipolar shaped melanocytes are forced to become a star-like shape (induced by colchicine or staurosporine). The analogy between nematic liquid crystal state analogue formed by elongated, migrating and interacting cells and the nematic liquid crystal phase formed by interacting elongated molecules is discussed

Magnetic Tracking and Electrocardiography-Guided Tip Confirmation System Versus Fluoroscopy for Placement of Peripherally Inserted Central Catheters: A Randomized, Noninferiority Comparison

Purpose!#!To determine whether the use of a magnetic tracking and electrocardiography-guided catheter tip confirmation system (TCS) is safe and noninferior to fluoroscopy concerning positioning accuracy of a peripheral inserted central catheter (PICC).!##!Methods!#!In this prospective, randomized, single-center study, adult patients scheduled for PICC insertion were assigned 1:1 either to TCS or fluoroscopy. The primary objective was a noninferiority comparison of correct PICC tip position confirmed by X-ray obtained immediately after catheter insertion. Time needed for PICC insertion and insertion-related complications up to 14 days after the procedure were secondary outcomes to be assessed for superiority.!##!Results!#!A total of 210 patients (62.3 ± 14.4 years, 63.8% male) were included at a single German center between June 2016 and October 2017. Correct PICC tip position was achieved in 84 of 103 TCS (82.4%) and 103 of 104 fluoroscopy patients (99.0%). One-sided 95% lower confidence limit on the difference between proportions was -23.1%. Thus, noninferiority of TCS was not established (p &amp;gt; 0.99). Insertion of PICC took longer with TCS compared to fluoroscopy (8.4 ± 3.7 min vs. 5.0 ± 2.7 min, p &amp;lt; 0.001). Incidence of complications within a mean follow-up of 5.0 ± 2.3 days did not differ significantly between groups.!##!Conclusion!#!Noninferiority of TCS to fluoroscopy in the incidence of correct PICC tip position was not reached. Ancillary benefit of TCS over fluoroscopy including less radiation exposure and lower resource requirements may nonetheless justify the use of TCS. The study is registered with Clinical.Trials.gov (Identifier: NCT02929368)

Niche separation in common prostome freshwater ciliates: the effect of food and temperature

We characterized the ecological niches of several planktonic prostome ciliates with respect to their food demand and temperature. We found intergeneric differences between Balanion planctonicum and the 2 Urotricha spp., U. furcata and U. farcta. There were also significant interspecific differences within the genus Urotricha and intraspecific differences between 2 Balanion spp. and 3 U, furcata isolates from distant lakes. Relative to Urotricha spp., Balanion appeared to be the superior competitor at low to medium food concentrations and reached high growth rates at moderate temperatures. The threshold prey concentration for positive population growth of B. planctonicum was lower than that obtained for the 2 Urotricha spp., but higher than that reported earlier for the marine species, B. comatum. A third Urotricha species, U. castalia, was investigated for its temperature response only, The temperature response revealed species-specific temperature adaptation between B. planctonicum and the sympatric U. furcata, and further differences within the genus Urotricha: U, farcta grew fastest at high temperatures; U. castalia was adapted to low temperatures; and U, furcata peaked at moderately warm temperature