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1. SIRT1 haplo-insufficiency results in reduced cortical bone thickness, increased porosity and decreased estrogen receptor alpha in bone in adult 129/Sv female mice

Author

Hanna Artsi, Einav Cohen-Kfir, Ron Shahar, Noga Kalish-Achrai, Natan Lishinsky, and Rivka Dresner-Pollak

Subjects
sirtuin1, estrogen receptor alpha, 129/Sv mice, microCT, femur, vertebrae, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

IntroductionSirtuin 1 (SIRT1) is a key player in aging and metabolism and regulates bone mass and architecture. Sexual dimorphism in skeletal effects of SIRT1 has been reported, with an unfavorable phenotype primarily in female mice.MethodsTo investigate the mechanisms of gender differences in SIRT1 skeletal effect, we investigated femoral and vertebral cortical and cancellous bone in global Sirt1 haplo-insufficient 129/Sv mice aged 2,7,12 months lacking Sirt1 exons 5,6,7 (Sirt1+/Δ) and their wild type (WT) counterparts.ResultsIn females, femoral bone mineral content, peak cortical thickness, and trabecular bone volume (BV/TV%), number and thickness were significantly lower in Sirt1+/Δ compared to WT mice. Increased femoral cortical porosity was observed in 7-month-old Sirt1+/Δ compared to WT female mice, accompanied by reduced biomechanical strength. No difference in vertebral indices was detected between Sirt1+/Δ and WT female mice. SIRT1 decreased with aging in WT female mice and was lower in vertebrae and femur in 18- and 30- versus 3-month-old 129/Sv and C57BL/6J female mice, respectively. Decreased bone estrogen receptor alpha (ERα) was observed in Sirt1+/Δ compared to WT female mice and was significantly higher in Sirt1 over-expressing C3HT101/2 murine mesenchymal stem cells. In males no difference in femoral indices was detected in Sirt1+/Δ versus WT mice, however vertebral BV/TV%, trabecular number and thickness were higher in Sirt1+/Δ vs. WT mice. No difference in androgen receptor (AR) was detected in bone in Sirt1+/Δ vs. WT male mice. Bone SIRT1 was significantly lower in male compared to female WT mice, suggesting that SIRT1 maybe more significant in female than male skeleton.DiscussionThese findings demonstrate that 50% reduction in SIRT1 is sufficient to induce the hallmarks of skeletal aging namely, decreased cortical thickness and increased porosity in female mice, highlighting the role of SIRT1 as a regulator of cortical bone quantity and quality. The effects of SIRT1 in cortical bone are likely mediated in part by its regulation of ERα. The age-associated decline in bone SIRT1 positions SIRT1 as a potential therapeutic target to ameliorate age-related cortical bone deterioration in females. The crosstalk between ERα, AR and SIRT1 in the bone microenvironment remains to be further investigated.

Published
2022
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2. Sirt1 Promotes a Thermogenic Gene Program in Bone Marrow Adipocytes: From Mice to (Wo)Men

Author

Hanna Artsi, Irina Gurt, Madi El-Haj, Ralph Müller, Gisela A. Kuhn, Gal Ben Shalom, Einav Cohen-Kfir, Eva Abramowitz, Leonid Kandel, Ori Safran, and Rivka Dresner-Pollak

Subjects
sirtuin1, marrow adipose tissue, PGC1-alpha, bone marrow mesenchymal stem cells, thermogenic genes, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Bone marrow adipose tissue (MAT) is influenced by nutritional cues, and participates in whole body energy metabolism. To investigate the role of Sirtuin1 (Sirt1), a key player in metabolism, in MAT, marrow adiposity was evaluated in inbred 5-month-old 129/Sv Sirt1 haplo-insufficient (Sirt1Δ/+) and wild type (WT) mice. Decreased expression of the thermogenic genes: Prdm16, Pgc1α, Foxc2, Dio2, and β3AR was detected in whole tibiae derived from Sirt1Δ/+ compared to WT female mice. Similarly, decreased expression of Prdm16 and Pgc1α was observed in primary bone marrow mesenchymal stem cell (BM-MSC) cultures obtained from Sirt1Δ/+ compared to WT female mice, suggesting a cell autonomous effect of Sirt1 in BM-MSCs. In vitro, Sirt1 over-expression in the mesenchymal embryonic fibroblast stem cell line C3HT101/2 increased Pgc1α and Prdm16 protein level. Similarly, pharmacologic activation of Sirt1 by SRT3025 increased Foxc2, Pgc1α, Dio2, Tfam, and Cyc1 expression while inhibition of Sirt1 by EX527 down-regulated UCP1 in C3HT101/2 cells. Importantly, in human femoral BM-MSCs obtained from female patients undergoing hip operations for fracture or osteoarthritis, Sirt1 activation by SRT3025 increased PGC1α mRNA and protein level. Blocking sclerostin, an inhibitor of the WNT pathway and a Sirt1 target, by the monoclonal humanized antibody (Sc-AbII), stimulated β3AR, PRDM16, and UCP1 gene expression, and increased PGC1α protein level. These results show that Sirt1 stimulates a thermogenic gene program in marrow adipocytes in mice and humans via PGC1α activation and sclerostin inhibition. The implications of these findings to bone health, hematopoiesis and whole body energy metabolism remain to be investigated.

Published
2019
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3. The Sirt1 Activators SRT2183 and SRT3025 Inhibit RANKL-Induced Osteoclastogenesis in Bone Marrow-Derived Macrophages and Down-Regulate Sirt3 in Sirt1 Null Cells.

Author

Irina Gurt, Hanna Artsi, Einav Cohen-Kfir, Gilad Hamdani, Gal Ben-Shalom, Ben Feinstein, Madi El-Haj, and Rivka Dresner-Pollak

Subjects
Medicine, Science
Abstract

Increased osteoclast-mediated bone resorption is characteristic of osteoporosis, malignant bone disease and inflammatory arthritis. Targeted deletion of Sirtuin1 (Sirt1), a key player in aging and metabolism, in osteoclasts results in increased osteoclast-mediated bone resorption in vivo, making it a potential novel therapeutic target to block bone resorption. Sirt1 activating compounds (STACs) were generated and were investigated in animal disease models and in humans however their mechanism of action was a source of controversy. We studied the effect of SRT2183 and SRT3025 on osteoclastogenesis in bone-marrow derived macrophages (BMMs) in vitro, and discovered that these STACs inhibit RANKL-induced osteoclast differentiation, fusion and resorptive capacity without affecting osteoclast survival. SRT2183 and SRT3025 activated AMPK, increased Sirt1 expression and decreased RelA/p65 lysine310 acetylation, critical for NF-κB activation, and an established Sirt1 target. However, inhibition of osteoclastogenesis by these STACs was also observed in BMMs derived from sirt1 knock out (sirt1-/-) mice lacking the Sirt1 protein, in which neither AMPK nor RelA/p65 lysine 310 acetylation was affected, confirming that these effects require Sirt1, but suggesting that Sirt1 is not essential for inhibition of osteoclastogenesis by these STACs under these conditions. In sirt1 null osteoclasts treated with SRT2183 or SRT3025 Sirt3 was found to be down-regulated. Our findings suggest that SRT2183 and SRT3025 activate Sirt1 and inhibit RANKL-induced osteoclastogenesis in vitro however under conditions of Sirt1 deficiency can affect Sirt3. As aging is associated with reduced Sirt1 level and activity, the influence of STACs on Sirt3 needs to be investigated in vivo in animal and human disease models of aging and osteoporosis.

Published
2015
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4. Intraoperative positive end-expiratory pressure and postoperative pulmonary complications: a patient-level meta-analysis of three randomised clinical trials

Author

Niklas S. Campos, Thomas Bluth, Sabrine N.T. Hemmes, Julian Librero, Natividad Pozo, Carlos Ferrando, Lorenzo Ball, Guido Mazzinari, Paolo Pelosi, Marcelo Gama de Abreu, Marcus J. Schultz, A. Serpa Neto, Sabrine NT. Hemmes, Paolo Severgnini, Markus W. Hollmann, Jan M. Binnekade, Hermann Wrigge, Jaume Canet, Michael Hiesmayr, Werner Schmid, Edda Tschernko, Samir Jaber, Göran Hedenstierna, Christian Putensen, Agnes Marti, Alessandro Bacuzzi, Alexander Brodhun, Alexandre Molin, Alfred Merten, Ana Parera, Andrea Brunelli, Andrea Cortegiani, Andreas Güldner, Andreas W. Reske, Angelo Gratarola, Antonino Giarratano, Bea Bastin, Bjorn Heyse, Branka Mazul-Sunko, Bruno Amantea, Bruno Barberis, Christopher Uhlig, Conrado Minguez Marín, Cristian Celentano, Daniela La Bella, David D’Antini, David Velghe, Demet Sulemanji, Edoardo De Robertis, Eric Hartmann, Francesca Montalto, Francesco Tropea, Gary H. Mills, Gilda Cinnella, Giorgio Della Rocca, Girolamo Caggianelli, Giulia Pellerano, Giuseppina Mollica, Guillermo Bugedo, Jan-Paul Mulier, Jeroen Vandenbrande, Johann Geib, Jonathan Yaqub, Jorge Florez, Juan F. Mayoral, Juraj Sprung, Jurgen Van Limmen, Lieuwe DJ. Bos, Luc de Baerdemaeker, Luc Jamaer, Luigi Spagnolo, Lydia Strys, Manuel Granell Gil, Marcos F. Vidal Melo, Maria Carmen Unzueta, Maria Victoria Moral, Marion Ferner, Martin Weiss, Massimo Vanoni, Maximilian S. Schaefer, Mercè Prieto, Michele Grio, Peter Markus Spieth, Philipp Simon, Phoebe Bodger, Pilar Sierra, Rita Laufenberg-Feldmann, Roberta Rusca, Rodolfo Proietti, Santi Maurizio Raineri, Santo Caroleo, Sergi Sabaté, Stefan De Hert, Stefano Pezzato, Tanja A. Treschan, Tatjana Goranovic, Thea Koch, Thomas Kiss, Valter Perilli, Virginia Cegarra, Javier Belda, Marina Soro, Carmen Unzueta, Fernando Suarez-Sipmann, Julián Librero, Alicia Llombart, Lucas Rovira, Manuel Granell, César Aldecoa, Oscar Diaz-Cambronero, Jaume Balust, Ignacio Garutti, Rafael Gonzalez, Lucia Gallego, Santiago Garcia del Valle, Javier Redondo, David Pestaña, Aurelio Rodríguez, Javier García, Manuel de la Matta, Maite Ibáñez, Francisco Barrios, Samuel Hernández, Vicente Torres, Salvador Peiró, Abigail Villena, Albert Carramiñana, Alberto Gallego-Casilda, Alejandro Duca, Amalia Alcón, Amanda Miñana, Ana Asensio, Ana Colás, Ana Isabel Galve, Ana Izquierdo, Ana Jurado, Ana María Pérez, Ana Mugarra, Andrea Gutierrez, Ángeles De Miguel, Angels Lozano, Antonio Katime, Antonio Romero, Beatriz Garrigues, Begoña Ayas, Blanca Arocas, Carlos Delgado, Carmen Fernández, Carolina Romero, Clara Gallego, Cristina Garcés, Cristina Lisbona, Cristina Parrilla, Daniel López-Herrera, Domingo González, Eduardo Llamazares, Elena Del Rio, Elena Lozano, Ernesto Pastor, Estefanía Chamorro, Estefanía Gracia, Ester Sánchez, Esther Romero, Fernando Díez, Ferran Serralta, Francisco Daviu, Francisco Sandín, Gerardo Aguilar, Gerardo Tusman, Gonzalo Azparren, Graciela Martínez-Pallí, Inmaculada Benítez, Inmaculada Hernandéz, Inmaculada India, Irene León, Isabel Fuentes, Isabel Ruiz, Jaume Puig, Javie Ignacio Román, Jesús Acosta, Jesús Rico-Feijoo, Jonathan Olmedo, Jose A. Carbonell, Jose M. Alonso, Jose María Pérez, Jose Miguel Marcos, Jose Navarro, Jose Valdivia, Juan Carrizo, Laura Piqueras, Laura Soriano, Laura Vaquero, Lisset Miguel, Lorena Muñoz, Lucia Valencia, Luis Olmedilla, Mᵃ Justina Etulain, Manuel Tisner, María Barrio, María Dolores Alonso, María García, María J. Hernández, María José Alberola, María Parra, María Pilar Argente, María Vila, Mario De Fez, Marta Agilaga, Marta Gine, Mercedes Ayuso, Mercedes García, Natalia Bejarano, Natalia Peña, Nazario Ojeda, Nilda Martínez, Nuria García, Oto Padrón, Pablo García, Paola Valls, Patricia Cruz, Patricia Piñeiro, Pedro Charco, Rafael Anaya, Ramiro López, Rayco Rodríguez, Rocío Martínez, Roger Pujol, Rosa Dosdá, Rosa Lardies, Ruben Díaz, Rubén Villazala, Sara Zapatero, Sergio Cabrera, Sergio Sánchez, Silvia Martin, Suzana Diaz, Tania Franco, Tania Moreno, Tania Socorro, Vicente Gilabert, Victor Balandrón, Victoria Moral, Virgina Cegarra, Viviana Varón, Fernando Abelha, Sühayla Abitağaoğlu, Marc Achilles, Afeez Adebesin, Ine Adriaensens, Charles Ahene, Fatima Akbar, Mohammed Al Harbi, Rita Al Khoury al Kallab, Xavier Albanel, Florence Aldenkortt, Rawan Abdullah Saleh Alfouzan, Reef Alruqaie, Fernando Altermatt, Bruno Luís de Castro Araujo, Genaro Arbesú, Hanna Artsi, Caterina Aurilio, Omer Hilmi Ayanoglu, Harris Baig, Yolanda Baird, Konstantin Balonov, Samantha Banks, Xiaodong Bao, Mélanie Baumgartner, Isabel Belda Tortosa, Alice Bergamaschi, Lars Bergmann, Luca Bigatello, Elena Biosca Pérez, Katja Birr, Elird Bojaxhi, Chiara Bonenti, Iwona Bonney, Elke M.E. Bos, Sara Bowman, Leandro Gobbo Braz, Elisa Brugnoni, Sorin J. Brull, Iole Brunetti, Andrea Bruni, Shonie L. Buenvenida, Cornelius Johannes Busch, Giovanni Camerini, Beatrice Capatti, Javiera Carmona, Jaime Carungcong, Marta Carvalho, Anat Cattan, Carla Cavaleiro, Davide Chiumello, Stefano Ciardo, Mark Coburn, Umberto Colella, Victor Contreras, Pelin Corman Dincer, Elizabeth Cotter, Marcia Crovetto, William Darrah, Simon Davies, Enrique Del Cojo Peces, Ellise Delphin, John Diaper, Paulo do Nascimento Junior, Valerio Donatiello, Jing Dong, Maria do Socorro Dourado, Alexander Dullenkopf, Felix Ebner, Hamed Elgendy, Christoph Ellenberger, Dilek Erdoğan Arı, Thomas Ermert, Fadi Farah, Ana Fernandez-Bustamante, Cristina Ferreira, Marco Fiore, Ana Fonte, Christina Fortià Palahí, Andrea Galimberti, Najia Garofano, Luca Gregorio Giaccari, Fernando Gilsanz, Felix Girrbach, Luca Gobbi, Marc Bernard Godfried, Nicolai Goettel, Peter A. Goldstein, Or Goren, Andrew Gorlin, Juan Graterol, Pierre Guyon, Kevin Haire, Philippe Harou, Antonia Helf, Gunther Hempel, María José Hernández Cádiz, Björn Heyse, Ivan Huercio, Jasmina Ilievska, Lien Jakus, Vijay Jeganath, Yvonne Jelting, Minoa Jung, Barbara Kabon, Aalok Kacha, Maja Karaman Ilić, Arunthevaraja Karuppiah, Ayse Duygu Kavas, Gleicy Keli Barcelos, Todd A. Kellogg, Johann Kemper, Romain Kerbrat, Suraya Khodr, Peter Kienbaum, Bunyamin Kir, Selin Kivrak, Vlasta Klarić, Ceren Köksal, Ana Kowark, Peter Kranke, Bahar Kuvaki, Biljana Kuzmanovska, John Laffey, Mirko Lange, Marília Freitas de Lemos, Marc-Joseph Licker, Manuel López-Baamonde, Antonio López-Hernández, Mercedes Lopez-Martinez, Stéphane Luise, Mark MacGregor, Danielle Magalhães, Julien Maillard, Patrizia Malerbi, Natesan Manimekalai, Michael Margarson, Klaus Markstaller, Archer K. Martin, David P. Martin, Yvette N. Martin, Julia Martínez-Ocon, Ignacio Martin-Loeches, Emilio Maseda, Idit Matot, Niamh McAuliffe, Travis J. McKenzie, Paulina Medina, Melanie Meersch, Angelika Menzen, Els Mertens, Bernd Meurer, Tanja Meyer-Treschan, Changhong Miao, Camilla Micalizzi, Morena Milić, Norma Sueli Pinheiro Módolo, Pierre Moine, Patrick Mölders, Ana Montero-Feijoo, Enrique Moret, Markus K. Muller, Zoe Murphy, Pramod Nalwaya, Filip Naumovski, Paolo Navalesi, Lais Helena Navarro e Lima, Višnja Nesek Adam, Claudia Neumann, Christopher Newell, Zoulfira Nisnevitch, Junaid Nizamuddin, Cecilia Novazzi, Michael O'Connor, Günther Oprea, Mukadder Orhan Sungur, Şule Özbilgin, Maria Caterina Pace, Marcos Pacheco, Balaji Packianathaswamy, Estefania Palma Gonzalez, Fotios Papaspyros, Sebastián Paredes, Maria Beatrice Passavanti, Juan Cristobal Pedemonte, Sanja Peremin, Christoph Philipsenburg, Daniela Pinho, Silvia Pinho, Linda M. Posthuma, Vincenzo Pota, Benedikt Preckel, Paolo Priani, Mohamed Aymen Rached, Aleksandar Radoeshki, Riccardo Ragazzi, Tamilselvan Rajamanickam, Arthi Rajamohan, Harish Ramakrishna, Desikan Rangarajan, Christian Reiterer, J. Ross Renew, Thomas Reynaud, Rhidian Rhys, Eva Rivas, Luisa Robitzky, Rolf Rossaint, Francesca Rubulotta, Humberto S. Machado, Catarina S. Nunes, Giovanni Sabbatini, Jon D. Samuels, Josep Martí Sanahuja, Pasquale Sansone, Alice Santos, Mohamed Sayedalahl, Martin Scharffenberg, Eduardo Schiffer, Nadja Schliewe, Raoul Schorer, Roman Schumann, Gabriele Selmo, Mar Sendra, Mert Senturk, Kate Shaw, Mirjana Shosholcheva, Abdulrazak Sibai, Francesca Simonassi, Claudia Sinno, Nukhet Sivrikoz, Vasiliki Skandalou, Neil Smith, Maria Soares, Tania Socorro Artiles, Diogo Sousa Castro, Miguel Sousa, Savino Spadaro, Emmanouil Stamatakis, Luzius A. Steiner, Andrea Stevenazzi, Alejandro Suarez-de-la-Rica, Mélanie Suppan, Robert Teichmann, José Maria Tena Guerrero, Bram Thiel, Raquel Tolós, Gulbin Tore Altun, Michelle Tucci, Zachary A. Turnbull, Žana Turudić, Matthias Unterberg, Yves Van Nieuwenhove, Julia Van Waesberghe, Marcos Francisco Vidal Melo, Bibiana Vitković, Luigi Vivona, Marcela Vizcaychipi, Carlo Alberto Volta, Anne Weber, Toby N. Weingarten, Jakob Wittenstein, Piet Wyffels, Julio Yagüe, David Yates, Ayşen Yavru, Lilach Zac, Jing Zhong, Anesthesiology, Intensive Care Medicine, ACS - Pulmonary hypertension & thrombosis, ACS - Diabetes & metabolism, ACS - Microcirculation, Campos, Niklas S, Bluth, Thoma, Hemmes, Sabrine N T, Librero, Julian, Pozo, Natividad, Ferrando, Carlo, Ball, Lorenzo, Mazzinari, Guido, Pelosi, Paolo, Gama de Abreu, Marcelo, Schultz, Marcus J, Serpa Neto, A, investigators for the PROVHILO study including, Cortegiani, Andrea, Raineri, Santi Maurizio, and Giarratano, Antonino

Subjects
Adult, Lung Diseases, PEEP, postoperative pulmonary complications, mechanical ventilation, Positive-Pressure Respiration, surgery, Anesthesiology and Pain Medicine, Postoperative Complications, Tidal Volume, Humans, Postoperative Period, Lung, Randomized Controlled Trials as Topic
Abstract

BACKGROUND: High intraoperative PEEP with recruitment manoeuvres may improve perioperative outcomes. We re-examined this question by conducting a patient-level meta-analysis of three clinical trials in adult patients at increased risk for postoperative pulmonary complications who underwent non-cardiothoracic and non-neurological surgery. METHODS: The three trials enrolled patients at 128 hospitals in 24 countries from February 2011 to February 2018. All patients received volume-controlled ventilation with low tidal volume. Analyses were performed using one-stage, two-level, mixed modelling (site as a random effect; trial as a fixed effect). The primary outcome was a composite of postoperative pulmonary complications within the first week, analysed using mixed-effect logistic regression. Pre-specified subgroup analyses of nine patient characteristics and seven procedure and care-delivery characteristics were also performed. RESULTS: Complete datasets were available for 1913 participants ventilated with high PEEP and recruitment manoeuvres, compared with 1924 participants who received low PEEP. The primary outcome occurred in 562/1913 (29.4%) participants randomised to high PEEP, compared with 620/1924 (32.2%) participants randomised to low PEEP (unadjusted odds ratio [OR]=0.87; 95% confidence interval [95% CI], 0.75-1.01; P=0.06). Higher PEEP resulted in 87/1913 (4.5%) participants requiring interventions for desaturation, compared with 216/1924 (11.2%) participants randomised to low PEEP (OR=0.34; 95% CI, 0.26-0.45). Intraoperative hypotension was associated more frequently (784/1913 [41.0%]) with high PEEP, compared with low PEEP (579/1924 [30.1%]; OR=1.87; 95% CI, 1.60-2.17). CONCLUSIONS: High PEEP combined with recruitment manoeuvres during low tidal volume ventilation in patients undergoing major surgery did not reduce postoperative pulmonary complications. CLINICAL TRIAL REGISTRATION: NCT03937375 (Clinicaltrials.gov).

Published
2022

5. High level of satisfaction among women who underwent oocyte retrieval without anesthesia

Author

Chaim Greenberger, Foad Azem, Hanna Artsi, Nivin Samara, and Idit Matot

Subjects
Adult, 0301 basic medicine, Attitude of Health Personnel, Oocyte Retrieval, 03 medical and health sciences, 0302 clinical medicine, Patient satisfaction, Physicians, Surveys and Questionnaires, Pelvic inflammatory disease, medicine, Clinical endpoint, Humans, Hypnotics and Sedatives, Anesthesia, Prospective Studies, Prospective cohort study, Pain, Postoperative, 030219 obstetrics & reproductive medicine, Transvaginal oocyte retrieval, business.industry, Obstetrics and Gynecology, Treatment Outcome, 030104 developmental biology, Reproductive Medicine, Patient Satisfaction, Feasibility Studies, Anxiety, Female, Willingness to recommend, medicine.symptom, business, Body mass index
Abstract

Objective To assess the level of satisfaction of women undergoing transvaginal oocyte retrieval (TOR) without anesthesia as well as the comfort of the gynecologists. Design Single-center, prospective cohort study of women undergoing TOR from July 2017 to January 2018. Setting This study was conducted in an academic public hospital. Patient(s) Women with ≤15 follicles for retrieval were eligible. Women with body mass index > 35, difficult vaginal approach, endometrioma > 5 cm, or pelvic inflammatory disease were excluded. Intervention(s) None. Main Outcome Measure(s) Our primary endpoint was patient satisfaction. Secondary endpoints were women’s willingness to recommend or undergo the procedure again without anesthesia, anxiety levels before the procedure, expected level of pain, actual pain levels during the procedure, and gynecologist’s level of difficulty or technical compromise. Result(s) During the study period, 500 TORs were performed, of which 402 (80%) were screened for study eligibility. Overall, data were analyzed for 50 eligible women who had their first in vitro fertilization cycle (participating in the study) without anesthesia. High rates of satisfaction were reported, and 90% would recommend the procedure without anesthesia to their friends. Physicians graded the difficulty of the procedure as very easy in 35 procedures; in only two procedures was difficulty reported. Conclusion(s) TOR without anesthesia is feasible, with a relatively high satisfaction rate from both patients and gynecologists, suggesting that it should be considered in selected women.

Published
2020
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6. Ventilation and outcomes following robotic-assisted abdominal surgery: an international, multicentre observational study

Author

Veronica N.F. Queiroz, Luis Guilherme V. da Costa, Flavio Takaoka, Paolo Pelosi, Marcelo Gama de Abreu, Marcus J. Schultz, Ary Serpa Neto, R.P. Barbosa, J. Canet, J.P. Cata, D.S. Cesar, R.C.F. Chaves, U.C. D’Orto, L.G.V. Da Costa, L. De Baerdemaeker, J.R. Galdi, M. Gama de Abreu, V. Gottumukkala, S.N.T. Hemmes, M.W. Hollmann, A.F. Kalmar, R. Mariano, I. Matot, G. Mazzinari, G.H. Mills, P. Pelosi, I.P. Posso, V.N.F. Queiroz, M.J. Schultz, A. Serpa Neto, J. Sprung, F. Takaoka, A. Teruya, M.F. Vidal Melo, Aalok V. Agarwala, Louise Akeroyd, Francesco Andorlini, Lisa Anicetti, Massimo Antonelli, Bruno S. Arantes, Jose J. Ariño Irujo, Hanna Artsi, Renata Babian, Rogerio P. Barbosa, Doug Barker, Diletta Basagni, Nicola Basso, Joan Beltran, Vittorio Bocciero, Giulia Bonatti, Ernesto Boriati, Mauro Bravo, Luca Brazzi, Chris Brearton, Andrew Brennan, Adam M. Bulinski, Sara Cafagna, Andrea Cardoni, Paula Castelló Mora, Juan P. Cata, Daniel S. Cesar, Renato CF. Chaves, Lee-Lynn Chen, Srikanth Chukkambotla, Alessandra Ciccozzi, Danae Cilia, Sean Cope, Ulisses C. D’Orto, Luis Guilherme V. Da Costa, Claire Dalton, Alessandra Davi, Marina del Barrio De Bonis, Angelo Raffaele De Gaudio, Lucilla De Luca, Carlos C. Delgado, Atousa Deljou, Cecilia Di Ruscio, Sijgje M. Droger, Stephen Duberley, Leonid A. Eidelman, Alison Evans, Constanza Fabiani, Umberto Fasciano, Jennifer Firth-Gieben, Jillian Fitchett, Angela Fundarò, Jose Roberto Galdi, Verdiana Gallo, Mattia Gavagni, Vijaya Gottumukkala, Chris Graham, Manuel Granell Gil, Angelo Gratarola, Chiara Grillandini, Harald-Thomas Groeben, Nesrine Ismail, Reni Jacob, Chris Jones, Rebecca Jones, Alain F. Kalmar, Ritoo Kapoor, Leigh Kelliher, Wiebke Köhne, Joseph SHA. Koopman, Prasad Lanka, Jae-Woo Lee, Bernard Liban, Francesca Livi, Renato Mariano, Ruth Martinez Plumed, Idit Matot, Marta Mazzella, Stewart McClure, Martina McMonagle, Gary H. Mills, Lucia Mirabella, Concepción Monsalve, Angela Moon, Laura Morchio, Frances Morris, Lorenzo Motroni, Benedetta Mura, Alessandro Nerini, Elodia C. Noumedem Sonna, Neil Oakes, Marina Orlandi, Antonella Paladini, Anita Patil, Vishal Patil, Valentina Patrone, Angela Pinder, Alba Piroli, Irimar P. Posso, Veronica NF. Queiroz, Yosef S. Rabbu, Robert Rabenalt, Stefano Romagnoli, Ariel Ronen, Felipe Rothman, Patrick Rusagara, Andrea Russo, Moldovan Sabov, Thomas Saitta, Nirav Shah, Neil Smith, Liliana Sollazzi, Juraj Sprung, Emma Stewart, Elizabeth Stones, Kim Storton, Beatriz Tena, Eleonora Terreni, Alexandre Teruya, Chiara Travaglia, Tanja A. Treschan, Henk Vanoverschelde, Harish Venkatesh, Marcos F. Vidal Melo, Gianluca Villa, Robbert Vossen, Stephen Webber, Toby N. Weingarten, Matt Willcocks, Luke Winslow, Lindsey Woods, ACS - Pulmonary hypertension & thrombosis, Intensive Care Medicine, APH - Quality of Care, ACS - Heart failure & arrhythmias, Anesthesiology, APH - Global Health, ACS - Diabetes & metabolism, and ACS - Microcirculation

Subjects
Lung Diseases, Male, medicine.medical_specialty, intraoperative ventilation, Lower risk, Risk Assessment, robotic-assisted surgery, Robotic Surgical Procedures, Risk Factors, Internal medicine, Epidemiology, Abdomen, robotic surgery, medicine, Humans, Prospective Studies, Prospective cohort study, Aged, business.industry, Incidence (epidemiology), Incidence, Absolute risk reduction, Oxygen Inhalation Therapy, Length of Stay, Middle Aged, abdominal surgery, Respiration, Artificial, Confidence interval, Clinical trial, postoperative pulmonary complications, Anesthesiology and Pain Medicine, Treatment Outcome, Female, business, Abdominal surgery
Abstract

Background: International data on the epidemiology, ventilation practice, and outcomes in patients undergoing abdominal robotic-assisted surgery (RAS) are lacking. The aim of the study was to assess the incidence of postoperative pulmonary complications (PPCs), and to describe ventilator management after abdominal RAS. Methods: This was an international, multicentre, prospective study in 34 centres in nine countries. Patients ≥18 yr of age undergoing abdominal RAS were enrolled between April 2017 and March 2019. The Assess Respiratory Risk in Surgical Patients in Catalonia (ARISCAT) score was used to stratify for higher risk of PPCs (≥26). The primary outcome was the incidence of PPCs. Secondary endpoints included the preoperative risk for PPCs and ventilator management. Results: Of 1167 subjects screened, 905 abdominal RAS patients were included. Overall, 590 (65.2%) patients were at increased risk for PPCs. Meanwhile, 172 (19%) patients sustained PPCs, which occurred more frequently in 132 (22.4%) patients at increased risk, compared with 40 (12.7%) patients at lower risk of PPCs (absolute risk difference: 12.2% [95% confidence intervals (CI), 6.8–17.6%]; P

Published
2021

7. Ventilation and outcomes following robotic-assisted abdominal surgery: an international, multicentre observational study. Assessment of Ventilation during general AnesThesia for Robotic surgery (AVATaR) Study

Author

Veronica N, F Queiroz, Luis Guilherme, V da Costa, Flavio, Takaoka, Paolo, Pelosi, Marcelo Gama de Abreu, Marcus, J Schultz, Ary Serpa Neto, P Barbosa, R, Canet, J, P Cata, J, S Cesar, D, R C, F Chaves, C D'Orto, U, L G, V Da Costa, L De Baerdemaeker, R Galdi, J, M Gama de Abreu, Gottumukkala, V, S N, T Hemmes, W Hollmann, M, F Kalmar, A, Mariano, R, Matot, I, Mazzinari, G, H Mills, G, Pelosi, P, P Posso, I, V N, F Queiroz, J Schultz, M, A Serpa Neto, Sprung, J, Takaoka, F, Teruya, A, F Vidal Melo, M, Aalok, V Agarwala, Louise, Akeroyd, Francesco, Andorlini, Lisa, Anicetti, Massimo, Antonelli, Bruno, S Arantes, Jose, J Ariño Irujo, Hanna, Artsi, Renata, Babian, Rogerio, P Barbosa, Doug, Barker, Diletta, Basagni, Nicola, Basso, Joan, Beltran, Vittorio, Bocciero, Giulia, Bonatti, Ernesto, Boriati, Mauro, Bravo, Luca, Brazzi, Chris, Brearton, Andrew, Brennan, Adam, M Bulinski, Sara, Cafagna, Andrea, Cardoni, Paula Castelló Mora, Juan, P Cata, Daniel, S Cesar, Renato Cf Chaves, Lee-Lynn, Chen, Srikanth, Chukkambotla, Ciccozzi, Alessandra, Danae, Cilia, Sean, Cope, Ulisses, C D'Orto, Luis Guilherme, V Da Costa, Claire, Dalton, Alessandra, Davi, Marina Del Barrio De Bonis, Angelo Raffaele De Gaudio, Lucilla De Luca, Carlos, C Delgado, Atousa, Deljou, Cecilia Di Ruscio, Sijgje, M Droger, Stephen, Duberley, Leonid, A Eidelman, Alison, Evans, Constanza, Fabiani, Umberto, Fasciano, Jennifer, Firth-Gieben, Jillian, Fitchett, Angela, Fundarò, Jose Roberto Galdi, Verdiana, Gallo, Mattia, Gavagni, Vijaya, Gottumukkala, Chris, Graham, Manuel Granell Gil, Angelo, Gratarola, Chiara, Grillandini, Harald-Thomas, Groeben, Nesrine, Ismail, Reni, Jacob, Chris, Jones, Rebecca, Jones, Alain, F Kalmar, Ritoo, Kapoor, Leigh, Kelliher, Wiebke, Köhne, Joseph Sha Koopman, Prasad, Lanka, Jae-Woo, Lee, Bernard, Liban, Francesca, Livi, Renato, Mariano, Ruth Martinez Plumed, Idit, Matot, Marta, Mazzella, Stewart, Mcclure, Martina, Mcmonagle, Gary, H Mills, Lucia, Mirabella, Concepción, Monsalve, Angela, Moon, Laura, Morchio, Frances, Morris, Lorenzo, Motroni, Benedetta, Mura, Alessandro, Nerini, Elodia, C Noumedem Sonna, Neil, Oakes, Marina, Orlandi, Paladini, Antonella, Anita, Patil, Vishal, Patil, Valentina, Patrone, Angela, Pinder, Piroli, Alba, Irimar, P Posso, Veronica Nf Queiroz, Yosef, S Rabbu, Robert, Rabenalt, Stefano, Romagnoli, Ariel, Ronen, Felipe, Rothman, Patrick, Rusagara, Andrea, Russo, Moldovan, Sabov, Thomas, Saitta, Nirav, Shah, Neil, Smith, Liliana, Sollazzi, Juraj, Sprung, Emma, Stewart, Elizabeth, Stones, Kim, Storton, Beatriz, Tena, Eleonora, Terreni, Alexandre, Teruya, Chiara, Travaglia, Tanja, A Treschan, Henk, Vanoverschelde, Harish, Venkatesh, Marcos, F Vidal Melo, Gianluca, Villa, Robbert, Vossen, Stephen, Webber, Toby, N Weingarten, Matt, Willcocks, Luke, Winslow, and Lindsey, Woods

Subjects
intraoperative ventilation, robotic surgery, postoperative pulmonary complications, abdominal surgery, robotic-assisted surgery
Published
2021

8. Sirt1 Promotes a Thermogenic Gene Program in Bone Marrow Adipocytes: From Mice to (Wo)Men

Author

Einav Cohen-Kfir, Ori Safran, Rivka Dresner-Pollak, Gal Ben Shalom, Ralph Müller, Leonid Kandel, Hanna Artsi, Gisela A. Kuhn, Irina Gurt, Eva Abramowitz, and Madi El-Haj

Subjects
0301 basic medicine, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Adipose tissue, 030209 endocrinology & metabolism, lcsh:Diseases of the endocrine glands. Clinical endocrinology, sirtuin1, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Adipocyte, Internal medicine, medicine, Original Research, PRDM16, lcsh:RC648-665, PGC1-alpha, Chemistry, bone marrow mesenchymal stem cells, TFAM, marrow adipose tissue, 030104 developmental biology, Primary bone, medicine.anatomical_structure, thermogenic genes, Sclerostin, PPARGC1A, Bone marrow
Abstract

Bone marrow adipose tissue (MAT) is influenced by nutritional cues, and participates in whole body energy metabolism. To investigate the role of Sirtuin1 (Sirt1), a key player in metabolism, in MAT, marrow adiposity was evaluated in inbred 5-month-old 129/Sv Sirt1 haplo-insufficient (Sirt1Δ/+) and wild type (WT) mice. Decreased expression of the thermogenic genes: Prdm16, Pgc1α, Foxc2, Dio2, and β3AR was detected in whole tibiae derived from Sirt1Δ/+ compared to WT female mice. Similarly, decreased expression of Prdm16 and Pgc1α was observed in primary bone marrow mesenchymal stem cell (BM-MSC) cultures obtained from Sirt1Δ/+ compared to WT female mice, suggesting a cell autonomous effect of Sirt1 in BM-MSCs. In vitro, Sirt1 over-expression in the mesenchymal embryonic fibroblast stem cell line C3HT101/2 increased Pgc1α and Prdm16 protein level. Similarly, pharmacologic activation of Sirt1 by SRT3025 increased Foxc2, Pgc1α, Dio2, Tfam, and Cyc1 expression while inhibition of Sirt1 by EX527 down-regulated UCP1 in C3HT101/2 cells. Importantly, in human femoral BM-MSCs obtained from female patients undergoing hip operations for fracture or osteoarthritis, Sirt1 activation by SRT3025 increased PGC1α mRNA and protein level. Blocking sclerostin, an inhibitor of the WNT pathway and a Sirt1 target, by the monoclonal humanized antibody (Sc-AbII), stimulated β3AR, PRDM16, and UCP1 gene expression, and increased PGC1α protein level. These results show that Sirt1 stimulates a thermogenic gene program in marrow adipocytes in mice and humans via PGC1α activation and sclerostin inhibition. The implications of these findings to bone health, hematopoiesis and whole body energy metabolism remain to be investigated., Frontiers in Endocrinology, 10, ISSN:1664-2392

Published
2019

10. Reduced Sirtuin1 expression at the femoral neck in women who sustained an osteoporotic hip fracture

Author

Rivka Dresner-Pollak, O Yakubovsky, V Dixit, Irina Gurt, Leonid Kandel, Madi El-Haj, Hanna Artsi, Einav Cohen-Kfir, and Ori Safran

Subjects
Genetic Markers, 0301 basic medicine, medicine.medical_specialty, Bone density, Lymphoid Enhancer-Binding Factor 1, Medial cortex, Arthroplasty, Replacement, Hip, Endocrinology, Diabetes and Metabolism, Osteoporosis, Urology, Osteoarthritis, 03 medical and health sciences, chemistry.chemical_compound, Sirtuin 1, Bone Density, medicine, Humans, Femur, Adaptor Proteins, Signal Transducing, Aged, Femoral neck, Aged, 80 and over, Extracellular Matrix Proteins, Hip fracture, Femur Neck, Hip Fractures, business.industry, Phosphoproteins, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, chemistry, Bone Morphogenetic Proteins, Sclerostin, Female, business, Osteoporotic Fractures
Abstract

To investigate the role of Sirtuin1 in osteoporosis, Sirtuin1 was determined at the femoral neck in female patients undergoing hip operation for fractured hip or osteoarthritis. Reduced Sirtuin1 was found in osteoporotic patients. Pharmacologic activation of Sirtuin1 reduced sclerostin, an inhibitor of bone formation. Activation of Sirtuin1 may be a new direction to generate therapies for osteoporosis.The aim of the study are to investigate the role of Sirtuin1 (Sirt1), an anti-aging factor and a player in age-associated diseases, in osteoporotic hip fractures, and test the hypothesis that Sirt1 is a negative regulator of sclerostin, a bone formation inhibitor, in human femoral bone marrow mesenchymal cells (BM-MSCs).Sirt1 and sclerostin were determined by western blot in bone samples obtained intra-operatively from the inferior medial cortex of the femoral neck (calcar region) in female patients undergoing partial hip replacement for fractured neck of femur (N = 10) or hip replacement for osteoarthritis (N = 8) (mean ± SD age 81 ± 8.1 vs. 68 ± 9.3 years; BMI 26.2 ± 3.6 vs. 25.9 ± 7.1 kg/m(2) in osteoporotic and osteoarthritis patients). Calcar thickness and femoral bone mineral density (BMD) were determined preoperatively by X-ray using a digital TraumaCad(™) software and DEXA. Femoral BM-MSCs were collected intra-operatively and treated with SRT3025, a Sirt1 activator. Sclerostin and dentin matrix acidic phosphoprotein (DMP1) were determined by western blot and messenger RNA (mRNA) expression of Lef1 and DMP1 was evaluated by quantitative real-time PCR.Osteoporotic (OP) patients had reduced cortical thickness, femoral neck, and total hip BMD compared to osteoarthritis (OA) patients. Calcar Sirt1 expression was significantly reduced, while sclerostin was markedly increased in OP compared to OA patients. Sirt1 and sclersotin expressions were inversely correlated (r = -0.49, P = 0.047). SRT3025 administration down-regulated sclerostin and up-regulated DMP1 protein level and increased LEF1 and DMP1 mRNA expressions in OP patient-derived BM-MSCs.Reduced femoral neck Sirt1 may play a role in osteoporotic hip fractures in part via influencing local sclerostin expression. The therapeutic potential of Sirt1 activation in osteoporosis warrants further investigation.

Published
2016
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11. The Sirtuin1 Activator SRT3025 Down-Regulates Sclerostin and Rescues Ovariectomy-Induced Bone Loss and Biomechanical Deterioration in Female Mice

Author

Rivka Dresner-Pollak, Einav Cohen-Kfir, Hanna Artsi, Irina Gurt, Alon Bajayo, Yankel Gabet, Noga Kalish, Ron Shahar, and Teresita Bellido

Subjects
medicine.medical_specialty, Anabolism, medicine.drug_class, Ovariectomy, Osteoporosis, Long bone, Down-Regulation, Enzyme Activators, Mice, chemistry.chemical_compound, Endocrinology, Sirtuin 1, Bone Density, Internal medicine, medicine, Animals, Humans, Osteoporosis, Postmenopausal, Adaptor Proteins, Signal Transducing, Glycoproteins, Activator (genetics), medicine.disease, Biomechanical Phenomena, Mice, Inbred C57BL, Osteopenia, medicine.anatomical_structure, chemistry, Estrogen, Osteocyte, Intercellular Signaling Peptides and Proteins, Sclerostin, Female, hormones, hormone substitutes, and hormone antagonists
Abstract

Estrogen deficiency leads to rapid bone loss and skeletal fragility. Sclerostin, encoded by the sost gene, and a product of the osteocyte, is a negative regulator of bone formation. Blocking sclerostin increases bone mass and strength in animals and humans. Sirtuin1 (Sirt1), a player in aging and metabolism, regulates bone mass and inhibits sost expression by deacetylating histone 3 at its promoter. We asked whether a Sirt1-activating compound could rescue ovariectomy (OVX)-induced bone loss and biomechanical deterioration in 9-week-old C57BL/6 mice. OVX resulted in a substantial decrease in skeletal Sirt1 expression accompanied by an increase in sclerostin. Oral administration of SRT3025, a Sirt1 activator, at 50 and 100 mg/kg·d for 6 weeks starting 6 weeks after OVX fully reversed the deleterious effects of OVX on vertebral bone mass, microarchitecture, and femoral biomechanical properties. Treatment with SRT3025 decreased bone sclerostin expression and increased cortical periosteal mineralizing surface and serum propeptide of type I procollagen, a bone formation marker. In vitro, in the murine long bone osteocyte-Y4 osteocyte-like cell line SRT3025 down-regulated sclerostin and inactive β-catenin, whereas a reciprocal effect was observed with EX-527, a Sirt1 inhibitor. Sirt1 activation by Sirt1-activating compounds is a potential novel pathway to down-regulate sclerostin and design anabolic therapies for osteoporosis concurrently ameliorating other metabolic and age-associated conditions.

Published
2014
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12. Sirt1 is a regulator of bone mass and a repressor of Sost encoding for sclerostin, a bone formation inhibitor

Author

Einav Cohen-Kfir, Hanna Artsi, Alon Bajayo, Avi Levin, Irina Gurt, Lei Zhong, Debra Toiber, Agustina D’Urso, Raul Mostoslavsky, Rivka Dresner-Pollak, and Eva Abramowitz

Subjects
Bone sialoprotein, medicine.medical_specialty, Bone density, Repressor, chemistry.chemical_compound, Mice, Endocrinology, Sirtuin 1, Bone Density, Bone Marrow, Osteogenesis, Internal medicine, medicine, Animals, Germ-Line Mutation, Adaptor Proteins, Signal Transducing, Glycoproteins, Regulation of gene expression, biology, Mesenchymal Stem Cells, enzymes and coenzymes (carbohydrates), medicine.anatomical_structure, chemistry, Gene Expression Regulation, Osteocalcin, biology.protein, Sclerostin, Intercellular Signaling Peptides and Proteins, Osteoporosis, Female, Bone marrow, Chromatin immunoprecipitation, hormones, hormone substitutes, and hormone antagonists
Abstract

Sirt1, the mammalian ortholog of the yeast Sir2 (silent information regulator 2), was shown to play an important role in metabolism and in age-associated diseases, but its role in skeletal homeostasis and osteoporosis has yet not been studied. Using 129/Sv mice with a germline mutation in the Sirt1 gene, we demonstrate that Sirt1 haplo-insufficient (Sirt1+/−) female mice exhibit a significant reduction in bone mass characterized by decreased bone formation and increased marrow adipogenesis. Importantly, we identify Sost, encoding for sclerostin, a critical inhibitor of bone formation, as a novel target of Sirt1. Using chromatin immunoprecipitation analysis, we reveal that Sirt1 directly and negatively regulates Sost gene expression by deacetylating histone 3 at lysine 9 at the Sost promoter. Sost down-regulation by small interfering RNA and the administration of a sclerostin-neutralizing antibody restore gene expression of osteocalcin and bone sialoprotein as well as mineralized nodule formation in Sirt1+/− marrow-derived mesenchymal stem cells induced to osteogenesis. These findings reveal a novel role for Sirt1 in bone as a regulator of bone mass and a repressor of sclerostin, and have potential implications suggesting that Sirt1 is a target for promoting bone formation as an anabolic approach for treatment of osteoporosis.

Published
2011

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