Seprase: An overview of an important matrix serine protease

Seprase or Fibroblast Activation Protein (FAP) is an integral membrane serine peptidase, which has been shown to have gelatinase activity. Seprase has a dual function in tumour progression. The proteolytic activity of Seprase has been shown to promote cell invasiveness towards the ECM and also to support tumour growth and proliferation. Seprase appears to act as a proteolytically active 170-kDa dimer, consisting of two 97- kDa subunits. It is a member of the group type II integral serine proteases, which includes dipeptidyl peptidase IV (DPPIV/CD26) and related type II transmembrane prolyl serine peptidases, which exert their mechanisms of action on the cell surface. DPPIV and Seprase exhibit multiple functions due to their abilities to form complexes with each other and to interact with other membrane-associated molecules. Localisation of these protease complexes at cell surface protrusions, called invadopodia, may have a prominent role in processing soluble factors and in the degradation of extracellular matrix components that are essential to the cellular migration and matrix invasion that occur during tumour invasion, metastasis and angiogenesis

Alemtuzumab induction in kidney transplant recipients

INTRODUCTION: Induction therapy has been used in sensitized patients, re-transplants, and in patients who have high risk to delayed graft function (DGF) after renal transplantation. METHODS: Retrospective study with aim to compare transplant endpoints between recipients of deceased donors which have received induction with alemtuzumab (n = 9) versus thymoglobulin (n = 18). Patients were matched for age, duration of dialysis treatment and cold ischemia time. RESULTS: There were no differences at demographic characteristics. All patients received kidney grafts from deceased donors and 67% of these donors met the expanded criteria. The incidence of DFG was similar in alemtuzumab and thymoglobulin groups, 55% and 56%. At 12 months, rates of rejection free survival (67% versus 89%, p = 0,13), graft survival (62,5% versus 76,6%; p = 0,73), graft with death censored (62,5% versus 76,6%; p = 0,82) and patient survival (83,3% versus 81,2%; p = 0,63) were similar between the two groups. Viral infections and renal function were similar between groups. At the end of the first month, alemtuzumab patients displayed a fewer lymphocyte number (135 ± 78 versus 263 ± 112 N/mm³, p < 0,05) followed by a more rapid recovery after 3 months (day 90: 683 ± 367 versus 282 ± 72 N/mm³; p < 0,05). Cost associated with alemtuzumab and thymoglobulin inductions therapies were R$1,388.00 and R$ 7,398.00. CONCLUSION: In this cohort of patients, alemtuzumab induction showed efficacy and safety comparable to thymoglobulin but with significant cost reduction.INTRODUÇÃO: Terapias de indução são usualmente utilizadas em receptores sensibilizados contra antígenos HLA, retransplantes e pacientes com risco de apresentar função tardia do enxerto (FTE). MÉTODO: Estudo retrospectivo com objetivo de avaliar os desfechos do transplante renal com doador falecido em pacientes que receberam indução com alentuzumabe (n = 9). Os pacientes do grupo controle, pareados conforme idade do receptor, tempo em diálise e tempo de isquemia fria, receberam timoglobulina (n = 18). RESULTADOS: Não houve diferença nas características demográficas entre os grupos. A idade média dos receptores foi de 47 anos e dos doadores, de 59 anos. Entre os doadores, 67% apresentavam critério expandido. A incidência de FTE foi de 55% e 56%, respectivamente. Ao final do primeiro ano, não houve diferença nas sobrevidas livre de rejeição aguda comprovada por biópsia (67,0% e 84,6%, p = 0,26), do paciente (83,3% e 81,2%; p = 0,63), do enxerto (62,5% e 66,7%; p = 0,82), do enxerto com óbito censorado (62,5% e 76,6%; p = 0,73) e na função renal (depuração de creatinina: 61,6 ± 18,2 versus 52,7 ± 26,1 mL/min, p = 0,503). Houve maior redução na contagem de linfócitos no sangue periférico no grupo alentuzumabe (dia 14:172 ± 129 versus 390 ± 195 N/mm³, p < 0,05; dia 30: 135 ± 78 versus 263±112 N/mm³, p < 0,05), porém com retorno mais rápido a valores normais após o transplante (dia 90: 683 ± 367 versus 282 ± 72 N/mm³, p < 0,05; dia 360: 1269 ± 806 versus 690±444 N/mm³, p < 0,05). O custo do tratamento com alentuzumabe foi de R$1.388,00, enquanto que o custo médio com timoglobulina foi de R$ 7.398,00. CONCLUSÃO: Essa experiência com alentuzumabe não demonstrou eficácia e/ou segurança superiores aos regimes com timoglobulina, apesar do custo ser em média cinco vezes menor.Universidade Federal de São Paulo (UNIFESP) Departamento de Medicina Hospital do Rim e HipertensãoUniversidade Federal de São Paulo (UNIFESP) Departamento de Patologia, Transplante Renal e NefropatologiaUNIFESP, Depto. de Medicina Hospital do Rim e HipertensãoUNIFESP, Depto. de Patologia, Transplante Renal e NefropatologiaSciEL

Stabilization of mid-sized silicon nanoparticles by functionalization with acrylic acid

We present an enhanced method to form stable dispersions of medium-sized silicon nanoparticles for solar cell applications by thermally induced grafting of acrylic acid to the nanoparticle surface. In order to confirm their covalent attachment on the silicon nanoparticles and to assess the quality of the functionalization, X-ray photoelectron spectroscopy and diffuse reflectance infrared Fourier spectroscopy measurements were carried out. The stability of the dispersion was elucidated by dynamic light scattering and Zeta-potential measurements, showing no sign of degradation for months

Cardiac action potential repolarization revisited: early repolarization shows all-or-none behaviour

[EN] In healthy mammalian hearts the action potential (AP) waveform initiates and modulates each contraction, or heartbeat. As a result, AP height and duration are key physiological variables. In addition, rate-dependent changes in ventricular AP duration (APD), and variations in APD at a fixed heart rate are both reliable biomarkers of electrophysiological stability. Present guidelines for the likelihood that candidate drugs will increase arrhythmias rely on small changes in APD and Q-T intervals as criteria for safety pharmacology decisions. However, both of these measurements correspond to the final repolarization of the AP. Emerging clinical evidence draws attention to the early repolarization phase of the action potential (and the J-wave of the ECG) as an additional important biomarker for arrhythmogenesis. Here we provide a mechanistic background to this early repolarization syndrome by summarizing the evidence that both the initial depolarization and repolarization phases of the cardiac action potential can exhibit distinct time- and voltage-dependent thresholds, and also demonstrating that both can show regenerative all-or-none behaviour. An important consequence of this is that not all of the dynamics of action potential repolarization in human ventricle can be captured by data from single myocytes when these results are expressed as repolarization reserve'. For example, the complex pattern of cell-to-cell current flow that is responsible for AP conduction (propagation) within the mammalian myocardium can change APD and the Q-T interval of the electrocardiogram alter APD stability, and modulate responsiveness to pharmacological agents (such as Class III anti-arrhythmic drugs).The Giles Laboratory acknowledges funding from the Canadian Institutes for Health Research. The computational work in Spain, was funded from the Ministerio de Economia, Industria y Competitividad of Spain (DPI2016-75799-R) and AEI/FEDER, UE, and the Programa Prometeu (PROMETEU/2016/088) de la Conselleria d'Educacio, Formacio/Ocupacio, Generalitat ValencianaTrenor Gomis, BA.; Cardona-Urrego, KE.; Saiz Rodríguez, FJ.; Noble, D.; Giles, W. (2017). Cardiac action potential repolarization revisited: early repolarization shows all-or-none behaviour. The Journal of Physiology. 595(21):6599-6612. https://doi.org/10.1113/JP273651S6599661259521Anderson, M. E., Al-Khatib, S. M., Roden, D. M., & Califf, R. M. (2002). Cardiac repolarization: Current knowledge, critical gaps, and new approaches to drug development and patient management. American Heart Journal, 144(5), 769-781. doi:10.1067/mhj.2002.125804ANTZELEVITCH, C. (2005). Modulation of Transmural Repolarization. Annals of the New York Academy of Sciences, 1047(1), 314-323. doi:10.1196/annals.1341.028Antzelevitch, C. (2012). Genetic, Molecular and Cellular Mechanisms Underlying the J Wave Syndromes. Circulation Journal, 76(5), 1054-1065. doi:10.1253/circj.cj-12-0284Antzelevitch, C., & Yan, G.-X. (2010). J wave syndromes. Heart Rhythm, 7(4), 549-558. doi:10.1016/j.hrthm.2009.12.006Antzelevitch, C., Yan, G.-X., & Viskin, S. (2011). Rationale for the Use of the Terms J-Wave Syndromes and Early Repolarization. Journal of the American College of Cardiology, 57(15), 1587-1590. doi:10.1016/j.jacc.2010.11.038Ballou, L. M., Lin, R. Z., & Cohen, I. S. (2015). Control of Cardiac Repolarization by Phosphoinositide 3-Kinase Signaling to Ion Channels. Circulation Research, 116(1), 127-137. doi:10.1161/circresaha.116.303975Bean, B. P. (2007). The action potential in mammalian central neurons. Nature Reviews Neuroscience, 8(6), 451-465. doi:10.1038/nrn2148Belardinelli, L., Giles, W. R., Rajamani, S., Karagueuzian, H. S., & Shryock, J. C. (2015). Cardiac late Na+ current: Proarrhythmic effects, roles in long QT syndromes, and pathological relationship to CaMKII and oxidative stress. Heart Rhythm, 12(2), 440-448. doi:10.1016/j.hrthm.2014.11.009Bondarenko, V. E., & Rasmusson, R. L. (2010). Transmural heterogeneity of repolarization and Ca2+ handling in a model of mouse ventricular tissue. American Journal of Physiology-Heart and Circulatory Physiology, 299(2), H454-H469. doi:10.1152/ajpheart.00907.2009Bouchard, R. A., Clark, R. B., & Giles, W. R. (1995). Effects of Action Potential Duration on Excitation-Contraction Coupling in Rat Ventricular Myocytes. Circulation Research, 76(5), 790-801. doi:10.1161/01.res.76.5.790Bouchard, R., Clark, R. B., Juhasz, A. E., & Giles, W. R. (2004). Changes in extracellular K+concentration modulate contractility of rat and rabbit cardiac myocytes via the inward rectifier K+currentIK1. The Journal of Physiology, 556(3), 773-790. doi:10.1113/jphysiol.2003.058248Bowes, J., Brown, A. J., Hamon, J., Jarolimek, W., Sridhar, A., Waldron, G., & Whitebread, S. (2012). Reducing safety-related drug attrition: the use of in vitro pharmacological profiling. Nature Reviews Drug Discovery, 11(12), 909-922. doi:10.1038/nrd3845Burashnikov, E., Pfeiffer, R., Barajas-Martinez, H., Delpón, E., Hu, D., Desai, M., … Antzelevitch, C. (2010). Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death. Heart Rhythm, 7(12), 1872-1882. doi:10.1016/j.hrthm.2010.08.026Chandler, W. K., & Meves, H. (1970). Evidence for two types of sodium conductance in axons perfused with sodium fluoride solution. The Journal of Physiology, 211(3), 653-678. doi:10.1113/jphysiol.1970.sp009298Chandler, W. K., & Meves, H. (1970). Slow changes in membrane permeability and long-lasting action potentials in axons perfused with fluoride solutions. The Journal of Physiology, 211(3), 707-728. doi:10.1113/jphysiol.1970.sp009300Chi, K. R. (2013). Revolution dawning in cardiotoxicity testing. Nature Reviews Drug Discovery, 12(8), 565-567. doi:10.1038/nrd4083CLARK, R. B., BOUCHARD, R. A., & GILES, W. R. (1996). Action Potential Duration Modulates Calcium Influx, Na+-Ca2+ Exchange, and Intracellular Calcium Release in Rat Ventricular Myocytesa. Annals of the New York Academy of Sciences, 779(1), 417-429. doi:10.1111/j.1749-6632.1996.tb44817.xClark, R. B., Tremblay, A., Melnyk, P., Allen, B. G., Giles, W. R., & Fiset, C. (2001). T-tubule localization of the inward-rectifier K+ channel in mouse ventricular myocytes: a role in K+ accumulation. The Journal of Physiology, 537(3), 979-992. doi:10.1113/jphysiol.2001.012708Coronel, R., Wilders, R., Verkerk, A. O., Wiegerinck, R. F., Benoist, D., & Bernus, O. (2013). Electrophysiological changes in heart failure and their implications for arrhythmogenesis. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1832(12), 2432-2441. doi:10.1016/j.bbadis.2013.04.002Cranefield, P. F., & Hoffman, B. F. (1958). PROPAGATED REPOLARIZATION IN HEART MUSCLE. Journal of General Physiology, 41(4), 633-649. doi:10.1085/jgp.41.4.633Fink, M., Giles, W. R., & Noble, D. (2006). Contributions of inwardly rectifying K + currents to repolarization assessed using mathematical models of human ventricular myocytes. Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences, 364(1842), 1207-1222. doi:10.1098/rsta.2006.1765Giebisch, G., & Weidmann, S. (1971). Membrane Currents in Mammalian Ventricular Heart Muscle Fibers Using a Voltage-Clamp Technique. Journal of General Physiology, 57(3), 290-296. doi:10.1085/jgp.57.3.290Gray, R. A., Mashburn, D. N., Sidorov, V. Y., & Wikswo, J. P. (2013). Quantification of Transmembrane Currents during Action Potential Propagation in the Heart. Biophysical Journal, 104(1), 268-278. doi:10.1016/j.bpj.2012.11.007Gussak, I., & Antzelevitch, C. (2000). Early repolarization syndrome: Clinical characteristics and possible cellular and ionic mechanisms. Journal of Electrocardiology, 33(4), 299-309. doi:10.1054/jelc.2000.18106Gussak, I., Antzelevitch, C., Hammill, S. C., Shen, W. K., & Bjerregaard, P. (2003). Cardiac Repolarization. doi:10.1385/1592593623Haïssaguerre, M., Derval, N., Sacher, F., Jesel, L., Deisenhofer, I., de Roy, L., … Clémenty, J. (2008). Sudden Cardiac Arrest Associated with Early Repolarization. New England Journal of Medicine, 358(19), 2016-2023. doi:10.1056/nejmoa071968HALL, A. E., & NOBLE, D. (1963). Transient Responses of Purkinje Fibres to Non-uniform Currents. Nature, 199(4900), 1294-1295. doi:10.1038/1991294a0Hoogendijk, M. G., Potse, M., & Coronel, R. (2012). Early repolarization patterns: The good, the bad, and the ugly? Heart Rhythm, 9(2), 230-231. doi:10.1016/j.hrthm.2011.09.064Hoogendijk, M. G., Potse, M., & Coronel, R. (2013). Critical appraisal of the mechanism underlying J waves. Journal of Electrocardiology, 46(5), 390-394. doi:10.1016/j.jelectrocard.2013.06.017Huxley, A. F. (1959). ION MOVEMENTS DURING NERVE ACTIVITY. Annals of the New York Academy of Sciences, 81(2), 221-246. doi:10.1111/j.1749-6632.1959.tb49311.xJanse, M. (2004). Electrophysiological changes in heart failure and their relationship to arrhythmogenesis. Cardiovascular Research, 61(2), 208-217. doi:10.1016/j.cardiores.2003.11.018Jost, N., Virág, L., Comtois, P., Ördög, B., Szuts, V., Seprényi, G., … Nattel, S. (2013). Ionic mechanisms limiting cardiac repolarization reserve in humans compared to dogs. The Journal of Physiology, 591(17), 4189-4206. doi:10.1113/jphysiol.2013.261198Kannankeril, P., Roden, D. M., & Darbar, D. (2010). Drug-Induced Long QT Syndrome. Pharmacological Reviews, 62(4), 760-781. doi:10.1124/pr.110.003723Kelly, A., Ghouri, I. A., Kemi, O. J., Bishop, M. J., Bernus, O., Fenton, F. H., … Smith, G. L. (2013). Subepicardial Action Potential Characteristics Are a Function of Depth and Activation Sequence in Isolated Rabbit Hearts. Circulation: Arrhythmia and Electrophysiology, 6(4), 809-817. doi:10.1161/circep.113.000334Kondo, R. P., Dederko, D. A., Teutsch, C., Chrast, J., Catalucci, D., Chien, K. R., & Giles, W. R. (2006). Comparison of contraction and calcium handling between right and left ventricular myocytes from adult mouse heart: a role for repolarization waveform. The Journal of Physiology, 571(1), 131-146. doi:10.1113/jphysiol.2005.101428Kramer, J., Obejero-Paz, C. A., Myatt, G., Kuryshev, Y. A., Bruening-Wright, A., Verducci, J. S., & Brown, A. M. (2013). MICE Models: Superior to the HERG Model in Predicting Torsade de Pointes. Scientific Reports, 3(1). doi:10.1038/srep02100Libbus, I., Wan, X., & Rosenbaum, D. S. (2004). Electrotonic load triggers remodeling of repolarizing current Ito in ventricle. American Journal of Physiology-Heart and Circulatory Physiology, 286(5), H1901-H1909. doi:10.1152/ajpheart.00581.2003Liu, M. B., Ko, C. Y., Song, Z., Garfinkel, A., Weiss, J. N., & Qu, Z. (2016). A Dynamical Threshold for Cardiac Delayed Afterdepolarization-Mediated Triggered Activity. Biophysical Journal, 111(11), 2523-2533. doi:10.1016/j.bpj.2016.10.009Macfarlane, P. W., Antzelevitch, C., Haissaguerre, M., Huikuri, H. V., Potse, M., Rosso, R., … Yan, G.-X. (2015). The Early Repolarization Pattern. Journal of the American College of Cardiology, 66(4), 470-477. doi:10.1016/j.jacc.2015.05.033Mirams, G. R., Davies, M. R., Cui, Y., Kohl, P., & Noble, D. (2012). Application of cardiac electrophysiology simulations to pro‐arrhythmic safety testing. British Journal of Pharmacology, 167(5), 932-945. doi:10.1111/j.1476-5381.2012.02020.xMirams, G. R., Pathmanathan, P., Gray, R. A., Challenor, P., & Clayton, R. H. (2016). Uncertainty and variability in computational and mathematical models of cardiac physiology. The Journal of Physiology, 594(23), 6833-6847. doi:10.1113/jp271671Mohri, S., Shimizu, J., Mika, Y., Shemer, I., Wang, J., Ben-Haim, S., & Burkhoff, D. (2003). Electric currents applied during refractory period enhance contractility and systolic calcium in the ferret heart. American Journal of Physiology-Heart and Circulatory Physiology, 284(4), H1119-H1123. doi:10.1152/ajpheart.00378.2002Moreno, J. D., Yang, P.-C., Bankston, J. R., Grandi, E., Bers, D. M., Kass, R. S., & Clancy, C. E. (2013). Ranolazine for Congenital and Acquired Late I Na -Linked Arrhythmias. Circulation Research, 113(7). doi:10.1161/circresaha.113.301971Myles, R. C., Bernus, O., Burton, F. L., Cobbe, S. M., & Smith, G. L. (2010). Effect of activation sequence on transmural patterns of repolarization and action potential duration in rabbit ventricular myocardium. American Journal of Physiology-Heart and Circulatory Physiology, 299(6), H1812-H1822. doi:10.1152/ajpheart.00518.2010Näbauer, M., Beuckelmann, D. J., & Erdmann, E. (1993). Characteristics of transient outward current in human ventricular myocytes from patients with terminal heart failure. Circulation Research, 73(2), 386-394. doi:10.1161/01.res.73.2.386Nattel, S. (2010). Sudden Cardio Arrest: When normal ECG variants turn lethal. Nature Medicine, 16(6), 646-647. doi:10.1038/nm0610-646Nerbonne, J. M., & Kass, R. S. (2005). Molecular Physiology of Cardiac Repolarization. Physiological Reviews, 85(4), 1205-1253. doi:10.1152/physrev.00002.2005NOBLE, D. (1960). Cardiac Action and Pacemaker Potentials based on the Hodgkin-Huxley Equations. Nature, 188(4749), 495-497. doi:10.1038/188495b0Noble, D. (1962). A modification of the Hodgkin-Huxley equations applicable to Purkinje fibre action and pacemaker potentials. The Journal of Physiology, 160(2), 317-352. doi:10.1113/jphysiol.1962.sp006849Noble, D. (1962). The Voltage Dependence of the Cardiac Membrane Conductance. Biophysical Journal, 2(5), 381-393. doi:10.1016/s0006-3495(62)86862-3Noble, D., & Tsien, R. W. (1972). The Repolarization Process of Heart Cells. Electrical Phenomena in the Heart, 133-161. doi:10.1016/b978-0-12-208950-3.50012-0O’Hara, T., Virág, L., Varró, A., & Rudy, Y. (2011). Simulation of the Undiseased Human Cardiac Ventricular Action Potential: Model Formulation and Experimental Validation. PLoS Computational Biology, 7(5), e1002061. doi:10.1371/journal.pcbi.1002061Osborn, J. J. (1953). Experimental Hypothermia: Respiratory and Blood ph Changes in Relation to Cardiac Function. American Journal of Physiology-Legacy Content, 175(3), 389-398. doi:10.1152/ajplegacy.1953.175.3.389Qu, Z., Xie, L.-H., Olcese, R., Karagueuzian, H. S., Chen, P.-S., Garfinkel, A., & Weiss, J. N. (2013). Early afterdepolarizations in cardiac myocytes: beyond reduced repolarization reserve. Cardiovascular Research, 99(1), 6-15. doi:10.1093/cvr/cvt104Reuter, H. (1973). Divalent cations as charge carriers in excitable membranes. Progress in Biophysics and Molecular Biology, 26, 1-43. doi:10.1016/0079-6107(73)90016-3Roden, D. M. (2004). Drug-Induced Prolongation of the QT Interval. New England Journal of Medicine, 350(10), 1013-1022. doi:10.1056/nejmra032426Roden, D. M. (2008). Repolarization Reserve. Circulation, 118(10), 981-982. doi:10.1161/circulationaha.108.798918Roden, D. M., & Abraham, R. L. (2011). Refining repolarization reserve. Heart Rhythm, 8(11), 1756-1757. doi:10.1016/j.hrthm.2011.06.024Roden, D. M., & Yang, T. (2005). Protecting the Heart Against Arrhythmias: Potassium Current Physiology and Repolarization Reserve. Circulation, 112(10), 1376-1378. doi:10.1161/circulationaha.105.562777Romero, L., Pueyo, E., Fink, M., & Rodríguez, B. (2009). Impact of ionic current variability on human ventricular cellular electrophysiology. American Journal of Physiology-Heart and Circulatory Physiology, 297(4), H1436-H1445. doi:10.1152/ajpheart.00263.2009Romero, L., Trenor, B., Yang, P.-C., Saiz, J., & Clancy, C. E. (2014). In silico screening of the impact of hERG channel kinetic abnormalities on channel block and susceptibility to acquired long QT syndrome. Journal of Molecular and Cellular Cardiology, 72, 126-137. doi:10.1016/j.yjmcc.2014.02.018Rosso, R., Adler, A., Halkin, A., & Viskin, S. (2011). Risk of sudden death among young individuals with J waves and early repolarization: Putting the evidence into perspective. Heart Rhythm, 8(6), 923-929. doi:10.1016/j.hrthm.2011.01.037Rosso, R., Glikson, E., Belhassen, B., Katz, A., Halkin, A., Steinvil, A., & Viskin, S. (2012). Distinguishing «benign» from «malignant early repolarization»: The value of the ST-segment morphology. Heart Rhythm, 9(2), 225-229. doi:10.1016/j.hrthm.2011.09.012Saegusa, N., Garg, V., & Spitzer, K. W. (2013). Modulation of ventricular transient outward K+ current by acidosis and its effects on excitation-contraction coupling. American Journal of Physiology-Heart and Circulatory Physiology, 304(12), H1680-H1696. doi:10.1152/ajpheart.00070.2013Sager, P. T., Gintant, G., Turner, J. R., Pettit, S., & Stockbridge, N. (2014). Rechanneling the cardiac proarrhythmia safety paradigm: A meeting report from the Cardiac Safety Research Consortium. American Heart Journal, 167(3), 292-300. doi:10.1016/j.ahj.2013.11.004Sah, R., Ramirez, R. J., Oudit, G. Y., Gidrewicz, D., Trivieri, M. G., Zobel, C., & Backx, P. H. (2003). Regulation of cardiac excitation-contraction coupling by action potential repolarization: role of the transient outward potassium current (Ito). The Journal of Physiology, 546(1), 5-18. doi:10.1113/jphysiol.2002.026468Sampson, K. J., & Henriquez, C. S. (2005). Electrotonic influences on action potential duration dispersion in small hearts: a simulation study. American Journal of Physiology-Heart and Circulatory Physiology, 289(1), H350-H360. doi:10.1152/ajpheart.00507.2004Sarkar, A. X., & Sobie, E. A. (2011). Quantification of repolarization reserve to understand interpatient variability in the response to proarrhythmic drugs: A computational analysis. Heart Rhythm, 8(11), 1749-1755. doi:10.1016/j.hrthm.2011.05.023Sarkar, A. X., Christini, D. J., & Sobie, E. A. (2012). Exploiting mathematical models to illuminate electrophysiological variability between individuals. The Journal of Physiology, 590(11), 2555-2567. doi:10.1113/jphysiol.2011.223313Silva, J., & Rudy, Y. (2005). Subunit Interaction Determines I Ks Participation in Cardiac Repolarization and Repolarization Reserve. Circulation, 112(10), 1384-1391. doi:10.1161/circulationaha.105.543306SPITZER, K. W., POLLARD, A. E., YANG, L., ZANIBONI, M., CORDEIRO, J. M., & HUELSING, D. J. (2006). Cell-to-Cell Electrical Interactions During Early and Late Repolarization. Journal of Cardiovascular Electrophysiology, 17(s1), S8-S14. doi:10.1111/j.1540-8167.2006.00379.xTadros, R., Ton, A.-T., Fiset, C., & Nattel, S. (2014). Sex Differences in Cardiac Electrophysiology and Clinical Arrhythmias: Epidemiology, Therapeutics, and Mechanisms. Canadian Journal of Cardiology, 30(7), 783-792. doi:10.1016/j.cjca.2014.03.032Taggart, P. (2001). Transmural repolarisation in the left ventricle in humans during normoxia and ischaemia. Cardiovascular Research, 50(3), 454-462. doi:10.1016/s0008-6363(01)00223-1Teutsch, C., Kondo, R. P., Dederko, D. A., Chrast, J., Chien, K. R., & Giles, W. R. (2007). Spatial distributions of Kv4 channels and KChip2 isoforms in the murine heart based on laser capture microdissection. Cardiovascular Research, 73(4), 739-749. doi:10.1016/j.cardiores.2006.11.034Tikkanen, J. T., Anttonen, O., Junttila, M. J., Aro, A. L., Kerola, T., Rissanen, H. A., … Huikuri, H. V. (2009). Long-Term Outcome Associated with Early Repolarization on Electrocardiography. New England Journal of Medicine, 361(26), 2529-2537. doi:10.1056/nejmoa0907589Thomsen, M. B. (2007). Double pharmacological challenge on repolarization opens new avenues for drug safety research. British Journal of Pharmacology, 151(7), 909-911. doi:10.1038/sj.bjp.0707299THOMSEN, M., OROS, A., SCHOENMAKERS, M., VANOPSTAL, J., MAAS, J., BEEKMAN, J., & VOS, M. (2007). Proarrhythmic electrical remodelling is associated with increased beat-to-beat variability of repolarisation. Cardiovascular Research, 73(3), 521-530. doi:10.1016/j.cardiores.2006.11.025Varkevisser, R., Wijers, S. C., van der Heyden, M. A. G., Beekman, J. D. M., Meine, M., & Vos, M. A. (2012). Beat-to-beat variability of repolarization as a new biomarker for proarrhythmia in vivo. Heart Rhythm, 9(10), 1718-1726. doi:10.1016/j.hrthm.2012.05.016Varró, A., & Baczkó, I. (2011). Cardiac ventricular repolarization reserve: a principle for understanding drug-related proarrhythmic risk. British Journal of Pharmacology, 164(1), 14-36. doi:10.1111/j.1476-5381.2011.01367.xVicente, J., Johannesen, L., Mason, J. W., Crumb, W. J., Pueyo, E., Stockbridge, N., & Strauss, D. G. (2015). Comprehensive T wave Morphology Assessment in a Randomized Clinical Study of Dofetilide, Quinidine, Ranolazine, and Verapamil. Journal of the American Heart Association, 4(4). doi:10.1161/jaha.114.001615Walmsley, J., Rodriguez, J. F., Mirams, G. R., Burrage, K., Efimov, I. R., & Rodriguez, B. (2013). mRNA Expression Levels in Failing Human Hearts Predict Cellular Electrophysiological Remodeling: A Population-Based Simulation Study. PLoS ONE, 8(2), e56359. doi:10.1371/journal.pone.0056359Wang, Y., Cheng, J., Joyner, R. W., Wagner, M. B., & Hill, J. A. (2006). Remodeling of Early-Phase Repolarization. Circulation, 113(15), 1849-1856. doi:10.1161/circulationaha.106.615682Weidmann, S. (1951). Effect of current flow on the membrane potential of cardiac muscle. The Journal of Physiology, 115(2), 227-236. doi:10.1113/jphysiol.1951.sp004667Weidmann, S. (1957). RESTING AND ACTION POTENTIALS OF CARDIAC MUSCLE. Annals of the New York Academy of Sciences, 65(6), 663-678. doi:10.1111/j.1749-6632.1957.tb36674.xWellens, H. J. (2008). Early Repolarization Revisited. New England Journal of Medicine, 358(19), 2063-2065. doi:10.1056/nejme0801060WOOD, E. H., HEPPNER, R. L., & WEIDMANN, S. (1969). Inotropic Effects of Electric Currents. Circulation Research, 24(3), 409-445. doi:10.1161/01.res.24.3.409Xiao, L., Xiao, J., Luo, X., Lin, H., Wang, Z., & Nattel, S. (2008). Feedback Remodeling of Cardiac Potassium Current Expression. Circulation, 118(10), 98

Longitudinal Diffusion Tensor Imaging Resembles Patterns of Pathology Progression in Behavioral Variant Frontotemporal Dementia (bvFTD)

Objective: Recently, the characteristic longitudinal distribution pattern of the underlying phosphorylated TDP-43 (pTDP-43) pathology in the behavioral variant of frontotemporal dementia (bvFTD) excluding Pick's disease (PiD) across specific brain regions was described. The aim of the present study was to investigate whether in vivo investigations of bvFTD patients by use of diffusion tensor imaging (DTI) were consistent with these proposed patterns of progression. Methods: Sixty-two bvFTD patients and 47 controls underwent DTI in a multicenter study design. Of these, 49 bvFTD patients and 34 controls had a follow-up scan after ~12 months. Cross-sectional and longitudinal alterations were assessed by a two-fold analysis, i.e., voxelwise comparison of fractional anisotropy (FA) maps and a tract of interest-based (TOI) approach, which identifies tract structures that could be assigned to brain regions associated with disease progression. Results: Whole brain-based spatial statistics showed white matter alterations predominantly in the frontal lobes cross-sectionally and longitudinally. The TOIs of bvFTD neuroimaging stages 1 and 2 (uncinate fascicle—bvFTD pattern I; corticostriatal pathway—bvFTD pattern II) showed highly significant differences between bvFTD patients and controls. The corticospinal tract-associated TOI (bvFTD pattern III) did not differ between groups, whereas the differences in the optic radiation (bvFTD pattern IV) reached significance. The findings in the corticospinal tract were due to a “dichotomous” behavior of FA changes there. Conclusion: Longitudinal TOI analysis demonstrated a pattern of white matter pathways alterations consistent with patterns of pTDP-43 pathology

Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

Purpose Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. Methods We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Results Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Conclusion Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome

Remodeling of the Cortical Structural Connectome in Posttraumatic Stress Disorder:Results from the ENIGMA-PGC PTSD Consortium

BACKGROUND: Posttraumatic stress disorder (PTSD) is accompanied by disrupted cortical neuroanatomy. We investigated alteration in covariance of structural networks associated with PTSD in regions that demonstrate the case-control differences in cortical thickness (CT) and surface area (SA). METHODS: Neuroimaging and clinical data were aggregated from 29 research sites in >1,300 PTSD cases and >2,000 trauma-exposed controls (age 6.2-85.2 years) by the ENIGMA-PGC PTSD working group. Cortical regions in the network were rank-ordered by effect size of PTSD-related cortical differences in CT and SA. The top-n (n = 2 to 148) regions with the largest effect size for PTSD > non-PTSD formed hypertrophic networks, the largest effect size for PTSD < non-PTSD formed atrophic networks, and the smallest effect size of between-group differences formed stable networks. The mean structural covariance (SC) of a given n-region network was the average of all positive pairwise correlations and was compared to the mean SC of 5,000 randomly generated n-region networks. RESULTS: Patients with PTSD, relative to non-PTSD controls, exhibited lower mean SC in CT-based and SA-based atrophic networks. Comorbid depression, sex and age modulated covariance differences of PTSD-related structural networks. CONCLUSIONS: Covariance of structural networks based on CT and cortical SA are affected by PTSD and further modulated by comorbid depression, sex, and age. The structural covariance networks that are perturbed in PTSD comport with converging evidence from resting state functional connectivity networks and networks impacted by inflammatory processes, and stress hormones in PTSD

A Comparison of Methods to Harmonize Cortical Thickness Measurements Across Scanners and Sites

Results of neuroimaging datasets aggregated from multiple sites may be biased by site-specific profiles in participants’ demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LME INT), (2) LME that models both site-specific random intercepts and age-related random slopes (LME INT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1,340 cases with posttraumatic stress disorder (PTSD) (6.2–81.8 years old) and 2,057 trauma-exposed controls without PTSD (6.3–85.2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM was more sensitive to the detection of significant case-control differences (Χ 2(3) = 63.704, p < 0.001) as well as case-control differences in age-related cortical thinning (Χ 2(3) = 12.082, p = 0.007). Both ComBat and ComBat-GAM outperformed LME methods in detecting sex differences (Χ 2(3) = 9.114, p = 0.028) in regional cortical thickness. ComBat-GAM also led to stronger estimates of age-related declines in cortical thickness (corrected p-values < 0.001), stronger estimates of case-related cortical thickness reduction (corrected p-values < 0.001), weaker estimates of age-related declines in cortical thickness in cases than controls (corrected p-values < 0.001), stronger estimates of cortical thickness reduction in females than males (corrected p-values < 0.001), and stronger estimates of cortical thickness reduction in females relative to males in cases than controls (corrected p-values < 0.001). Our results support the use of ComBat-GAM to minimize confounds and increase statistical power when harmonizing data with non-linear effects, and the use of either ComBat or ComBat-GAM for harmonizing data with linear effects

Increased serum miR-193a-5p during non-alcoholic fatty liver disease progression: Diagnostic and mechanistic relevance

Background &amp; Aims: Serum microRNA (miRNA) levels are known to change in non-alcoholic fatty liver disease (NAFLD) and may serve as useful biomarkers. This study aimed to profile miRNAs comprehensively at all NAFLD stages. Methods: We profiled 2,083 serum miRNAs in a discovery cohort (183 cases with NAFLD representing the complete NAFLD spectrum and 10 population controls). miRNA libraries generated by HTG EdgeSeq were sequenced by Illumina NextSeq. Selected serum miRNAs were profiled in 372 additional cases with NAFLD and 15 population controls by quantitative reverse transcriptase PCR. Results: Levels of 275 miRNAs differed between cases and population controls. Fewer differences were seen within individual NAFLD stages, but miR-193a-5p consistently showed increased levels in all comparisons. Relative to NAFL/non-alcoholic steatohepatitis (NASH) with mild fibrosis (stage 0/1), 3 miRNAs (miR-193a-5p, miR-378d, and miR378d) were increased in cases with NASH and clinically significant fibrosis (stages 2–4), 7 (miR193a-5p, miR-378d, miR-378e, miR-320b, miR-320c, miR-320d, and miR-320e) increased in cases with NAFLD activity score (NAS) 5–8 compared with lower NAS, and 3 (miR-193a-5p, miR-378d, and miR-378e) increased but 1 (miR-19b-3p) decreased in steatosis, activity, and fibrosis (SAF) activity score 2–4 compared with lower SAF activity. The significant findings for miR-193a-5p were replicated in the additional cohort with NAFLD. Studies in Hep G2 cells showed that following palmitic acid treatment, miR-193a-5p expression decreased significantly. Gene targets for miR-193a-5p were investigated in liver RNAseq data for a case subgroup (n = 80); liver GPX8 levels correlated positively with serum miR-193a-5p. Conclusions: Serum miR-193a-5p levels correlate strongly with NAFLD activity grade and fibrosis stage. MiR-193a-5p may have a role in the hepatic response to oxidative stress and is a potential clinically tractable circulating biomarker for progressive NAFLD. Lay summary: MicroRNAs (miRNAs) are small pieces of nucleic acid that may turn expression of genes on or off. These molecules can be detected in the blood circulation, and their levels in blood may change in liver disease including non-alcoholic fatty liver disease (NAFLD). To see if we could detect specific miRNA associated with advanced stages of NAFLD, we carried out miRNA sequencing in a group of 183 patients with NAFLD of varying severity together with 10 population controls. We found that a number of miRNAs showed changes, mainly increases, in serum levels but that 1 particular miRNA miR-193a-5p consistently increased. We confirmed this increase in a second group of cases with NAFLD. Measuring this miRNA in a blood sample may be a useful way to determine whether a patient has advanced NAFLD without an invasive liver biopsy

Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: An individual patient data meta-analysis

Objective Liver biopsy is still needed for fibrosis staging in many patients with non-alcoholic fatty liver disease. The aims of this study were to evaluate the individual diagnostic performance of liver stiffness measurement by vibration controlled transient elastography (LSM-VCTE), Fibrosis-4 Index (FIB-4) and NAFLD (non-alcoholic fatty liver disease) Fibrosis Score (NFS) and to derive diagnostic strategies that could reduce the need for liver biopsies. Design Individual patient data meta-analysis of studies evaluating LSM-VCTE against liver histology was conducted. FIB-4 and NFS were computed where possible. Sensitivity, specificity and area under the receiver operating curve (AUROC) were calculated. Biomarkers were assessed individually and in sequential combinations. Results Data were included from 37 primary studies (n=5735; 45% women; median age: 54 years; median body mass index: 30 kg/m2; 33% had type 2 diabetes; 30% had advanced fibrosis). AUROCs of individual LSM-VCTE, FIB-4 and NFS for advanced fibrosis were 0.85, 0.76 and 0.73. Sequential combination of FIB-4 cut-offs (&lt;1.3; ≥2.67) followed by LSM-VCTE cut-offs (&lt;8.0; ≥10.0 kPa) to rule-in or rule-out advanced fibrosis had sensitivity and specificity (95% CI) of 66% (63-68) and 86% (84-87) with 33% needing a biopsy to establish a final diagnosis. FIB-4 cut-offs (&lt;1.3; ≥3.48) followed by LSM cut-offs (&lt;8.0; ≥20.0 kPa) to rule out advanced fibrosis or rule in cirrhosis had a sensitivity of 38% (37-39) and specificity of 90% (89-91) with 19% needing biopsy. Conclusion Sequential combinations of markers with a lower cut-off to rule-out advanced fibrosis and a higher cut-off to rule-in cirrhosis can reduce the need for liver biopsies