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

Author

Mozes, F. E., Lee, J. A., Selvaraj, E. A., Jayaswal, A. N. A., Trauner, M., Boursier, J., Fournier, C., Staufer, K., Stauber, R. E., Bugianesi, E., Younes, R., Gaia, S., Lupsor-Platon, M., Petta, S., Shima, T., Okanoue, T., Mahadeva, S., Chan, W. -K., Eddowes, P. J., Newsome, P. N., Wong, V. W. -S., de Ledinghen, V., Fan, J., Shen, F., Cobbold, J. F., Sumida, Y., Okajima, A., Schattenberg, J. M., Labenz, C., Kim, W., Lee, M. S., Wiegand, J., Karlas, T., Yilmaz, Y., Aithal, G. P., Palaniyappan, N., Cassinotto, C., Aggarwal, S., Garg, H., Ooi, G. J., Nakajima, A., Yoneda, M., Ziol, M., Barget, N., Geier, A., Tuthill, T., Brosnan, M. J., Anstee, Q. M., Neubauer, S., Harrison, S. A., Bossuyt, P. M., Pavlides, M., Anstee, Q., Daly, A., Johnson, K., Govaere, O., Cockell, S., Tiniakos, D., Bedossa, P., Oakley, F., Cordell, H., Day, C., Wonders, K., Bossuyt, P., Zafarmand, H., Vali, Y., Lee, J., Ratziu, V., Clement, K., Pais, R., Schuppan, D., Schattenberg, J., Vidal-Puig, T., Vacca, M., Rodrigues-Cuenca, S., Allison, M., Kamzolas, I., Petsalaki, E., Oresic, M., Hyotylainen, T., Mcglinchey, A., Mato, J. M., Millet, O., Dufour, J. -F., Berzigotti, A., Harrison, S., Cobbold, J., Mozes, F., Akhtar, S., Banerjee, R., Kelly, M., Shumbayawonda, E., Dennis, A., Erpicum, C., Graham, M., Romero-Gomez, M., Gomez-Gonzalez, E., Ampuero, J., Castell, J., Gallego-Duran, R., Fernandez, I., Montero-Vallejo, R., Karsdal, M., Erhardtsen, E., Rasmussen, D., Leeming, D. J., Fisker, M. J., Sinisi, A., Musa, K., Betsou, F., Sandt, E., Tonini, M., Rosso, C., Armandi, A., Marra, F., Gastaldelli, A., Svegliati, G., Francque, S., Vonghia, L., Ekstedt, M., Kechagias, S., Yki-Jarvinen, H., Porthan, K., van Mil, S., Papatheodoridis, G., Cortez-Pinto, H., Valenti, L., Miele, L., Trautwein, C., Aithal, G., Hockings, P., Newsome, P., Wenn, D., Rodrigues, C. M. P., Chaumat, P., Hanf, R., Trylesinski, A., Ortiz, P., Duffin, K., Brosnan, J., Mcleod, E., Ertle, J., Ostroff, R., Alexander, L., Kjaer, M. S., Mikkelsen, L. F., Balp, M. -M., Brass, C., Jennings, L., Martic, M., Loeffler, J., Hanauer, G., Shankar, S., Pepin, K., Ehman, R., Myers, J., Ho, G., Torstenson, R., Myers, R., Doward, L., LITMUS Investigators, University of Denver, Medizinische Universität Wien = Medical University of Vienna, Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), SUACI Alpes du Nord, Medical University Graz, Mozes, Ferenc Emil, Lee, Jenny A., Selvaraj, Emmanuel Anandraj, Jayaswal, Arjun Narayan Ajmer, Trauner, Michael, Boursier, Jerome, Fournier, Celine, Staufer, Katharina, Stauber, Rudolf E., Bugianesi, Elisabetta, Younes, Ramy, Gaia, Silvia, Lupsor-Platon, Monica, Petta, Salvatore, Shima, Toshihide, Okanoue, Takeshi, Mahadeva, Sanjiv, Chan, Wah-Kheong, Eddowes, Peter J., Hirschfield, Gideon M., Newsome, Philip Noel, Wong, Vincent Wai-Sun, de Ledinghen, Victor, Fan, Jiangao, Shen, Feng, Cobbold, Jeremy F., Sumida, Yoshio, Okajima, Akira, Schattenberg, Joern M., Labenz, Christian, Kim, Won, Lee, Myoung Seok, Wiegand, Johannes, Karlas, Thomas, Yilmaz, Yusuf, Aithal, Guruprasad Padur, Palaniyappan, Naaventhan, Cassinotto, Christophe, Aggarwal, Sandeep, Garg, Harshit, Ooi, Geraldine J., Nakajima, Atsushi, Yoneda, Masato, Ziol, Marianne, Barget, Nathalie, Geier, Andreas, Tuthill, Theresa, Brosnan, M. Julia, Anstee, Quentin Mark, Neubauer, Stefan, Harrison, Stephen A., Bossuyt, Patrick M., Pavlides, Michael, Epidemiology and Data Science, APH - Methodology, APH - Personalized Medicine, ACS - Atherosclerosis & ischemic syndromes, APH - Aging & Later Life, ARD - Amsterdam Reproduction and Development, Graduate School, Mozes F.E., Lee J.A., Selvaraj E.A., Jayaswal A.N.A., Trauner M., Boursier J., Fournier C., Staufer K., Stauber R.E., Bugianesi E., Younes R., Gaia S., Lupsor-Platon M., Petta S., Shima T., Okanoue T., Mahadeva S., Chan W.-K., Eddowes P.J., Newsome P.N., Wong V.W.-S., de Ledinghen V., Fan J., Shen F., Cobbold J.F., Sumida Y., Okajima A., Schattenberg J.M., Labenz C., Kim W., Lee M.S., Wiegand J., Karlas T., Yilmaz Y., Aithal G.P., Palaniyappan N., Cassinotto C., Aggarwal S., Garg H., Ooi G.J., Nakajima A., Yoneda M., Ziol M., Barget N., Geier A., Tuthill T., Brosnan M.J., Anstee Q.M., Neubauer S., Harrison S.A., Bossuyt P.M., Pavlides M., Anstee Q., Daly A., Johnson K., Govaere O., Cockell S., Tiniakos D., Bedossa P., Oakley F., Cordell H., Day C., Wonders K., Bossuyt P., Zafarmand H., Vali Y., Lee J., Ratziu V., Clement K., Pais R., Schuppan D., Schattenberg J., Vidal-Puig T., Vacca M., Rodrigues-Cuenca S., Allison M., Kamzolas I., Petsalaki E., Oresic M., Hyotylainen T., McGlinchey A., Mato J.M., Millet O., Dufour J.-F., Berzigotti A., Harrison S., Cobbold J., Mozes F., Akhtar S., Banerjee R., Kelly M., Shumbayawonda E., Dennis A., Erpicum C., Graham M., Romero-Gomez M., Gomez-Gonzalez E., Ampuero J., Castell J., Gallego-Duran R., Fernandez I., Montero-Vallejo R., Karsdal M., Erhardtsen E., Rasmussen D., Leeming D.J., Fisker M.J., Sinisi A., Musa K., Betsou F., Sandt E., Tonini M., Rosso C., Armandi A., Marra F., Gastaldelli A., Svegliati G., Francque S., Vonghia L., Ekstedt M., Kechagias S., Yki-Jarvinen H., Porthan K., van Mil S., Papatheodoridis G., Cortez-Pinto H., Valenti L., Miele L., Trautwein C., Aithal G., Hockings P., Newsome P., Wenn D., Rodrigues C.M.P., Chaumat P., Hanf R., Trylesinski A., Ortiz P., Duffin K., Brosnan J., McLeod E., Ertle J., Ostroff R., Alexander L., Kjaer M.S., Mikkelsen L.F., Balp M.-M., Brass C., Jennings L., Martic M., Loeffler J., Hanauer G., Shankar S., Pepin K., Ehman R., Myers J., Ho G., Torstenson R., Myers R., and Doward L.

Subjects
Liver Cirrhosis, Male, Cirrhosis, LIVER STIFFNESS MEASUREMENT, Biopsy, [SDV]Life Sciences [q-bio], biostatistics, Gastroenterology, DISEASE, clinical decision making, fatty liver, hepatic fibrosis, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Fibrosis, 2. Zero hunger, 0303 health sciences, medicine.diagnostic_test, NONALCOHOLIC STEATOHEPATITIS, TRANSIENT ELASTOGRAPHY, Fatty liver, CHRONIC HEPATITIS, Middle Aged, 3. Good health, Settore AGR/03 - Arboricoltura Generale E Coltivazioni Arboree, Liver, Liver biopsy, BIOPSY, Elasticity Imaging Techniques, Female, 030211 gastroenterology & hepatology, Median body, medicine.medical_specialty, CONTROLLED ATTENUATION PARAMETER, 610 Medicine & health, 03 medical and health sciences, Internal medicine, SCORE, medicine, Humans, biostatistics, clinical decision making, fatty liver, hepatic fibrosis, 030304 developmental biology, Receiver operating characteristic, business.industry, medicine.disease, Diabetes Mellitus, Type 2, XL PROBE, business, Hepatic fibrosis, Transient elastography, Biomarkers, PROSPECTIVE DERIVATION
Abstract

ObjectiveLiver 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.DesignIndividual 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.ResultsData 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 (ConclusionSequential 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.

Published
2022

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

Author

Mózes, F.E. Lee, J.A. Selvaraj, E.A. Jayaswal, A.N.A. Trauner, M. Boursier, J. Fournier, C. Staufer, K. Stauber, R.E. Bugianesi, E. Younes, R. Gaia, S. Lupșor-Platon, M. Petta, S. Shima, T. Okanoue, T. Mahadeva, S. Chan, W.-K. Eddowes, P.J. Newsome, P.N. Wong, V.W.-S. de Ledinghen, V. Fan, J. Shen, F. Cobbold, J.F. Sumida, Y. Okajima, A. Schattenberg, J.M. Labenz, C. Kim, W. Lee, M.S. Wiegand, J. Karlas, T. Yılmaz, Y. Aithal, G.P. Palaniyappan, N. Cassinotto, C. Aggarwal, S. Garg, H. Ooi, G.J. Nakajima, A. Yoneda, M. Ziol, M. Barget, N. Geier, A. Tuthill, T. Brosnan, M.J. Anstee, Q.M. Neubauer, S. Harrison, S.A. Bossuyt, P.M. Pavlides, M. Anstee, Q. Daly, A. Johnson, K. Govaere, O. Cockell, S. Tiniakos, D. Bedossa, P. Oakley, F. Cordell, H. Day, C. Wonders, K. Bossuyt, P. Zafarmand, H. Vali, Y. Lee, J. Ratziu, V. Clement, K. Pais, R. Schuppan, D. Schattenberg, J. Schuppan, D. Schattenberg, J. Vidal-Puig, T. Vacca, M. Rodrigues-Cuenca, S. Allison, M. Kamzolas, I. Petsalaki, E. Oresic, M. Hyötyläinen, T. McGlinchey, A. Mato, J.M. Millet, O. Dufour, J.-F. Berzigotti, A. Pavlides, M. Harrison, S. Neubauer, S. Cobbold, J. Mozes, F. Akhtar, S. Banerjee, R. Kelly, M. Shumbayawonda, E. Dennis, A. Erpicum, C. Graham, M. Romero-Gómez, M. Gómez-González, E. Ampuero, J. Castell, J. Gallego-Durán, R. Fernández, I. Montero-Vallejo, R. Karsdal, M. Erhardtsen, E. Rasmussen, D. Leeming, D.J. Fisker, M.J. Sinisi, A. Musa, K. Betsou, F. Sandt, E. Tonini, M. Bugianesi, E. Rosso, C. Armandi, A. Marra, F. Gastaldelli, A. Svegliati, G. Boursier, J. Francque, S. Vonghia, L. Ekstedt, M. Kechagias, S. Yki-Jarvinen, H. Porthan, K. van Mil, S. Papatheodoridis, G. Cortez-Pinto, H. Valenti, L. Petta, S. Miele, L. Geier, A. Trautwein, C. Aithal, G. Hockings, P. Newsome, P. Wenn, D. Rodrigues, C.M.P. Chaumat, P. Hanf, R. Trylesinski, A. Ortiz, P. Duffin, K. Brosnan, J. Tuthill, T. McLeod, E. Ertle, J. Younes, R. Ostroff, R. Alexander, L. Kjær, M.S. Mikkelsen, L.F. Balp, M.-M. Brass, C. Jennings, L. Martic, M. Loeffler, J. Hanauer, G. Shankar, S. Fournier, C. Pepin, K. Ehman, R. Myers, J. Ho, G. Torstenson, R. Myers, R. Doward, L. LITMUS Investigators

Abstract

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 (

Published
2021

6. Diagnostic accuracy of elastography and magnetic resonance imaging in patients with NAFLD: A systematic review and meta-analysis

Author

Selvaraj, E.A. Mózes, F.E. Jayaswal, A.N.A. Zafarmand, M.H. Vali, Y. Lee, J.A. Levick, C.K. Young, L.A.J. Palaniyappan, N. Liu, C.-H. Aithal, G.P. Romero-Gómez, M. Brosnan, M.J. Tuthill, T.A. Anstee, Q.M. Neubauer, S. Harrison, S.A. Bossuyt, P.M. Pavlides, M. Daly, A. Johnson, K. Govaere, O. Cockell, S. Tiniakos, D. Bedossa, P. Oakley, F. Cordell, H. Day, C. Wonders, K. Bossuyt, P. Zafarmand, H. Lee, J. Ratziu, V. Clement, K. Pais, R. Schuppan, D. Schattenberg, J. Vidal-Puig, T. Vacca, M. Rodrigues-Cuenca, S. Allison, M. Kamzolas, I. Petsalaki, E. Oresic, M. Hyötyläinen, T. McGlinchey, A. Mato, J.M. Millet, O. Dufour, J.-F. Berzigotti, A. Harrison, S. Cobbold, J. Mozes, F. Akhtar, S. Banerjee, R. Kelly, M. Shumbayawonda, E. Dennis, A. Erpicum, C. Gómez-González, E. Ampuero, J. Castell, J. Gallego-Durán, R. Fernández, I. Montero-Vallejo, R. Karsdal, M. Erhardtsen, E. Rasmussen, D. Leeming, D.J. Fisker, M.J. Sinisi, A. Musa, K. Betsou, F. Sandt, E. Tonini, M. Bugianesi, E. Rosso, C. Armandi, A. Marra, F. Gastaldelli, A. Svegliati, G. Boursier, J. Francque, S. Vonghia, L. Ekstedt, M. Kechagias, S. Yki-Jarvinen, H. Luukkonen, P. van Mil, S. Papatheodoridis, G. Cortez-Pinto, H. Valenti, L. Petta, S. Miele, L. Geier, A. Trautwein, C. Aithal, G. Hockings, P. Newsome, P. Wenn, D. Pereira Rodrigues, C.M. Chaumat, P. Hanf, R. Trylesinski, A. Ortiz, P. Duffin, K. Brosnan, J. Tuthill, T. McLeod, E. Ertle, J. Younes, R. Ostroff, R. Alexander, L. Kjær, M.S. Mikkelsen, L.F. Balp, M.-M. Brass, C. Jennings, L. Martic, M. Loeffler, J. Hanauer, G. Shankar, S. Fournier, C. Pepin, K. Ehman, R. Myers, J. Ho, G. Torstenson, R. Myers, R. Doward, L. LITMUS Investigators

Abstract

Background and Aims: Vibration-controlled transient elastography (VCTE), point shear wave elastography (pSWE), 2-dimensional shear wave elastography (2DSWE), magnetic resonance elastography (MRE), and magnetic resonance imaging (MRI) have been proposed as non-invasive tests for patients with non-alcoholic fatty liver disease (NAFLD). This study evaluated their diagnostic accuracy for liver fibrosis and non-alcoholic steatohepatitis (NASH). Methods: PubMED/MEDLINE, EMBASE and the Cochrane Library were searched for studies examining the diagnostic accuracy of these index tests, against histology as the reference standard, in adult patients with NAFLD. Two authors independently screened and assessed methodological quality of studies and extracted data. Summary estimates of sensitivity, specificity and area under the curve (sAUC) were calculated for fibrosis stages and NASH, using a random effects bivariate logit-normal model. Results: We included 82 studies (14,609 patients). Meta-analysis for diagnosing fibrosis stages was possible in 53 VCTE, 11 MRE, 12 pSWE and 4 2DSWE studies, and for diagnosing NASH in 4 MRE studies. sAUC for diagnosis of significant fibrosis were: 0.83 for VCTE, 0.91 for MRE, 0.86 for pSWE and 0.75 for 2DSWE. sAUC for diagnosis of advanced fibrosis were: 0.85 for VCTE, 0.92 for MRE, 0.89 for pSWE and 0.72 for 2DSWE. sAUC for diagnosis of cirrhosis were: 0.89 for VCTE, 0.90 for MRE, 0.90 for pSWE and 0.88 for 2DSWE. MRE had sAUC of 0.83 for diagnosis of NASH. Three (4%) studies reported intention-to-diagnose analyses and 15 (18%) studies reported diagnostic accuracy against pre-specified cut-offs. Conclusions: When elastography index tests are acquired successfully, they have acceptable diagnostic accuracy for advanced fibrosis and cirrhosis. The potential clinical impact of these index tests cannot be assessed fully as intention-to-diagnose analyses and validation of pre-specified thresholds are lacking. Lay summary: Non-invasive tests that measure liver stiffness or use magnetic resonance imaging (MRI) have been suggested as alternatives to liver biopsy for assessing the severity of liver scarring (fibrosis) and fatty inflammation (steatohepatitis) in patients with non-alcoholic fatty liver disease (NAFLD). In this study, we summarise the results of previously published studies on how accurately these non-invasive tests can diagnose liver fibrosis and inflammation, using liver biopsy as the reference. We found that some techniques that measure liver stiffness had a good performance for the diagnosis of severe liver scarring. © 2021 The Author(s)

Published
2021

8. Validation of NIS4 algorithm for detection of NASH at risk of cirrhosis in 467 NAFLD patients prospectively screened for inclusion in the RESOLVE-IT trial

Author

Hanf, R., primary, Pierre, C., additional, Zouher, M., additional, Cordonnier, G., additional, Brozek, J., additional, Praca, E., additional, Sudrick, F.B., additional, Bedossa, P., additional, Anstee, Q., additional, Francque, S., additional, Harrison, S., additional, Ratziu, V., additional, Megnien, S., additional, Roudot, A., additional, Hum, D., additional, and Sanyal, A., additional

Published
2018
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9. Next-Generation Sequencing (NGS) of two independent cohorts identifies eleven circulating miRNAs for diagnosis of NASH and fibrosis

Author

Francque, S., primary, Cordonnier, G., additional, Texier, F., additional, Ratziu, V., additional, Harrison, S., additional, Bedossa, P., additional, Anstee, Q., additional, Roudot, A., additional, Megnien, S., additional, Hum, D., additional, Staels, B., additional, Chaumat, P., additional, Hanf, R., additional, and Sanyal, A., additional

Published
2017
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10. A new non-invasive diagnostic score to monitor change in disease activity and predict fibrosis evolution in patients with NASH

Author

Harrison, S., primary, Praca, E., additional, Brozek, J., additional, Cordonnier, G., additional, Sudrik, F.B., additional, Roudot, A., additional, Bedossa, P., additional, Ratziu, V., additional, Staels, B., additional, Hum, D., additional, Megnien, S., additional, Chaumat, P., additional, Hanf, R., additional, and Sanyal, A., additional

Published
2017
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14. Relationship between Baseline Hepatic Disease Severity and the Cardiometabolic and Anti-Inflammatory Effects of Elafibranor in Patients with Non-Alcoholic Steatohepatitis

Author

Francque, S.M., primary, Harrison, S.A., additional, Sanyal, A., additional, Bedossa, P., additional, Serfaty, L., additional, Romero-Gomez, M., additional, Boursier, J., additional, Abdelmalek, M., additional, Caldwell, S., additional, Drenth, J., additional, Anstee, Q., additional, Hum, D., additional, Hanf, R., additional, Roudot, A., additional, Megnien, S., additional, Staels, B., additional, and Ratziu, V., additional

Published
2016
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15. A New Method including the Quantification of Circulating Mirnas Allows the Efficient Identification of Nash Patients at Risk who should be Treated

Author

Sanyal, A., primary, Cordonnier, G., additional, Brozek, J., additional, Roudot, A., additional, Deledicque, S., additional, Barbazanges, M., additional, Praca, E., additional, Sudrik, F.B., additional, Megnien, S., additional, Hanf, R., additional, Staels, B., additional, Bedossa, P., additional, Ratziu, V., additional, Hum, D., additional, and Darteil, R., additional

Published
2016
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16. A Post-Hoc Analysis ofthe Golden505 Trial Demonstrates Histological and Cardiometabolic Efficacy of Elafibranor-120 Mg in Patients with Moderate or Severe Nash That Are Eligible for Pharmacotherapy

Author

Ratziu, V., primary, Harrison, S., additional, Francque, S., additional, Bedossa, P., additional, Anstee, Q., additional, Serfaty, L., additional, Romero-Gomez, M., additional, Boursier, J., additional, Abdelmalek, M., additional, Caldwell, S., additional, Drenth, J., additional, Hum, D., additional, Hanf, R., additional, Roudot, A., additional, Megnien, S., additional, Sanyal, A., additional, and Staels, B., additional

Published
2016
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17. PLPNA3 Status in Nash is Associated with Increased Histological Severity at Baseline but Not with Response to Therapy in the Golden-505 Elafibranor Trial

Author

Ratziu, V., primary, Francque, S., additional, Harrison, S., additional, Sanyal, A., additional, Bedossa, P., additional, Serfaty, L., additional, Romero-Gomez, M., additional, Boursier, J., additional, Abdelmalek, M., additional, Caldwell, S., additional, Drenth, J., additional, Hum, D., additional, Hanf, R., additional, Roudot, A., additional, Megnien, S., additional, Staels, B., additional, and Anstee, Q., additional

Published
2016
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25. Histamine-induced biphasic macromolecular leakage in the microcirculation of the conscious hamster: evidence for a delayed nitric oxide-dependent leakage

Author

Gimeno, G, Carpentier, P H, Desquand-Billiald, S, Hanf, R, and Finet, M

Subjects
Male, omega-N-Methylarginine, Dose-Response Relationship, Drug, Mesocricetus, Microcirculation, Nitric Oxide Synthase Type II, Nitric Oxide, Guanidines, Dexamethasone, Capillary Permeability, NG-Nitroarginine Methyl Ester, Polysaccharides, Cricetinae, Papers, Animals, Enzyme Inhibitors, Nitric Oxide Synthase, Histamine
Abstract

1. Late effects (up to 3 h) of intravenously-injected histamine on FITC-dextran extravasation were investigated in the conscious hamster, by use of computer-assisted image analysis of fluorescence distribution in a microscopic window of dorsal skin fold preparations. This analysis allowed measurement of local (skin) and general (all organs) extravasations caused by a bolus injection of histamine (1 mg kg(-1), i.v.) 2. Histamine doses higher than 0.01 mg kg(-1) caused biphasic local and general extravasations. Initial phases developed fully within 15 min (for local) and 60 min (for general) and were followed by late phases beginning 90 min after histamine injection. Although the initial and late phases of histamine-induced extravasations had differential apparent reactivities to the autacoid, all the effects of histamine on the microcirculation (1 mg kg[-1]) were inhibited by pyrilamine (1 mg kg(-1), i.v.) but not by cimetidine (1 mg kg(-1), i.v.). 3. Pretreatment with N(G)-monomethyl-L-arginine (L-NMMA, 30 mg kg(-1), i.v.) or N(G)-nitro-L-arginine methyl ester (L-NAME, 100 mg kg(-1), i.v.) did not affect the initial phases but did prevent the late phases of local and general extravasations triggered by 1 mg kg(-1) histamine. The inhibitory effects of L-NAME were reversed by L-arginine (30 mg kg[-1]) but not by D-arginine (30 mg kg[-1]) according to the enantioselectivity of nitric oxide synthase (NOS). A late NO-mediated venular dilatation occurred in response to plasma histamine. 4. A low dose of aminoguanidine (1 mg kg(-1), i.v.), a selective inhibitor of the inducible isoform of NOS (iNOS), mimicked the inhibitory effects of L-NAME on the late phases of histamine-induced macromolecular extravasations and venular dilatation. 5. Pretreatment with dexamethasone (1 mg kg(-1), i.v.) prevented both the initial and late phases of histamine-induced extravasations. Fucoidan (1 or 25 mg kg(-1), i.v.) prevented the late phases without affecting initial phases, consistent with a role for leukocytes adhesion in the development of the late NO-mediated effects of histamine. 6. We conclude that intravenous injection of histamine triggers a biphasic inflammatory cascade via initial activation of H1 receptors which induces a late NO-mediated PMN-dependent extravasation process.

Published
1998

41. Bioaccumulation of fossil fuel components during single-compound and complex-mixture exposures of Daphnia magna.

Author

Dauble, D., Carlile, D., and Hanf, R.

Subjects
BIOACCUMULATION, FOSSIL fuels, DAPHNIA magna, PHENOL, LITER, MAMMALS
Abstract

The article presents a study which evaluates the potential ecological consequences from bioaccumulation of fossil fuel chemicals during complex-mixture and single-compound exposures of daphnia magna. The study were done in adult daphnids and analyzes water-soluble fraction (WSF). Results indicate that mean water concentrations of phenol expose to daphnids had minor declined from 696 µ grams per liter (g/L) at zero hours to 634 µg/L at 24 hours.

Published
1986
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42. High affinity forskolin inhibition of L-type Ca2+ current in cardiac cells.

Author

Boutjdir, M, Méry, P F, Hanf, R, Shrier, A, and Fischmeister, R

Abstract

The diterpene forskolin is widely known for its ability to directly activate adenylyl cyclase and consequently increase intracellular cAMP. In cardiac cells, one result is a cAMP-mediated increase in the L-type Ca2(+)-channel current (ICa). However, forskolin was also shown recently to affect a number of ionic channels in noncardiac cells by mechanisms that do not involve activation of adenylyl cyclase. The present study reveals such an effect of forskolin on cardiac Ca2+ channels. Indeed, under appropriate conditions, forskolin was found to cause an inhibition of ICa. Although the stimulation of adenylyl cyclase and ICa requires micromolar concentrations of forskolin, the inhibitory effect of forskolin was observed in the nanomolar range of concentrations, i.e., 2-3 orders of magnitude lower. This high affinity forskolin inhibition of ICa was observed when ICa was previously enhanced via a cAMP-dependent pathway, but not when ICa was at its basal level or when the current was elevated by the dihydropyridine Bay K 8644. The inhibitory effect occurred at a site of action remote from adenylyl cyclase, because forskolin similarly inhibited ICa that had been previously elevated by isoprenaline (a beta-adrenergic agonist) or directly by intracellular perfusion with cAMP. Under these conditions, forskolin was inhibitory when applied to either side of the cell membrane, but only in its lipid-soluble form. The inhibitory effect of forskolin appeared to be independent of membrane potential and was not accompanied by a change in the time constants of ICa activation and inactivation. This may indicate that forskolin mainly reduces the number of functional Ca2+ channels without changing the gating of individual channels. However, the reduction in ICa amplitude was not equally distributed among the different exponential components that constitute ICa, which suggests that forskolin also modifies the resting state of the channels. This novel high affinity forskolin inhibition of ICa may take place at some step in the pathway between cAMP and Ca2+ channel phosphorylation and/or at Ca2+ channels only after they have been phosphorylated.

Published
1990

44. High affinity forskolin inhibition of L-type Ca2+ current in cardiac cells

Author

Boutjdir M, Pierre-François Méry, Hanf R, Shrier A, and Fischmeister R

Subjects
Kinetics, Myocardium, Colforsin, Cyclic AMP, Animals, Rana esculenta, Calcium Channels, 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester, In Vitro Techniques, Phosphorylation
Abstract

The diterpene forskolin is widely known for its ability to directly activate adenylyl cyclase and consequently increase intracellular cAMP. In cardiac cells, one result is a cAMP-mediated increase in the L-type Ca2(+)-channel current (ICa). However, forskolin was also shown recently to affect a number of ionic channels in noncardiac cells by mechanisms that do not involve activation of adenylyl cyclase. The present study reveals such an effect of forskolin on cardiac Ca2+ channels. Indeed, under appropriate conditions, forskolin was found to cause an inhibition of ICa. Although the stimulation of adenylyl cyclase and ICa requires micromolar concentrations of forskolin, the inhibitory effect of forskolin was observed in the nanomolar range of concentrations, i.e., 2-3 orders of magnitude lower. This high affinity forskolin inhibition of ICa was observed when ICa was previously enhanced via a cAMP-dependent pathway, but not when ICa was at its basal level or when the current was elevated by the dihydropyridine Bay K 8644. The inhibitory effect occurred at a site of action remote from adenylyl cyclase, because forskolin similarly inhibited ICa that had been previously elevated by isoprenaline (a beta-adrenergic agonist) or directly by intracellular perfusion with cAMP. Under these conditions, forskolin was inhibitory when applied to either side of the cell membrane, but only in its lipid-soluble form. The inhibitory effect of forskolin appeared to be independent of membrane potential and was not accompanied by a change in the time constants of ICa activation and inactivation. This may indicate that forskolin mainly reduces the number of functional Ca2+ channels without changing the gating of individual channels. However, the reduction in ICa amplitude was not equally distributed among the different exponential components that constitute ICa, which suggests that forskolin also modifies the resting state of the channels. This novel high affinity forskolin inhibition of ICa may take place at some step in the pathway between cAMP and Ca2+ channel phosphorylation and/or at Ca2+ channels only after they have been phosphorylated.

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

Author

Raluca Pais, Rachel Ostroff, Stephen Harrison, Lars Friis Mikkelsen, Elisabeth Erhardtsen, Sudha Shankar, Kimmo Porthan, Jérôme Boursier, Antonia Sinisi, Michael Kalutkiewicz, Sven Francque, Miljen Martic, Vanessa Pellegrinelli, Phil N. Newsome, Guido Hanauer, Hannele Yki-Järvinen, Rebecca Darlay, Joel Myers, Carla Yunis, Salvatore Petta, Mette Skalshøi Kjær, Pablo Ortiz, Ann K. Daly, James H. Clark, Dina Tiniakos, Yasaman Vali, Hadi Zafarmand, Matej Orešič, Maurizio Parola, Estelle Sandt, Lori L. Jennings, Matt Kelly, Tuulia Hyötyläinen, Detlef Schuppan, Céline Fournier, Chiara Rosso, Diane E. Shevell, Maria Manuela Tonini, Paul Hockings, Aidan McGlinchey, Salma Akhtar, Mette Juul Fisker, Morten A. Karsdal, Diane Whalley, Melissa R. Miller, Aldo Trylesinski, Mattias Ekstedt, Stefan Neubauer, Jeremy M. Palmer, Partho Sen, Michael Pavlides, Per Qvist, Isabel Fernández, Luca Miele, Fabio Marra, Stergios Kechagias, Richard Torstenson, Katherine Johnson, Jean-François Dufour, Elisabetta Bugianesi, M. Julia Brosnan, George V. Papatheodoridis, Kay M. Pepin, Daniel Guldager Kring Rasmussen, Henrik Landgren, Rachel Queen, Simon Cockell, Michael Allison, Patrick M.M. Bossuyt, Rocío Gallego-Durán, Christian Rosenquist, Leigh Alexander, Elizabeth Shumbayawonda, Michele Vacca, Antonio Vidal-Puig, David Wenn, Rémy Hanf, Oscar Millet, Michalina Zatorska, R. Myers, José M. Mato, Jenny Lee, Theresa Tuthill, James Twiss, Ramy Younes, Peter Leary, Lynda Doward, Kristy Wonders, Guruprasad P. Aithal, Sarah Charlton, Vlad Ratziu, Cecília M. P. Rodrigues, Christian Trautwein, Helena Cortez-Pinto, Gideon Ho, Matt J. Barter, Judith Ertle, Jörn M. Schattenberg, Maria-Magdalena Balp, Yang-Lin Liu, Clifford A. Brass, Olivier Govaere, Amalia Gastaldelli, Sergio Rodriguez Cuenca, Pierre Chaumat, Fiona Oakley, Luca Valenti, Simon J. Cockell, Saskia W.C. van Mil, Ferenc E. Mózes, Andreas Geier, Timothy Hardy, Pierre Bedossa, Andrea Dennis, Richard L. Ehman, Charlotte Erpicum, Karine Clément, Jeremy F. L. Cobbold, Christopher P. Day, Rajarshi Banerjee, Manuel Romero-Gómez, Quentin M. Anstee, Adriaan G. Holleboom, Heather J. Cordell, Kevin L. Duffin, Diana Julie Leeming, Epidemiology and Data Science, APH - Methodology, APH - Personalized Medicine, Vascular Medicine, ACS - Diabetes & metabolism, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, APH - Aging & Later Life, ARD - Amsterdam Reproduction and Development, Graduate School, Investigators, LITMUS Consortium, Johnson K., Leary P.J., Govaere O., Barter M.J., Charlton S.H., Cockell S.J., Tiniakos D., Zatorska M., Bedossa P., Brosnan M.J., Cobbold J.F., Ekstedt M., Aithal G.P., Clement K., Schattenberg J.M., Boursier J., Ratziu V., Bugianesi E., Anstee Q.M., Daly A.K., Clark J., Cordell H.J., Darlay R., Day C.P., Hardy T., Liu Y.-L., Oakley F., Palmer J., Queen R., Wonders K., Bossuyt P.M., Holleboom A.G., Zafarmand H., Vali Y., Lee J., Pais R., Schuppan D., Allison M., Cuenca S.R., Pellegrinelli V., Vacca M., Vidal-Puig A., Hyotylainen T., McGlinchey A., Oresic M., Sen P., Mato J., Millet O., Dufour J.-F., Harrison S., Neubauer S., Pavlides M., Mozes F., Akhtar S., Banerjee R., Kelly M., Shumbayawonda E., Dennis A., Erpicum C., Romero-Gomez M., Gallego-Duran R., Fernandez I., Karsdal M., Leeming D., Fisker M.J., Erhardtsen E., Rasmussen D., Qvist P., Sinisi A., Sandt E., Tonini M.M., Parola M., Rosso C., Marra F., Gastaldelli A., Francque S., Kechagias S., Yki-Jarvinen H., Porthan K., van Mil S., Papatheodoridis G., Cortez-Pinto H., Valenti L., Petta S., Miele L., Geier A., Trautwein C., Hockings P., Newsome P., Wenn D., Pereira Rodrigues C.M., Hanf R., Chaumat P., Rosenquist C., Trylesinski A., Ortiz P., Duffin K., Yunis C., Miller M., Tuthill T., Ertle J., Younes R., Alexander L., Ostroff R., Kjaer M.S., Mikkelsen L.F., Brass C., Jennings L., Balp M.-M., Martic M., Hanauer G., Shankar S., Torstenson R., Fournier C., Ehman R., Kalutkiewicz M., Pepin K., Myers J., Shevell D., Ho G., Landgren H., Myers R., Doward L., Whalley D., Twiss J., Miller, Melissa, Tuthill, Theresa, Ertle, Judith, Younes, Ramy, Alexander, Leigh, Ostroff, Rachel, Kjær, Mette Skalshøi, Mikkelsen, Lars Friis, Brass, Clifford, Jennings, Lori, Balp, Maria-Magdalena, Martic, Miljen, Hanauer, Guido, Shankar, Sudha, Torstenson, Richard, Fournier, Céline, Ehman, Richard, Kalutkiewicz, Michael, Pepin, Kay, Myers, Joel, Shevell, Diane, Ho, Gideon, Landgren, Henrik, Myers, Rob, Doward, Lynda, Whalley, Diane, Twiss, James, Clark, James, Cordell, Heather J., Darlay, Rebecca, Day, Christopher P., Hardy, Tim, Liu, Yang-Lin, Oakley, Fiona, Palmer, Jeremy, Queen, Rachel, Wonders, Kristy, Bossuyt, Patrick M., Holleboom, Adriaan G., Zafarmand, Hadi, Vali, Yasaman, Lee, Jenny, Clement, Karine, Pais, Raluca, Schuppan, Detlef, Allison, Michael, Cuenca, Sergio Rodriguez, Pellegrinelli, Vanessa, Vacca, Michele, Vidal-Puig, Antonio, Hyötyläinen, Tuulia, McGlinchey, Aidan, Orešič, Matej, Sen, Partho, Mato, Jose, Millet, Óscar, Dufour, Jean-Francois, Harrison, Stephen, Neubauer, Stefan, Pavlides, Michael, Mozes, Ferenc, Akhtar, Salma, Banerjee, Rajarshi, Kelly, Matt, Shumbayawonda, Elizabeth, Dennis, Andrea, Erpicum, Charlotte, Romero-Gomez, Manuel, Gallego-Durán, Rocío, Fernández, Isabel, Karsdal, Morten, Leeming, Diana, Fisker, Mette Juul, Erhardtsen, Elisabeth, Rasmussen, Daniel, Qvist, Per, Sinisi, Antonia, Sandt, Estelle, Tonini, Maria Manuela, Parola, Maurizio, Rosso, Chiara, Marra, Fabio, Gastaldelli, Amalia, Francque, Sven, Kechagias, Stergios, Yki-Järvinen, Hannele, Porthan, Kimmo, van Mil, Saskia, Papatheodoridis, George, Cortez-Pinto, Helena, Valenti, Luca, Petta, Salvatore, Miele, Luca, Geier, Andreas, Trautwein, Christian, Hockings, Paul, Newsome, Phil, Wenn, David, Pereira Rodrigues, Cecília Maria, Hanf, Rémy, Chaumat, Pierre, Rosenquist, Christian, Trylesinski, Aldo, Ortiz, Pablo, Duffin, Kevin, and Yunis, Carla

Subjects
SCORING SYSTEM, CPM, counts per million, AUROC, area under the receiver operating characteristic, RC799-869, AST, aspartate aminotransferase, MicroRNA, Non-alcoholic fatty liver disease, Biomarker, Sequencing, TGF-β, transforming growth factor-beta, Gastroenterology, STEATOHEPATITIS, Liver disease, 0302 clinical medicine, Fibrosis, miRNA, microRNA, logFC, log2 fold change, FIBROSIS, Immunology and Allergy, 0303 health sciences, education.field_of_study, NAS, NAFLD activity score, medicine.diagnostic_test, Fatty liver, GTEx, Genotype-Tissue Expression, Diseases of the digestive system. Gastroenterology, 3. Good health, Real-time polymerase chain reaction, Biomarker, MicroRNA, Non-alcoholic fatty liver disease, Sequencing, Liver biopsy, ACID, Biomarker (medicine), 030211 gastroenterology & hepatology, Life Sciences & Biomedicine, Research Article, EXPRESSION, medicine.medical_specialty, NAFLD, non-alcoholic fatty liver disease, NASH, non-alcoholic steatohepatitis, Population, Gastroenterology and Hepatology, SAF, steatosis–activity–fibrosis, VALIDATION, ER, endoplasmic reticulum, 03 medical and health sciences, cDNA, complementary DNA, Internal medicine, ALT, alanine aminotransferase, Gastroenterologi, Internal Medicine, medicine, NAFL, non-alcoholic fatty liver, ALGORITHM, FIB-4, fibrosis-4, education, 030304 developmental biology, PCA, principal component analysis, Science & Technology, Gastroenterology & Hepatology, Hepatology, business.industry, FC, fold change, medicine.disease, digestive system diseases, FLIP, fatty liver inhibition of progression, Ct, cycle threshold, Steatosis, qPCR, quantitative PCR, business
Abstract

Background & 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., Graphical abstract, Highlights • Serum miRNA was sequenced in 183 NAFLD cases of varying severity and 10 population controls. • Plasma levels of miR-193a-5p were significantly increased in patients with advanced fibrosis, high NAS scores, or high SAF scores. • Other miRNAs including miR378d and miR378e were also significantly increased in certain comparisons. • The findings for miR-193a-5p were replicated in a cohort of 372 additional NAFLD cases.

Published
2022

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