The Essential Role of IL-17 as the Pathogenetic Link between Psoriasis and Metabolic-Associated Fatty Liver Disease

IL-17; Enfermedad del hígado graso asociada al metabolismo; PsoriasisIL-17; Metabolic-associated fatty liver disease; PsoriasisIL-17; Malaltia del fetge gras associada al metabolisme; PsoriasiInterleukin 17 (IL-17) is an effector cytokine that plays a key role in the pathogenesis of both psoriasis and metabolic-associated fatty liver disease (MAFLD), a condition that is more prevalent and severe in patients with psoriasis. In liver inflammation, IL-17 is mainly produced by CD4+ T (TH17) and CD8+ T cells (Tc17), although numerous other cells (macrophages, natural killer cells, neutrophils and Tγδ cells) also contribute to the production of IL-17. In hepatocytes, IL-17 mediates systemic inflammation and the recruitment of inflammatory cells to the liver, and it is also implicated in the development of fibrosis and insulin resistance. IL-17 levels have been correlated with progression from MAFLD to steatohepatitis, cirrhosis, and even hepatocellular carcinoma. Clinical trials have shown that inhibiting IL-17A in patients with psoriasis could potentially contribute to the improvement of metabolic and liver parameters. A better understanding of the key factors involved in the pathogenesis of these chronic inflammatory processes could potentially lead to more efficient treatment for both psoriasis and MAFLD, and help to develop holistic strategies to improve the management of these patients.Financial support for the expert meetings and manuscript preparation were provided by Novartis Farmacéutica S.A

Quality and acceptability of microwave and conventionally pasteurized kiwifruit puree

The final publication is available at link.springer.com[EN] The development and optimisation of food preservation processes seem to be necessary in order to address consumer expectations related to secure, fresh-like foods. To this end, the sensory, nutritional and functional properties must be maximally retained. In order to contribute to the acquisition of knowledge about the adequacy of microwave processing as a means of preserving fruit-based products, the present study compares the impact of microwave heating with conventional thermal processing. The consumer acceptance of fresh and pasteurised kiwifruit puree was studied as was the content of water, soluble solids and bioactive compounds and the pH, consistency, viscosity, colour coordinates and antioxidant capacity, as well as the effect of the thermal treatment on enzyme and microbial inactivation. As bioactive compounds, the content of vitamins C, A and E and the total flavonoid, phenol and tannin content have been considered. As the obtained results show, not only was microwaved puree preferred by consumers, but it also exhibited a superior maintenance of the nutritive and functional properties of the fruit, smaller colour changes and a content of inactivated enzymes and microorganisms equal to or greater than the conventionally heated sample.The authors thank the Ministerio de Educacion y Ciencia for the financial support given throughout the Project AGL 2010-22176 and AGL 2010-22206-C02-01 and the grant awarded to the author Maria Benlloch.Benlloch Tinoco, M.; Igual Ramo, M.; Salvador Alcaraz, A.; Rodrigo Aliaga, MD.; Martínez Navarrete, N. (2014). Quality and acceptability of microwave and conventionally pasteurized kiwifruit puree. Food and Bioprocess Technology. 7(11):3282-3292. https://doi.org/10.1007/s11947-014-1315-9S32823292711Awuah, G. B., Ramaswamy, H. 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La aplicación de materiales multimedia en la enseñanza de conceptos constructivos

La llegada de las nuevas Tecnologías al aprendizaje y a la docencia universitaria, se está produciendo con grandes desfases entre las diversas asignaturas e incluso titulaciones de nuestras universidades. Presentamos nuestras experiencias y la investigación desarrollada en la asignatura de Introducción a la Construcción, correspondiente al primer curso de los estudios de Arquitectura Superior en la Universidad Politécnica de Valencia. Durante los últimos dos cursos 2002/03 y 2003/04 hemos aplicado distintos medios audiovisuales para la elaboración de materiales multimedia. Estos materiales, confeccionados con la ayuda de diversos programas informáticos, han demostrado ser de gran ayuda para acelerar el proceso de aprendizaje de los nuevos contenidos planteados a los alumnos de reciente ingreso. Por un lado, los conceptos teóricos se han podido captar rápidamente de una manera visual, mediante gráficos, dibujos, fotografías y animaciones o videos reales. Por otra parte, han servido como apoyo a las prácticas realizadas semanalmente, de manera tutorizada, que siguen el “método del descubrimiento” a partir de las explicaciones genéricas de teoría. La costosa elaboración de estos materiales ha sido recompensada sobradamente por la buena acogida y resultados obtenidos por ls alumnos. Consideramos que esta metodología ha producido una satisfactoria asimilación de los conocimientos, quedando reconocido por los propios alumnos como por profesores de otras asignaturas. Esto nos anima y nos lleva a procurar su difusión pues consideramos estos medios como elemento indispensable para estrategias de mejora del aprendizaje.The arrival of new technologies applied to the learning and university teaching, has become with large differences among the diverse subjects and even qualifications in our Universities. We present our experiences and investigation developed in the Introduction to the Construction subject, corresponding to the first course studies of Architecture in the Universidad Politécnica de Valencia. During the last two courses, 2002/03 and 2003/04, we have applied different audiovisual media for the elaboration of multimedia materials. These materials, concocted with the aid of diverse data processing programs, have shown to be of great aid to accelerate the new contents learning process presented to the recent income students. On the one hand, the theoretical concepts have been able to be acquire quickly in a visual way, by using graphic, drawings, photographs and animations or real videos. On the other hand, have served as support to the practices carried out weekly, with tutoring instruction, that follow the “discovery method ” from the generic theory explanations. The hard work in these materials elaboration has been fully rewarded with the academic results obtained by the students. We believe this methodology has produced a satisfactory knowledge comprehension, recognized by the students as well as other subjects teachers. This encourages and carries us to seek its diffusion, because we consider these media are indispensable elements in learning improvement strategies

Stress hormones promote growth of B16-F10 melanoma metastases: an interleukin 6-and glutathione-dependent mechanism

[EN] Background: Interleukin (IL)-6 (mainly of tumor origin) activates glutathione (GSH) release from hepatocytes and its interorgan transport to B16-F10 melanoma metastatic foci. We studied if this capacity to overproduce IL-6 is regulated by cancer cell-independent mechanisms. Methods: Murine B16-F10 melanoma cells were cultured, transfected with red fluorescent protein, injected i.v. into syngenic C57BL/6J mice to generate lung and liver metastases, and isolated from metastatic foci using high-performance cell sorting. Stress hormones and IL-6 levels were measured by ELISA, and CRH expression in the brain by in situ hybridization. DNA binding activity of NF-kappa B, CREB, AP-1, and NF-IL-6 was measured using specific transcription factor assay kits. IL-6 expression was measured by RT-PCR, and silencing was achieved by transfection of anti-IL-6 small interfering RNA. GSH was determined by HPLC. Cell death analysis was distinguished using fluorescence microscopy, TUNEL labeling, and flow cytometry techniques. Statistical analyses were performed using Student's t test. Results: Plasma levels of stress-related hormones (adrenocorticotropin hormone, corticosterone, and noradrenaline) increased, following a circadian pattern and as compared to non-tumor controls, in mice bearing B16-F10 lung or liver metastases. Corticosterone and noradrenaline, at pathophysiological levels, increased expression and secretion of IL-6 in B16-F10 cells in vitro. Corticosterone- and noradrenaline-induced transcriptional up-regulation of IL-6 gene involves changes in the DNA binding activity of nuclear factor-kappa B, cAMP response element-binding protein, activator protein-1, and nuclear factor for IL-6. In vivo inoculation of B16-F10 cells transfected with anti-IL-6-siRNA, treatment with a glucocorticoid receptor blocker (RU-486) or with a beta-adrenoceptor blocker (propranolol), increased hepatic GSH whereas decreased plasma IL-6 levels and metastatic growth. Corticosterone, but not NORA, also induced apoptotic cell death in metastatic cells with low GSH content. Conclusions: Our results describe an interorgan system where stress-related hormones, IL-6, and GSH coordinately regulate metastases growthThis research was supported by grant (SAF2009-07729 and IPT-010000-2010-21) from the Ministerio de Economia y Competitividad (http://www.idi.mineco.gob.es), Spain.Valles, SL.; Benlloch, M.; Rodriguez, ML.; Mena-Mollá, S.; Pellicer, JA.; Asensi-Miralles, MÁ.; Obrador, E.... (2013). Stress hormones promote growth of B16-F10 melanoma metastases: an interleukin 6-and glutathione-dependent mechanism. 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Pathology & Oncology Research, 17(3), 729-734. doi:10.1007/s12253-011-9377-8Tsuji, M., Kuno, T., Tanaka, C., Ichihashi, M., & Mishima, Y. (1983). Beta-adrenergic receptors of B16 melanoma cell. Archives of Dermatological Research, 275(6), 415-416. doi:10.1007/bf00417345Im, A., & Appleman, L. J. (2010). Mifepristone: pharmacology and clinical impact in reproductive medicine, endocrinology and oncology. Expert Opinion on Pharmacotherapy, 11(3), 481-488. doi:10.1517/14656560903535880Smoak, K. A., & Cidlowski, J. A. (2004). Mechanisms of glucocorticoid receptor signaling during inflammation. Mechanisms of Ageing and Development, 125(10-11), 697-706. doi:10.1016/j.mad.2004.06.010Cole, S. W., & Sood, A. K. (2011). Molecular Pathways: Beta-Adrenergic Signaling in Cancer: Figure 1. Clinical Cancer Research, 18(5), 1201-1206. doi:10.1158/1078-0432.ccr-11-0641Matsusaka, T., Fujikawa, K., Nishio, Y., Mukaida, N., Matsushima, K., Kishimoto, T., & Akira, S. (1993). Transcription factors NF-IL6 and NF-kappa B synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8. Proceedings of the National Academy of Sciences, 90(21), 10193-10197. doi:10.1073/pnas.90.21.10193McEwen, B. S. (2007). Physiology and Neurobiology of Stress and Adaptation: Central Role of the Brain. Physiological Reviews, 87(3), 873-904. doi:10.1152/physrev.00041.2006Lee, J.-H., Yoo, S. B., Kim, N. Y., Cha, M. J., & Jahng, J. W. (2008). Interleukin-6 and the Hypothalamic-Pituitary-Adrenal Activation in a Tumor Bearing Mouse. International Journal of Neuroscience, 118(3), 355-364. doi:10.1080/00207450701592915Li, Y.-F., He, R.-R., Tsoi, B., Li, X.-D., Li, W.-X., Abe, K., & Kurihara, H. (2012). Anti-Stress Effects of Carnosine on Restraint-Evoked Immunocompromise in Mice through Spleen Lymphocyte Number Maintenance. PLoS ONE, 7(4), e33190. doi:10.1371/journal.pone.0033190Sarabdjitsingh, R. A., Kofink, D., Karst, H., de Kloet, E. R., & Joëls, M. (2012). Stress-Induced Enhancement of Mouse Amygdalar Synaptic Plasticity Depends on Glucocorticoid and ß-Adrenergic Activity. PLoS ONE, 7(8), e42143. doi:10.1371/journal.pone.0042143Moreno-Smith, M., Lutgendorf, S. K., & Sood, A. K. (2010). Impact of stress on cancer metastasis. Future Oncology, 6(12), 1863-1881. doi:10.2217/fon.10.142Tissing, W. J. E., Meijerink, J. P. P., den Boer, M. L., & Pieters, R. (2003). Molecular determinants of glucocorticoid sensitivity and resistance in acute lymphoblastic leukemia. Leukemia, 17(1), 17-25. doi:10.1038/sj.leu.2402733Anderer, G., Schrappe, M., Brechlin, A. M., Lauten, M., Muti, P., Welte, K., & Stanulla, M. (2000). Polymorphisms within glutathione S-transferase genes and initial response to glucocorticoids in childhood acute lymphoblastic leukaemia. Pharmacogenetics, 10(8), 715-726. doi:10.1097/00008571-200011000-00006Thaker, P. H., & Sood, A. K. (2008). Neuroendocrine influences on cancer biology. Seminars in Cancer Biology, 18(3), 164-170. doi:10.1016/j.semcancer.2007.12.005Takeda, T., Kurachi, H., Yamamoto, T., Nishio, Y., Nakatsuji, Y., Morishige, K., … Murata, Y. (1998). Crosstalk between the interleukin-6 (IL-6)-JAK-STAT and the glucocorticoid-nuclear receptor pathway: synergistic activation of IL-6 response element by IL-6 and glucocorticoid. Journal of Endocrinology, 159(2), 323-330. doi:10.1677/joe.0.1590323Rodriguez-Rocha, H., Garcia Garcia, A., Zavala-Flores, L., Li, S., Madayiputhiya, N., & Franco, R. (2012). Glutaredoxin 1 Protects Dopaminergic Cells by Increased Protein Glutathionylation in Experimental Parkinson’s Disease. Antioxidants & Redox Signaling, 17(12), 1676-1693. doi:10.1089/ars.2011.4474Tome, M. E., Jaramillo, M. C., & Briehl, M. M. (2011). Hydrogen peroxide signaling is required for glucocorticoid-induced apoptosis in lymphoma cells. Free Radical Biology and Medicine, 51(11), 2048-2059. doi:10.1016/j.freeradbiomed.2011.09.002Lázár-Molnár, E., Hegyesi, H., Tóth, S., & Falus, A. (2000). AUTOCRINE AND PARACRINE REGULATION BY CYTOKINES AND GROWTH FACTORS IN MELANOMA. Cytokine, 12(6), 547-554. doi:10.1006/cyto.1999.0614Sansone, P., & Bromberg, J. (2012). Targeting the Interleukin-6/Jak/Stat Pathway in Human Malignancies. Journal of Clinical Oncology, 30(9), 1005-1014. doi:10.1200/jco.2010.31.8907Arrigo, A.-P. (1999). Gene expression and the thiol redox state. Free Radical Biology and Medicine, 27(9-10), 936-944. doi:10.1016/s0891-5849(99)00175-6Antelmann, H., & Helmann, J. D. (2011). Thiol-Based Redox Switches and Gene Regulation. Antioxidants & Redox Signaling, 14(6), 1049-1063. doi:10.1089/ars.2010.3400Leibowitz, B., & Yu, J. (2010). Mitochondrial signaling in cell death via the Bcl-2 family. Cancer Biology & Therapy, 9(6), 417-422. doi:10.4161/cbt.9.6.11392Powe, D. G., Voss, M. J., Habashy, H. O., Zänker, K. S., Green, A. R., Ellis, I. O., & Entschladen, F. (2011). Alpha- and beta-adrenergic receptor (AR) protein expression is associated with poor clinical outcome in breast cancer: an immunohistochemical study. Breast Cancer Research and Treatment, 130(2), 457-463. doi:10.1007/s10549-011-1371-zPowe, D. G., & Entschladen, F. (2011). Using β-blockers to inhibit breast cancer progression. Nature Reviews Clinical Oncology, 8(9), 511-512. doi:10.1038/nrclinonc.2011.12

Variables asociadas a necrosis pancreática en pacientes con Pancreatitis Aguda Grave

Hem fet un estudi retrospectiu de 73 adults amb pancreatitis aguda greu recollint variables analítiques i radiològiques a l'ingrés i a les 48h i relacionant-les amb l'existència de necrosi pancreàtica a la TC. Les variables relacionades amb la necrosi van ser: edat, leucòcits, VSG, TP, INR, glucèmia, urea, creatinina, proteïnes, albúmina, LDH, calci, PCR i presència de vessament pleural a la Rx. D'aquestes, el vessament pleural a l'ingrés i la hipoalbuminemia, les xifres altes de LDH i PCR a les 48 hores es van relacionar significativament, la qual cosa permet identificar pacients amb major risc en els quals instaurar mesures precocesHemos realizado un estudio retrospectivo de 73 adultos con pancreatitis aguda grave recogiendo variables analíticas y radiológicas al ingreso y a las 48h y relacionándolas con la existencia de necrosis pancreática en la TC. Las variables relacionadas con la necrosis fueron: edad, leucocitos, VSG, TP, INR, glucemia, urea, creatinina, proteínas, albúmina, LDH, calcio, PCR y presencia de derrame pleural en la Rx. De éstas, el derrame pleural al ingreso y la hipoalbuminemia, las cifras altas de LDH y PCR a las 48 horas se relacionaron significativamente, permitiendo así identificar pacientes con mayor riesgo en los que instaurar medidas precoces

Glucocorticoid receptor antagonism overcomes resistance to BRAF inhibition in BRAFV600E-mutated metastatic melanoma

Clinical applications of glucocorticoids (GC) in Oncology are dependent on their pro-apoptotic action to treat lymphoproliferative cancers, and to alleviate side effects induced by chemotherapy and/or radiotherapy. However, the mechanism(s) by which GC may also promote tumor progression remains unclear. GC receptor (GR) knockdown decreases the antioxidant protection of highly metastatic B16-F10 melanoma cells. We hypothesize that a GR antagonist (RU486, mifepristone) could increase the efficacy of BRAF-related therapy in BRAFV600E-mutated metastatic melanoma. In vivo formed spontaneous skin tumors were reinoculated into nude mice to expand the metastases of different human BRAFV600E melanoma cells. The GR content of melanoma cell lines was measured by [3H]-labeled ligand binding assay. Nuclear Nrf2 and its transcription activity was investigated by RT-PCR, western blotting, and by measuring Nrf2- and redox state-related enzyme activities and metabolites. GR knockdown was achieved using lentivirus, and GR overexpression by transfection with the NR3C1 plasmid. shRNA-induced selective Bcl-xL, Mcl-1, AKT1 or NF-κB/p65 depletion was used to test the efficacy of vemurafenib (VMF) and RU486 against BRAFV600E-mutated metastatic melanoma. During early progression of skin melanoma metastases, RU486 and VMF induced a drastic metastases regression. However, treatment at an advanced stage of growth demonstrated the development of resistance to RU486 and VMF. This resistance was mechanistically linked to overexpression of specific proteins of the Bcl-2 family (Bcl-xL and Mcl-1 in our experimental models). We found that melanoma resistance is decreased if AKT and NF-κB signaling pathways are blocked. Our results highlight mechanisms by which metastatic melanoma cells adapt to survive

Comfort in trams

[EN] In the railway sector, one of the key aspects in the design phase of the vehicles is the passenger¿s comfort, for which is important to take into account the passengers¿ opinion. Biomechanics Institute of Valencia (IBV), at the request of Vossloh, has carried out a study to know the main factors that influence the comfort perceived by passengers¿ trams.[ES] En el sector ferroviario, uno de los aspectos clave en la fase de diseño de los vehículos es el confort de los pasajeros, para lo cual resulta clave tener en cuenta su opinión. El Instituto de Biomecánica (IBV), a petición de Vossloh, ha llevado a cabo un estudio cuyo objetivo ha consistido en conocer los principales factores que influyen en el confort de los viajeros del tranvía.Palomares Olivares, N.; Marzo Rosello, R.; Solaz Sanahuja, JS.; Signes Pérez, E.; Pérez Antón, S.; Marsilla Benlloch, M.; Chirivella Moreno, C.... (2013). Confort en el tranvía. Revista de biomecánica. 59:13-14. http://hdl.handle.net/10251/38775S13145

The MINDVIEW project: First results

[EN] We present the first results of the MINDVIEW project. An innovative imaging system for the human brain examination, allowing simultaneous acquisition of PET/MRI images, has been designed and constructed. It consists of a high sensitivity and high resolution PET scanner integrated in a novel, head-dedicated, radio frequency coil for a 3T MRI scanner. Preliminary measurements from the PET scanner show sensitivity 3 times higher than state-of-the-art PET systems that will allow safe repeated studies on the same patient. The achieved spatial resolution, close to 1 mm, will enable differentiation of relevant brain structures for schizophrenia. A cost-effective and simple method of radiopharmaceutical production from C-11-carbon monoxide and a mini-clean room has been demonstrated. It has been shown that C-11-raclopride has higher binding potential in a new VAAT null mutant mouse model of schizophrenia compared to wild type control animals. A significant reduction in TSPO binding has been found in gray matter in a small sample of drug-naive, first episode psychosis patients, suggesting a reduced number or an altered function of immune cells in brain at early stage schizophrenia. (c) 2018 Elsevier Masson SAS. All rights reserved.This project is funded by EU grant FP7-HEALTH-F2-2013-603002.Benlloch Baviera, JM.; González Martínez, AJ.; Pani, R.; Preziosi, E.; Jackson, C.; Murphy, J.; Barbera Ballester, J.... (2018). The MINDVIEW project: First results. European Psychiatry. 50:21-27. https://doi.org/10.1016/j.eurpsy.2018.01.002S212750Gonzalez, A. J., Gonzalez-Montoro, A., Aguilar, A., Conde, P., Canizares, G., Hernandez, L., … Benlloch, J. M. (2016). A brain PET insert MR compatible: Final design and first results. 2016 IEEE Nuclear Science Symposium, Medical Imaging Conference and Room-Temperature Semiconductor Detector Workshop (NSS/MIC/RTSD). doi:10.1109/nssmic.2016.8069619Dahl, K., Schou, M., Ulin, J., Sjöberg, C.-O., Farde, L., & Halldin, C. (2015). 11C-carbonylation reactions using gas–liquid segmented microfluidics. RSC Advances, 5(108), 88886-88889. doi:10.1039/c5ra20646d[26] Långström B and Sjöberg CO, System for controlling environment in reaction box, From PCT Int. Appl. (2013), WO 2013103312 A1 20130711.Autret, A., Bert, J., Strauss, O., & Visvikis, D. (2012). Projector with realistic detector scatter modelling for PET list-mode reconstruction. 2012 IEEE Nuclear Science Symposium and Medical Imaging Conference Record (NSS/MIC). doi:10.1109/nssmic.2012.6551759[10] Young JW Head and Face Antropometry of Adult U.S. Citizens, Civil Aeromedical Institute, Federal Aviation Administration, U.S. Department of Transportation, Report number DOT/FAA/AM-93/10, July 1993.Braff, D. L. (1990). Sensorimotor Gating and Schizophrenia. Archives of General Psychiatry, 47(2), 181. doi:10.1001/archpsyc.1990.01810140081011Preziosi, E., Sánchez, S., González, A. J., Pani, R., Borrazzo, C., Bettiol, M., … Benlloch, J. M. (2016). Performance study of a PET scanner based on monolithic scintillators for different DoI-dependent methods. Journal of Instrumentation, 11(12), C12076-C12076. doi:10.1088/1748-0221/11/12/c12076Howes, O., McCutcheon, R., & Stone, J. (2015). Glutamate and dopamine in schizophrenia: An update for the 21st century. Journal of Psychopharmacology, 29(2), 97-115. doi:10.1177/0269881114563634Moliner, L., Correcher, C., González, A. J., Conde, P., Hernández, L., Orero, A., … Benlloch, J. M. (2013). Implementation and analysis of list mode algorithm using tubes of response on a dedicated brain and breast PET. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 702, 129-132. doi:10.1016/j.nima.2012.08.029Zelano, J., Mikulovic, S., Patra, K., Kühnemund, M., Larhammar, M., Emilsson, L., … Kullander, K. (2013). The synaptic protein encoded by the gene Slc10A4 suppresses epileptiform activity and regulates sensitivity to cholinergic chemoconvulsants. Experimental Neurology, 239, 73-81. doi:10.1016/j.expneurol.2012.09.006Antich, P., Malakhov, N., Parkey, R., Slavin, N., & Tsyganov, E. (2002). 3D position readout from thick scintillators. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 480(2-3), 782-787. doi:10.1016/s0168-9002(01)01214-1Gonzalez-Montoro, A., Benlloch, J. M., Gonzalez, A. J., Aguilar, A., Canizares, G., Conde, P., … Sanchez, F. (2017). Performance Study of a Large Monolithic LYSO PET Detector With Accurate Photon DOI Using Retroreflector Layers. IEEE Transactions on Radiation and Plasma Medical Sciences, 1(3), 229-237. doi:10.1109/trpms.2017.2692819Rahman, O., Takano, A., Amini, N., Dahl, K., Kanegawa, N., Långström, B., … Halldin, C. (2015). Synthesis of ([11C]carbonyl)raclopride and a comparison with ([11C]methyl)raclopride in a monkey PET study. Nuclear Medicine and Biology, 42(11), 893-898. doi:10.1016/j.nucmedbio.2015.07.003Howes, O. D., Kambeitz, J., Kim, E., Stahl, D., Slifstein, M., Abi-Dargham, A., & Kapur, S. (2012). The Nature of Dopamine Dysfunction in Schizophrenia and What This Means for Treatment. Archives of General Psychiatry, 69(8). doi:10.1001/archgenpsychiatry.2012.169Ling, T., Lewellen, T. K., & Miyaoka, R. S. (2007). Depth of interaction decoding of a continuous crystal detector module. Physics in Medicine and Biology, 52(8), 2213-2228. doi:10.1088/0031-9155/52/8/012González, A. J., Majewski, S., Sánchez, F., Aussenhofer, S., Aguilar, A., Conde, P., … Benlloch, J. M. (2016). The MINDView brain PET detector, feasibility study based on SiPM arrays. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 818, 82-90. doi:10.1016/j.nima.2016.02.046Wong, D. F., Waterhouse, R., Kuwabara, H., Kim, J., Brasic, J. R., Chamroonrat, W., … Mozley, P. D. (2013). 18F-FPEB, a PET Radiopharmaceutical for Quantifying Metabotropic Glutamate 5 Receptors: A First-in-Human Study of Radiochemical Safety, Biokinetics, and Radiation Dosimetry. Journal of Nuclear Medicine, 54(3), 388-396. doi:10.2967/jnumed.112.107995Jackson, C., O’Neill, K., Wall, L., & McGarvey, B. (2014). High-volume silicon photomultiplier production, performance, and reliability. Optical Engineering, 53(8), 081909. doi:10.1117/1.oe.53.8.081909Rahman, O., Långström, B., & Halldin, C. (2016). Alkyl Iodides and [11 C]CO in Nickel-Mediated Cross-Coupling Reactions: Successful Use of Alkyl Electrophiles containing a β Hydrogen Atom in Metal-Mediated [11 C]Carbonylation. ChemistrySelect, 1(10), 2498-2501. doi:10.1002/slct.201600643Sullivan, J. M., Lim, K., Labaree, D., Lin, S., McCarthy, T. J., Seibyl, J. P., … Morris, E. D. (2012). Kinetic Analysis of the Metabotropic Glutamate Subtype 5 Tracer [18F]FPEB in Bolus and Bolus-Plus-Constant-Infusion Studies in Humans. Journal of Cerebral Blood Flow & Metabolism, 33(4), 532-541. doi:10.1038/jcbfm.2012.195Levin, C. S. (2003). Detector design issues for compact nuclear emission cameras dedicated to breast imaging. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 497(1), 60-74. doi:10.1016/s0168-9002(02)01893-4Larhammar, M., Patra, K., Blunder, M., Emilsson, L., Peuckert, C., Arvidsson, E., … Kullander, K. (2015). SLC10A4 Is a Vesicular Amine-Associated Transporter Modulating Dopamine Homeostasis. Biological Psychiatry, 77(6), 526-536. doi:10.1016/j.biopsych.2014.07.017Kaul, M., Surti, S., & Karp, J. S. (2013). Combining Surface Treatments With Shallow Slots to Improve the Spatial Resolution Performance of Continuous, Thick LYSO Detectors for PET. IEEE Transactions on Nuclear Science, 60(1), 44-52. doi:10.1109/tns.2013.2240315Bleich, A., Brown, S.-L., Kahn, R., & van Praag, H. M. (1988). The Role of Serotonin in Schizophrenia. Schizophrenia Bulletin, 14(2), 297-315. doi:10.1093/schbul/14.2.29

Definite and indeterminate nonalcoholic steatohepatitis share similar clinical features and prognosis: A longitudinal study of 1893 biopsy-proven nonalcoholic fatty liver disease subjects

[Background and Aim] Histological score systems may not fully capture the essential nonalcoholic steatohepatitis (NASH) features, which is one of the leading causes of screening failure in clinical trials. We assessed the NASH distribution and its components across the fibrosis stages and their impact on the prognosis and their relationship with the concept of metabolic-associated fatty liver disease (MAFLD).[Methods] Spanish multicenter study including 1893 biopsy-proven nonalcoholic fatty liver disease (NAFLD) patients from HEPAmet registry. NASH was diagnosed by NAS score ≥4 (including steatosis, ballooning and lobular inflammation) and fibrosis by Kleiner score. The presence of MAFLD was determined. Progression to cirrhosis, first episode of decompensated cirrhosis and death were collected during the follow-up (4.7 ± 3.8 years).[Results] Fibrosis was F0 34.3% (649/1893), F1 27% (511/1893), F2 16.5% (312/1893), F3 15% (284/1893) and F4 7.2% (137/1893). NASH diagnosis 51.9% (982/1893), and its individual components (severe steatosis, ballooning and lobular inflammation), increased from F0 (33.6%) to F2 (68.6%), and decreased significantly in F4 patients (51.8%) (P = .0001). More than 70% of non-NASH patients showed some inflammatory activity (ballooning or lobular inflammation), showing a similar MAFLD rate than NASH (96.2% [945/982] vs. 95.2% [535/562]) and significantly higher than nonalcoholic fatty liver (NAFL) subjects (89.1% [311/349]) (P < .0001). Progression to cirrhosis was similar between NASH (9.5% [51/539]) and indeterminate NASH (7.9% [25/316]), and higher than steatosis (5% [14/263]) (logRank 8.417; P = .015). Death and decompensated cirrhosis were similar between these.[Conclusions] The prevalence of steatohepatitis decreased in advanced liver disease. However, most of these patients showed some inflammatory activity histologically and had metabolic disturbances. These findings should be considered in clinical trials whose main aim is to prevent cirrhosis progression and complications, liver transplant and death.This project has been partially funded by the ‘Consejería de Salud de la Junta de Andalucía’ (PI-0075-2014) and the ‘Spanish Ministry of Economy, Innovation and Competition, Instituto de Salud Carlos III’ (PI19/01404, PI16/01842, PI17/00535 and GLD19/00100).Peer reviewe

Development and Validation of Hepamet Fibrosis Scoring System A Simple, Noninvasive Test to Identify Patients With Nonalcoholic Fatty Liver Disease With Advanced Fibrosis

Background & Aims Fibrosis affects prognoses for patients with nonalcoholic fatty liver disease (NAFLD). Several non-invasive scoring systems have aimed to identify patients at risk for advanced fibrosis, but inconclusive results and variations in features of patients (diabetes, obesity and older age) reduce their diagnostic accuracy. We sought to develop a scoring system based on serum markers to identify patients with NAFLD at risk for advanced fibrosis. Methods We collected data from 2452 patients with NAFLD at medical centers in Italy, France, Cuba, and China. We developed the Hepamet fibrosis scoring system using demographic, anthropometric, and laboratory test data, collected at time of liver biopsy, from a training cohort of patients from Spain (n = 768) and validated the system using patients from Cuba (n = 344), Italy (n = 288), France (n = 830), and China (n = 232). Hepamet fibrosis score (HFS) were compared with those of previously developed fibrosis scoring systems (the NAFLD fibrosis score [NFS] and FIB-4). The diagnostic accuracy of the Hepamet fibrosis scoring system was assessed based on area under the receiver operating characteristic (AUROC) curve, sensitivity, specificity, diagnostic odds ratio, and positive and negative predictive values and likelihood ratios. Results Variables used to determine HFS were patient sex, age, homeostatic model assessment score, presence of diabetes, levels of aspartate aminotransferase, and albumin, and platelet counts; these were independently associated with advanced fibrosis. HFS discriminated between patients with and without advanced fibrosis with an AUROC curve value of 0.85 whereas NFS or FIB-4 did so with AUROC values of 0.80 (P = .0001). In the validation set, cut-off HFS of 0.12 and 0.47 identified patients with and without advanced fibrosis with 97.2% specificity, 74% sensitivity, a 92% negative predictive value, a 76.3% positive predictive value, a 13.22 positive likelihood ratio, and a 0.31 negative likelihood ratio. HFS were not affected by patient age, body mass index, hypertransaminasemia, or diabetes. The Hepamet fibrosis scoring system had the greatest net benefit in identifying patients who should undergo liver biopsy analysis and led to significant improvements in reclassification, reducing the number of patients with undetermined results to 20% from 30% for the FIB-4 and NFS systems (P < .05). Conclusions Using clinical and laboratory data from patients with NAFLD, we developed and validated the Hepamet fibrosis scoring system, which identified patients with advanced fibrosis with greater accuracy than the FIB-4 and NFS systems. the Hepamet system provides a greater net benefit for the decision-making process to identify patients who should undergo liver biopsy analysis