Development of General Purpose Liquid Chromatography Simulator for the Exploration of Novel Liquid Chromatographic Strategies

The method development process in liquid chromatography (LC) involves optimization of a variety of method parameters including stationary phase chemistry, column temperature, initial and final mobile phase compositions, and gradient time when gradient mobile phases are used. Here, a general simulation program to predict the results (i.e., retention time, peak width and peak shape) of LC separations, with the ability to study various complex chromatographic conditions is described. The simulation program is based on the Craig distribution model where the column is divided into discrete distance (Δz) and time (Δt) segments in a grid and is based on parameterization with either the linear solvent strength or Neue-Kuss models for chromatographic retention. This algorithm is relatively simple to understand and produces results that agree well with closed form theory when available. The set of simulation programs allows for the use of any eluent composition profile (linear and nonlinear), any column temperature, any stationary phase composition (constant or non-constant), and any composition and shape of the injected sample profile. The latter addition to our program is particularly useful in characterizing the solvent mismatch effect in comprehensive two-dimensional liquid chromatography (2D-LC), in which there is a mismatch between the first dimension (1D) effluent and second dimension (2D) initial mobile phase composition. This solvent mismatch causes peak distortion and broadening. The use of simulations can provide a better understanding of this phenomenon and a guide for the method development for 2D-LC. Another development that is proposed to have a great impact on the enhancement of 2D-LC methods is the use of continuous stationary phase gradients. When using rapid mobile phase gradients in the second dimension separation with diode array detection (DAD), refractive index changes cause large backgrounds such as an injection ridge (from solvent mismatch) and sloping baselines which can be problematic for achieving accurate quantitation. Use of a stationary phase gradient may enable the use of an isocratic mobile phase in the 2D, thus minimizing these background signals. Finally, our simulator can be used as an educational tool. Unlike commercially available simulators, our program can capture the evolution of the chromatogram in the form of movies and/or snapshots of the analyte distribution over time and/or distance to facilitate a better understanding of the separation process under complicated circumstances. We plan to make this simulation program publically available to all chromatographers and educators to aid in more efficient method development and chromatographic training

Respiratory Health among Korean Pupils in Relation to Home, School and Outdoor Environment

There are few studies about school-environment in relation to pupils' respiratory health, and Korean school-environment has not been characterized. All pupils in 4th grade in 12 selected schools in three urban cities in Korea received a questionnaire (n = 2,453), 96% participated. Gaseous pollutants and ultrafine particles (UFPs) were measured indoors (n = 34) and outdoors (n = 12) during winter, 2004. Indoor dampness at home was investigated by the questionnaire. To evaluate associations between respiratory health and environment, multiple logistic- and multi-level regression models were applied adjusting for potential confounders. The mean age of pupils was 10 yr and 49% were boys. No school had mechanical ventilation and CO2-levels exceeded 1,000 ppm in all except one of the classrooms. The indoor mean concentrations of SO2, NO2, O3 and formaldehyde were 0.6 µg/m3, 19 µg/m3, 8 µg/m3 and 28 µg/m3, respectively. The average level of UFPs was 18,230 pt/cm3 in the classrooms and 16,480 pt/cm3 outdoors. There were positive associations between wheeze and outdoor NO2, and between current asthma and outdoor UFPs. With dampness at home, pupils had more wheeze. In conclusion, outdoor UFPs and even low levels of NO2 may adversely contribute to respiratory health in children. High CO2-levels in classrooms and indoor dampness/mold at home should be reduced

Analytical approaches for the evaluation of data deficient simulated leachable compounds in ENDS products: a case study

Leachable investigations are routinely undertaken across a range of sectors (e.g., pharmaceuticals, medical devices, etc.) to determine whether chemicals from a container closure system transfer into a product under normal conditions of use. For Electronic Nicotine Delivery Systems (ENDS) the container closure system includes all materials in contact with the e-liquid that is aerosolized and subsequently inhaled by the user. Currently, there is no guidance for conducting leachable studies for ENDS products, however, there are relevant guidance documents for orally inhaled drug products that can be applied to an ENDS container closure system. We present a case study of the analytical investigation of two leachable compounds identified in simulated leachable studies using aged JUULpods filled with unflavored e-liquid (PG/VG/nicotine/benzoic acid). Both compounds had limited toxicological information and were considered data deficient. A qualitative analysis of the aerosol collected from aged commercial JUULpods (Virginia Tobacco and Menthol), using a similar analytical method (LC-MS/MS) used in the simulated leachable studies, showed no trace or detectable levels of either leachable compound. Therefore, this qualitative analysis did not provide semi-quantitative values for the data-deficient leachable compounds necessary to support toxicological risk assessment. Further, no commercial authentic standards or reasonable synthetic route were available due to the molecular size and structural complexity of the compounds. Instead, method limits were established using an alternative approach to standard ICH guidelines. The experimentally determined method limit of quantitation, using spiked samples of simulated leachable e-liquid, provided conservative semi-quantitative values for each data deficient leachable compound in the aerosol that enabled a transfer efficiency from e-liquid to aerosol to be estimated. The transfer efficiency of each leachable compound was experimentally determined to be less than 2% based on the limit of quantitation, which then could be used to define a relevant exposure limit for the toxicological risk assessment. This work details a novel analytical approach for determining the transfer efficiency of data deficient leachable compounds from ENDS container closure systems into the ENDS aerosol to support toxicological health risk assessments

Anesthesia triggers drug delivery to experimental glioma in mice by hijacking caveolar transport

Background Pharmaceutical intervention in the CNS is hampered by the shielding function of the blood–brain barrier (BBB). To induce clinical anesthesia, general anesthetics such as isoflurane readily penetrate the BBB. Here, we investigated whether isoflurane can be utilized for therapeutic drug delivery. Methods Barrier function in primary endothelial cells was evaluated by transepithelial/transendothelial electrical resistance, and nanoscale STED and SRRF microscopy. In mice, BBB permeability was quantified by extravasation of several fluorescent tracers. Mouse models including the GL261 glioma model were evaluated by MRI, immunohistochemistry, electron microscopy, western blot, and expression analysis. Results Isoflurane enhances BBB permeability in a time- and concentration-dependent manner. We demonstrate that, mechanistically, isoflurane disturbs the organization of membrane lipid nanodomains and triggers caveolar transport in brain endothelial cells. BBB tightness re-establishes directly after termination of anesthesia, providing a defined window for drug delivery. In a therapeutic glioblastoma trial in mice, simultaneous exposure to isoflurane and cytotoxic agent improves efficacy of chemotherapy. Conclusions Combination therapy, involving isoflurane-mediated BBB permeation with drug administration has far-reaching the

Reflective arrayed waveguide gratings based on Sagnac loop reflectors with custom spectral response

© 2014 Optical Society of America. One print or electronic copy may be made for personal use only. Systematic reproduction and distribution, duplication of any material in this paper for a fee or for commercial purposes, or modifications of the content of this paper are prohibitedIn this paper, a model for the analysis and design of a reflective Arrayed Waveguide Grating is presented. The device consists of one half of a regular AWG where each arm waveguide in the array is terminated with a phase shifter and a Sagnac loop reflector. By individually adjusting the phase shifter and Sagnac reflectivity in each arm, additional functionality to that previously reported in the literature is attained, since this enables tailoring the spectral response of the AWG. The design and experimental demonstration of Gaussian pass-band shape devices in Silicon-on-Insulator technology are reported. Methods to obtain flattened and arbitrary spectral responses are described and supported by simulation results. (C) 2014 Optical Society of AmericaThe authors acknowledge financial support by the Spanish MINECO projects TEC2010-21337, TEC2013-42332-P; FEDER UPVOV 10-3E-492 and UPVOV 08-3E-008. B. Gargallo acknowledges financial support through FPI grant BES-2011-046100. The authors thank J.S. Fandino for helpful discussions.Gargallo Jaquotot, BA.; Muñoz Muñoz, P.; Baños López, R.; Giesecke, AL.; Bolten, J.; Wahlbrink, T.; Kleinjans, H. (2014). Reflective arrayed waveguide gratings based on Sagnac loop reflectors with custom spectral response. Optics Express. 22(12):14348-14362. https://doi.org/10.1364/OE.22.014348S14348143622212Brackett, C. A. (1990). Dense wavelength division multiplexing networks: principles and applications. IEEE Journal on Selected Areas in Communications, 8(6), 948-964. doi:10.1109/49.57798Kirchain, R., & Kimerling, L. (2007). A roadmap for nanophotonics. Nature Photonics, 1(6), 303-305. doi:10.1038/nphoton.2007.84Pennings, E., Khoe, G.-D., Smit, M. K., & Staring, T. (1996). Integrated-optic versus microoptic devices for fiber-optic telecommunication systems: a comparison. IEEE Journal of Selected Topics in Quantum Electronics, 2(2), 151-164. doi:10.1109/2944.577349Smit, M. K., & Van Dam, C. (1996). PHASAR-based WDM-devices: Principles, design and applications. IEEE Journal of Selected Topics in Quantum Electronics, 2(2), 236-250. doi:10.1109/2944.577370Dragone, C., Edwards, C. A., & Kistler, R. C. (1991). Integrated optics N*N multiplexer on silicon. IEEE Photonics Technology Letters, 3(10), 896-899. doi:10.1109/68.93254Lycett, R. J., Gallagher, D. F. G., & Brulis, V. J. (2013). Perfect Chirped Echelle Grating Wavelength Multiplexor: Design and Optimization. IEEE Photonics Journal, 5(2), 2400123-2400123. doi:10.1109/jphot.2013.2251874Ryckeboer, E., Gassenq, A., Muneeb, M., Hattasan, N., Pathak, S., Cerutti, L., … Roelkens, G. (2013). Silicon-on-insulator spectrometers with integrated GaInAsSb photodiodes for wide-band spectroscopy from 1510 to 2300 nm. Optics Express, 21(5), 6101. doi:10.1364/oe.21.006101Pruessner, M. W., Stievater, T. H., & Rabinovich, W. S. (2007). Integrated waveguide Fabry-Perot microcavities with silicon/air Bragg mirrors. Optics Letters, 32(5), 533. doi:10.1364/ol.32.000533De Peralta, L. G., Bernussi, A. A., Frisbie, S., Gale, R., & Temkin, H. (2003). Reflective arrayed waveguide grating multiplexer. IEEE Photonics Technology Letters, 15(10), 1398-1400. doi:10.1109/lpt.2003.818223Inoue, Y., Himeno, A., Moriwaki, K., & Kawachi, M. (1995). Silica-based arrayed-waveguide grating circuit as optical splitter/router. Electronics Letters, 31(9), 726. doi:10.1049/el:19950497Soole, J. B. D., Amersfoort, M. R., LeBlanc, H. P., Rajhel, A., Caneau, C., Youtsey, C., & Adesida, I. (1996). Compact polarisation independent InP reflective arrayed waveguide grating filter. Electronics Letters, 32(19), 1769. doi:10.1049/el:19961212Dai, D., Fu, X., Shi, Y., & He, S. (2010). Experimental demonstration of an ultracompact Si-nanowire-based reflective arrayed-waveguide grating (de)multiplexer with photonic crystal reflectors. Optics Letters, 35(15), 2594. doi:10.1364/ol.35.002594Tsai, J.-C., Huang, S., Hah, D., Toshiyoshi, H., & Wu, M. C. (2004). Open-Loop Operation of MEMS-Based<tex>$1,times N$</tex>Wavelength-Selective Switch With Long-Term Stability and Repeatability. IEEE Photonics Technology Letters, 16(4), 1041-1043. doi:10.1109/lpt.2004.824652Okamoto, K., & Ishida, K. (2013). Fabrication of silicon reflection-type arrayed-waveguide gratings with distributed Bragg reflectors. Optics Letters, 38(18), 3530. doi:10.1364/ol.38.003530Okamoto, K., & Yamada, H. (1995). Arrayed-waveguide grating multiplexer with flat spectral response. Optics Letters, 20(1), 43. doi:10.1364/ol.20.000043Doerr, C. R., Zhang, L., & Winzer, P. J. (2011). Monolithic InP Multiwavelength Coherent Receiver Using a Chirped Arrayed Waveguide Grating. Journal of Lightwave Technology, 29(4), 536-541. doi:10.1109/jlt.2010.2097240Munoz, P., Pastor, D., & Capmany, J. (2002). Modeling and design of arrayed waveguide gratings. Journal of Lightwave Technology, 20(4), 661-674. doi:10.1109/50.996587Jinguji, K., Takato, N., Hida, Y., Kitoh, T., & Kawachi, M. (1996). Two-port optical wavelength circuits composed of cascaded Mach-Zehnder interferometers with point-symmetrical configurations. Journal of Lightwave Technology, 14(10), 2301-2310. doi:10.1109/50.541222Soldano, L. B., & Pennings, E. C. M. (1995). Optical multi-mode interference devices based on self-imaging: principles and applications. Journal of Lightwave Technology, 13(4), 615-627. doi:10.1109/50.372474Bachmann, M., Besse, P. A., & Melchior, H. (1994). General self-imaging properties in N × N multimode interference couplers including phase relations. Applied Optics, 33(18), 3905. doi:10.1364/ao.33.003905Besse, P. A., Gini, E., Bachmann, M., & Melchior, H. (1996). New 2×2 and 1×3 multimode interference couplers with free selection of power splitting ratios. Journal of Lightwave Technology, 14(10), 2286-2293. doi:10.1109/50.541220Leuthold, J., & Joyner, C. W. (2001). Multimode interference couplers with tunable power splitting ratios. Journal of Lightwave Technology, 19(5), 700-707. doi:10.1109/50.923483Seok-Hwan Jeong, & Morito, K. (2010). Novel Optical 90$^{\circ}$ Hybrid Consisting of a Paired Interference Based 2$\,\times\,$4 MMI Coupler, a Phase Shifter and a 2$\,\times\,$2 MMI Coupler. Journal of Lightwave Technology, 28(9), 1323-1331. doi:10.1109/jlt.2010.2042278Talahashi, H., Oda, K., Toba, H., & Inoue, Y. (1995). Transmission characteristics of arrayed waveguide N×N wavelength multiplexer. Journal of Lightwave Technology, 13(3), 447-455. doi:10.1109/50.372441Munoz, P., Pastor, D., Capmany, J., Ortega, D., Pujol, A., & Bonar, J. R. (2004). AWG Model Validation Through Measurement of Fabricated Devices. Journal of Lightwave Technology, 22(12), 2763-2777. doi:10.1109/jlt.2004.833275Kleijn, E., Smit, M. K., & Leijtens, X. J. M. (2013). New Analytical Arrayed Waveguide Grating Model. Journal of Lightwave Technology, 31(20), 3309-3314. doi:10.1109/jlt.2013.2281612Bogaerts, W., Dumon, P., Thourhout, D. V., Taillaert, D., Jaenen, P., Wouters, J., … Baets, R. G. (2006). Compact Wavelength-Selective Functions in Silicon-on-Insulator Photonic Wires. IEEE Journal of Selected Topics in Quantum Electronics, 12(6), 1394-1401. doi:10.1109/jstqe.2006.884088Pathak, S., Van Thourhout, D., & Bogaerts, W. (2013). Design trade-offs for silicon-on-insulator-based AWGs for (de)multiplexer applications. Optics Letters, 38(16), 2961. doi:10.1364/ol.38.002961Van Laere, F., Claes, T., Schrauwen, J., Scheerlinck, S., Bogaerts, W., Taillaert, D., … Baets, R. (2007). Compact Focusing Grating Couplers for Silicon-on-Insulator Integrated Circuits. IEEE Photonics Technology Letters, 19(23), 1919-1921. doi:10.1109/lpt.2007.908762Henschel, W., Georgiev, Y. M., & Kurz, H. (2003). Study of a high contrast process for hydrogen silsesquioxane as a negative tone electron beam resist. Journal of Vacuum Science & Technology B: Microelectronics and Nanometer Structures, 21(5), 2018. doi:10.1116/1.1603284LEMME, M. (2004). Highly selective HBr etch process for fabrication of Triple-Gate nano-scale SOI-MOSFETs. Microelectronic Engineering, 73-74, 346-350. doi:10.1016/s0167-9317(04)00123-6Bolten, J., Wahlbrink, T., Koo, N., Kurz, H., Stammberger, S., Hofmann, U., & Ünal, N. (2010). Improved CD control and line edge roughness in E-beam lithography through combining proximity effect correction with gray scale techniques. Microelectronic Engineering, 87(5-8), 1041-1043. doi:10.1016/j.mee.2009.11.097Sakai, A., Fukazawa, T., & Baba, T. (2004). Estimation of Polarization Crosstalk at a Micro-Bend in Si-Photonic Wire Waveguide. Journal of Lightwave Technology, 22(2), 520-525. doi:10.1109/jlt.2004.824357Kleijn, E., Williams, P. J., Whitbread, N. D., Wale, M. J., Smit, M. K., & Leijtens, X. J. M. (2012). Sidelobes in the response of arrayed waveguide gratings caused by polarization rotation. Optics Express, 20(20), 22660. doi:10.1364/oe.20.022660Pathak, S., Vanslembrouck, M., Dumon, P., Van Thourhout, D., Verheyen, P., Lepage, G., … Bogaerts, W. (2014). Effect of Mask Discretization on Performance of Silicon Arrayed Waveguide Gratings. IEEE Photonics Technology Letters, 26(7), 718-721. doi:10.1109/lpt.2014.2303793Okamoto, K., & Sugita, A. (1996). Flat spectral response arrayed-waveguide grating multiplexer with parabolic waveguide horns. Electronics Letters, 32(18), 1661. doi:10.1049/el:19961108Munoz, P., Pastor, D., & Capmany, J. (2001). Analysis and design of arrayed waveguide gratings with MMI couplers. Optics Express, 9(7), 328. doi:10.1364/oe.9.000328Doerr, C. R., Cappuzzo, M. A., Chen, E. Y., Wong-Foy, A., Gomez, L. T., & Buhl, L. L. (2006). Wideband Arrayed Waveguide Grating With Three Low-Loss Maxima Per Passband. IEEE Photonics Technology Letters, 18(21), 2308-2310. doi:10.1109/lpt.2006.885208Leaird, D. E., Weiner, A. M., Kamei, S., Ishii, M., Sugita, A., & Okamoto, K. (2002). Generation of flat-topped 500-GHz pulse bursts using loss engineered arrayed waveguide gratings. IEEE Photonics Technology Letters, 14(6), 816-818. doi:10.1109/lpt.2002.100310

Floral gene resources from basal angiosperms for comparative genomics research

BACKGROUND: The Floral Genome Project was initiated to bridge the genomic gap between the most broadly studied plant model systems. Arabidopsis and rice, although now completely sequenced and under intensive comparative genomic investigation, are separated by at least 125 million years of evolutionary time, and cannot in isolation provide a comprehensive perspective on structural and functional aspects of flowering plant genome dynamics. Here we discuss new genomic resources available to the scientific community, comprising cDNA libraries and Expressed Sequence Tag (EST) sequences for a suite of phylogenetically basal angiosperms specifically selected to bridge the evolutionary gaps between model plants and provide insights into gene content and genome structure in the earliest flowering plants. RESULTS: Random sequencing of cDNAs from representatives of phylogenetically important eudicot, non-grass monocot, and gymnosperm lineages has so far (as of 12/1/04) generated 70,514 ESTs and 48,170 assembled unigenes. Efficient sorting of EST sequences into putative gene families based on whole Arabidopsis/rice proteome comparison has permitted ready identification of cDNA clones for finished sequencing. Preliminarily, (i) proportions of functional categories among sequenced floral genes seem representative of the entire Arabidopsis transcriptome, (ii) many known floral gene homologues have been captured, and (iii) phylogenetic analyses of ESTs are providing new insights into the process of gene family evolution in relation to the origin and diversification of the angiosperms. CONCLUSION: Initial comparisons illustrate the utility of the EST data sets toward discovery of the basic floral transcriptome. These first findings also afford the opportunity to address a number of conspicuous evolutionary genomic questions, including reproductive organ transcriptome overlap between angiosperms and gymnosperms, genome-wide duplication history, lineage-specific gene duplication and functional divergence, and analyses of adaptive molecular evolution. Since not all genes in the floral transcriptome will be associated with flowering, these EST resources will also be of interest to plant scientists working on other functions, such as photosynthesis, signal transduction, and metabolic pathways

Endocrinologic, neurologic, and visual morbidity after treatment for craniopharyngioma

Craniopharyngiomas are locally aggressive tumors which typically are focused in the sellar and suprasellar region near a number of critical neural and vascular structures mediating endocrinologic, behavioral, and visual functions. The present study aims to summarize and compare the published literature regarding morbidity resulting from treatment of craniopharyngioma. We performed a comprehensive search of the published English language literature to identify studies publishing outcome data of patients undergoing surgery for craniopharyngioma. Comparisons of the rates of endocrine, vascular, neurological, and visual complications were performed using Pearson’s chi-squared test, and covariates of interest were fitted into a multivariate logistic regression model. In our data set, 540 patients underwent surgical resection of their tumor. 138 patients received biopsy alone followed by some form of radiotherapy. Mean overall follow-up for all patients in these studies was 54 ± 1.8 months. The overall rate of new endocrinopathy for all patients undergoing surgical resection of their mass was 37% (95% CI = 33–41). Patients receiving GTR had over 2.5 times the rate of developing at least one endocrinopathy compared to patients receiving STR alone or STR + XRT (52 vs. 19 vs. 20%, χ2P < 0.00001). On multivariate analysis, GTR conferred a significant increase in the risk of endocrinopathy compared to STR + XRT (OR = 3.45, 95% CI = 2.05–5.81, P < 0.00001), after controlling for study size and the presence of significant hypothalamic involvement. There was a statistical trend towards worse visual outcomes in patients receiving XRT after STR compared to GTR or STR alone (GTR = 3.5% vs. STR 2.1% vs. STR + XRT 6.4%, P = 0.11). Given the difficulty in obtaining class 1 data regarding the treatment of this tumor, this study can serve as an estimate of expected outcomes for these patients, and guide decision making until these data are available

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension