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101. Maternal low-protein diet during mouse pre-implantation development induces vascular dysfunction and altered renin–angiotensin-system homeostasis in the offspring

Author

Watkins, Adam J., primary, Lucas, Emma S., additional, Torrens, Christopher, additional, Cleal, Jane K., additional, Green, Lauren, additional, Osmond, Clive, additional, Eckert, Judith J., additional, Gray, William P., additional, Hanson, Mark A., additional, and Fleming, Tom P., additional

Published
2010
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107. Adaptive Responses by Mouse Early Embryos to Maternal Diet Protect Fetal Growth but Predispose to Adult Onset Disease1

Author

Watkins, Adam J., primary, Ursell, Elizabeth, additional, Panton, Rose, additional, Papenbrock, Thomas, additional, Hollis, Lisa, additional, Cunningham, Colm, additional, Wilkins, Adrian, additional, Perry, V. Hugh, additional, Sheth, Bhavwanti, additional, Kwong, Wing Yee, additional, Eckert, Judith J., additional, Wild, Arthur E., additional, Hanson, Mark A., additional, Osmond, Clive, additional, and Fleming, Tom P., additional

Published
2008
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108. Epigenetic regulation of histone modifications and Gata6 gene expression induced by maternal diet in mouse embryoid bodies in a model of developmental programming.

Author

Congshan Sun, Denisenko, Oleg, Sheth, Bhavwanti, Cox, Andy, Lucas, Emma S., Smyth, Neil R., and Fleming, Tom P.

Subjects
EPIGENETICS, HISTONE deacetylase, ENDODERM, CELL lines, BLASTOCYST, PHYSIOLOGY
Abstract

Background Dietary interventions during pregnancy alter offspring fitness. We have shown mouse maternal low protein diet fed exclusively for the preimplantation period (Emb-LPD) before return to normal protein diet (NPD) for the rest of gestation, is sufficient to cause adult offspring cardiovascular and metabolic disease. Moreover, Emb-LPD blastocysts sense altered nutrition within the uterus and activate compensatory cellular responses including stimulated endocytosis within extra-embryonic trophectoderm and primitive endoderm (PE) lineages to protect fetal growth rate. However, these responses associate with later disease. Here, we investigate epigenetic mechanisms underlying nutritional programming of PE that may contribute to its altered phenotype, stabilised during subsequent development. We use embryonic stem (ES) cell lines established previously from Emb-LPD and NPD blastocysts that were differentiated into embryoid bodies (EBs) with outer PE-like layer. Results Emb-LPD EBs grow to a larger size than NPD EBs and express reduced Gata6 transcription factor (regulator of PE differentiation) at mRNA and protein levels, similar to Emb-LPD PE derivative visceral yolk sac tissue in vivo in later gestation. We analysed histone modifications at the Gata6 promoter in Emb-LPD EBs using chromatin immunoprecipitation assay. We found significant reduction in histone H3 and H4 acetylation and RNA polymerase II binding compared with NPD EBs, all markers of reduced transcription. Other histone modifications, H3K4Me2, H3K9Me3 and H3K27Me3, were unaltered. A similar but generally non-significant histone modification pattern was found on the Gata4 promoter. Consistent with these changes, histone deacetylase Hdac-1, but not Hdac-3, gene expression was upregulated in Emb-LPD EBs. Conclusions First, these data demonstrate ES cells and EBs retain and propagate nutritional programming adaptations in vitro, suitable for molecular analysis of mechanisms, reducing animal use. Second, they reveal maternal diet induces persistent changes in histone modifications to regulate Gata6 expression and PE growth and differentiation that may affect lifetime health. [ABSTRACT FROM AUTHOR]

Published
2015
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112. The Embryo and Its Future1

Author

Fleming, Tom P., primary, Kwong, Wing Yee, additional, Porter, Richard, additional, Ursell, Elizabeth, additional, Fesenko, Irina, additional, Wilkins, Adrian, additional, Miller, Daniel J., additional, Watkins, Adam J., additional, and Eckert, Judith J., additional

Published
2004
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119. Tight Junctions during Development.

Author

Gonzalez-Mariscal, Lorenza, Sheth, Bhavwanti, Eckert, Judith, Thomas, Fay, and Fleming, Tom P.

Abstract

During early development, tight junction biogenesis and the differentiation of the first epithelium in the blastocyst is critical for embryonic patterning and organization. Here, we discuss the programme of exactly timed transcription, translation, and post-translational modification of specific junctional proteins that regulates the stepwise membrane assembly of tight junctions during cleavage in the mouse model. Underlying mechanisms that coordinate these processes are discussed along with newly emerging data from other mammalian species. In the mouse embryo, junction assembly follows the establishment of cell polarity at the 8-cell stage and is characterized by sequential membrane delivery of JAM-1, ZO-1α− and Rab13, cingulin and ZO-2 followed by ZO-1α+ and occludin. Tight junction assembly occurs over three developmental stages; compaction, first differentiative division and cavitation. Post-translational modification of occludin, the late expression of ZO-1α+ isoform and their intracellular colocalisation may all contribute to the rapid coordinated delivery of these two proteins to the membrane, resulting in the final sealing of the tight junction followed by blastocoel cavitation. This coordinated delivery of these two tight junction-associated proteins may therefore provide a rate limiting step for the sealing of tight junctions and regulated timing of blastocoel cavitation. Taken together, our studies in mouse, human and bovine embryos suggest that defects in the tightly controlled programming of early development may contribute to reduced embryo viability. [ABSTRACT FROM AUTHOR]

Published
2006
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122. Global, regional, and national levels of maternal mortality, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015

Author

Kassebaum, Nicholas J, Barber, Ryan M, Bhutta, Zulfiqar A, Dandona, Lalit, Gething, Peter W, Hay, Simon I, Kinfu, Yohannes, Larson, Heidi J, Liang, Xiaofeng, Lim, Stephen S, Lopez, Alan D, Lozano, Rafael, Mensah, George A, Mokdad, Ali H, Naghavi, Mohsen, Pinho, Christine, Salomon, Joshua A, Steiner, Caitlyn, Vos, Theo, Wang, Haidong, Abajobir, Amanuel Alemu, Abate, Kalkidan Hassen, Abbas, Kaja M, Abd-Allah, Foad, Abdallat, Mahmud A, Abdulle, Abdishakur M, Abera, Semaw Ferede, Aboyans, Victor, Abubakar, Ibrahim, Abu-Rmeileh, Niveen M E, Achoki, Tom, Adebiyi, Akindele Olupelumi, Adedeji, Isaac Akinkunmi, Adelekan, Ademola Lukman, Adou, Arsène Kouablan, Afanvi, Kossivi Agbelenko, Agarwal, Arnav, Kiadaliri, Aliasghar Ahmad, Ajala, Oluremi N, Akinyemiju, Tomi F, Akseer, Nadia, Al-Aly, Ziyad, Alam, Khurshid, Alam, Noore K M, Alasfoor, Deena, Aldhahri, Saleh Fahed, Aldridge, Robert William, Alhabib, Samia, Ali, Raghib, Alkerwi, Ala'a, Alla, François, Al-Raddadi, Rajaa, Alsharif, Ubai, Martin, Elena Alvarez, Alvis-Guzman, Nelson, Amare, Azmeraw T, Amberbir, Alemayehu, Amegah, Adeladza Kofi, Ammar, Walid, Amrock, Stephen Marc, Andersen, Hjalte H, Anderson, Gregory M, Antoine, Rose Mayerline, Antonio, Carl Abelardo T, Aregay, Atsede Fantahun, Ärnlöv, Johan, Arora, Megha, Arsenijevic, Valentina S Arsic, Artaman, Al, Asayesh, Hamid, Atique, Suleman, Avokpaho, Euripide Frinel G Arthur, Awasthi, Ashish, Quintanilla, Beatriz Paulina Ayala, Azzopardi, Peter, Bacha, Umar, Badawi, Alaa, Bahit, Maria C, Balakrishnan, Kalpana, Banerjee, Amitava, Barac, Aleksandra, Barker-Collo, Suzanne L, Bärnighausen, Till, Basu, Sanjay, Bayou, Tigist Assefa, Bayou, Yibeltal Tebekaw, Bazargan-Hejazi, Shahrzad, Beardsley, Justin, Wang, Neeraj Haidong, Bedi, Bekele, Tolesa, Bell, Michelle L, Bennett, Derrick A, Bensenor, Isabela M, Berhane, Adugnaw, Bernabé, Eduardo, Betsu, Balem Demtsu, Beyene, Addisu Shunu, Biadgilign, Sibhatu, Bikbov, Boris, Abdulhak, Aref A Bin, Biroscak, Brian J, Biryukov, Stan, Bisanzio, Donal, Bjertness, Espen, Blore, Jed D, Brainin, Michael, Brazinova, Alexandra, Breitborde, Nicholas J K, Brugha, Traolach S, Butt, Zahid A, Campos-Nonato, Ismael Ricardo, Campuzano, Julio Cesar, Cárdenas, Rosario, Carrero, Juan Jesus, Carter, Austin, Casey, Daniel C, Castañeda-Orjuela, Carlos A, Castro, Ruben Estanislao, Catalá-López, Ferrán, Cavalleri, Fiorella, Chang, Hsing-Yi, Chang, Jung-Chen, Chavan, Laxmikant, Chibueze, Chioma Ezinne, Chisumpa, Vesper Hichilombwe, Choi, Jee-Young Jasmine, Chowdhury, Rajiv, Christopher, Devasahayam Jesudas, Ciobanu, Liliana G, Cirillo, Massimo, Coates, Matthew M, Coggeshall, Megan, Colistro, Valentina, Colquhoun, Samantha M, Cooper, Cyrus, Cooper, Leslie Trumbull, Cortinovis, Monica, Dahiru, Tukur, Damasceno, Albertino, Danawi, Hadi, Dandona, Rakhi, das Neves, José, Leo, Diego De, Dellavalle, Robert P, Deribe, Kebede, Deribew, Amare, Des Jarlais, Don C, Dharmaratne, Samath D, Dicker, Daniel J, Ding, Eric L, Dossou, Edem, Dubey, Manisha, Ebel, Beth E, Ellingsen, Christian Lycke, Elyazar, Iqbal, Endries, Aman Yesuf, Ermakov, Sergey Petrovich, Eshrati, Babak, Esteghamati, Alireza, Faraon, Emerito Jose Aquino, Farid, Talha A, Farinha, Carla Sofia e Sa, Faro, André, Farvid, Maryam S, Farzadfar, Farshad, Fereshtehnejad, Seyed-Mohammad, Fernandes, Joao C, Fischer, Florian, Fitchett, Joseph R A, Fleming, Tom, Foigt, Nataliya, Franca, Elisabeth Barboza, Franklin, Richard C, Fraser, Maya S, Friedman, Joseph, Fullman, Nancy, Fürst, Thomas, Futran, Neal D, Gambashidze, Ketevan, Gamkrelidze, Amiran, Gebre, Teshome, Gebrehiwot, Tsegaye Tewelde, Gebremedhin, Amanuel Tesfay, Gebremedhin, Mengistu, Gebru, Alemseged Aregay, Geleijnse, Johanna M, Gibney, Katherine B, Giref, Ababi Zergaw, Giroud, Maurice, Gishu, Melkamu Dedefo, Glaser, Elizabeth, Goenka, Shifalika, Gomez-Dantes, Hector, Gona, Philimon, Goodridge, Amador, Gopalani, Sameer Vali, Goto, Atsushi, Graetz, Nicholas, Gugnani, Harish Chander, Guo, Yuming, Gupta, Rahul, Gupta, Rajeev, Gupta, Vipin, Hafezi-Nejad, Nima, Hailu, Alemayehu Desalegne, Hailu, Gessessew Bugssa, Hamadeh, Randah Ribhi, Hamidi, Samer, Hancock, Jamie, Handal, Alexis J, Hankey, Graeme J, Harb, Hilda L, Harikrishnan, Sivadasanpillai, Harun, Kimani M, Havmoeller, Rasmus, Hoek, Hans W, Horino, Masako, Horita, Nobuyuki, Hosgood, H Dean, Hoy, Damian G, Htet, Aung Soe, Hu, Guoqing, Huang, Hsiang, Huang, John J, Huybrechts, Inge, Huynh, Chantal, Iannarone, Marissa, Iburg, Kim Moesgaard, Idrisov, Bulat T, Iyer, Veena J, Jacobsen, Kathryn H, Jahanmehr, Nader, Jakovljevic, Mihajlo B, Javanbakht, Mehdi, Jayatilleke, Achala Upendra, Jee, Sun Ha, Jeemon, Panniyammakal, Jha, Vivekanand, Jiang, Guohong, Jiang, Ying, Jibat, Tariku, Jonas, Jost B, Kabir, Zubair, Kamal, Ritul, Kan, Haidong, Karch, André, Karletsos, Dimitris, Kasaeian, Amir, Kaul, Anil, Kawakami, Norito, Kayibanda, Jeanne Françoise, Kazanjan, Konstantin, Kazi, Dhruv S, Keiyoro, Peter Njenga, Kemmer, Laura, Kemp, Andrew Haddon, Kengne, Andre Pascal, Keren, Andre, Kereselidze, Maia, Kesavachandran, Chandrasekharan Nair, Khader, Yousef Saleh, Khan, Abdur Rahman, Khan, Ejaz Ahmad, Khang, Young-Ho, Khonelidze, Irma, Khosravi, Ardeshir, Khubchandani, Jagdish, Kim, Yun Jin, Kivipelto, Miia, Knibbs, Luke D, Kokubo, Yoshihiro, Kosen, Soewarta, Koul, Parvaiz A, Koyanagi, Ai, Krishnaswami, Sanjay, Defo, Barthelemy Kuate, Bicer, Burcu Kucuk, Kudom, Andreas A, Kulikoff, Xie Rachel, Kulkarni, Chanda, Kumar, G Anil, Kutz, Michael J, Lal, Dharmesh Kumar, Lalloo, Ratilal, Lam, Hilton, Lamadrid-Figueroa, Hector, Lan, Qing, Larsson, Anders, Laryea, Dennis Odai, Leigh, James, Leung, Ricky, Li, Yichong, Li, Yongmei, Lipshultz, Steven E, Liu, Patrick Y, Liu, Shiwei, Liu, Yang, Lloyd, Belinda K, Lotufo, Paulo A, Lunevicius, Raimundas, Ma, Stefan, Razek, Hassan Magdy Abd El, Razek, Mohammed Magdy Abd El, Majdan, Marek, Majeed, Azeem, Malekzadeh, Reza, Mapoma, Chabila C, Marcenes, Wagner, Margolis, David Joel, Marquez, Neal, Masiye, Felix, Marzan, Melvin Barrientos, Mason-Jones, Amanda J, Mazorodze, Tasara T, Meaney, Peter A, Mehari, Alem, Mehndiratta, Man Mohan, Mejia-Rodriguez, Fabiola, Mekonnen, Alemayehu B, Melaku, Yohannes Adama, Memish, Ziad A, Mendoza, Walter, Meretoja, Atte, Meretoja, Tuomo J, Mhimbira, Francis Apolinary, Miller, Ted R, Mills, Edward J, Mirarefin, Mojde, Misganaw, Awoke, Ibrahim, Norlinah Mohamed, Mohammad, Karzan Abdulmuhsin, Mohammadi, Alireza, Mohammed, Shafiu, Mola, Glen Liddell D, Monasta, Lorenzo, de la Cruz Monis, Jonathan, Hernandez, Julio Cesar Montañez, Montero, Pablo, Montico, Marcella, Mooney, Meghan D, Moore, Ami R, Moradi-Lakeh, Maziar, Morawska, Lidia, Mori, Rintaro, Mueller, Ulrich O, Murthy, Gudlavalleti Venkata Satyanarayana, Murthy, Srinivas, Nachega, Jean B, Naheed, Aliya, Naldi, Luigi, Nand, Devina, Nangia, Vinay, Nash, Denis, Neupane, Subas, Newton, John N, Ng, Marie, Ngalesoni, Frida Namnyak, Nguhiu, Peter, Nguyen, Grant, Nguyen, Quyen Le, Nisar, Muhammad Imran, Nomura, Marika, Norheim, Ole F, Norman, Rosana E, Nyakarahuka, Luke, Obermeyer, Carla Makhlouf, Ogbo, Felix Akpojene, Oh, In-Hwan, Ojelabi, Foluke Adetola, Olivares, Pedro R, Olusanya, Bolajoko Olubukunola, Olusanya, Jacob Olusegun, Opio, John Nelson, Oren, Eyal, Ota, Erika, Oyekale, Abayomi Samuel, PA, Mahesh, Pain, Amanda, Papantoniou, Nikolaos, Park, Eun-Kee, Park, Hye-Youn, Caicedo, Angel J Paternina, Patten, Scott B, Paul, Vinod K, Pereira, David M, Perico, Norberto, Pesudovs, Konrad, Petzold, Max, Phillips, Michael Robert, Pillay, Julian David, Pishgar, Farhad, Polinder, Suzanne, Pope, Daniel, Pourmalek, Farshad, Qorbani, Mostafa, Rafay, Anwar, Rahimi, Kazem, Rahimi-Movaghar, Vafa, Rahman, Mahfuzar, Rahman, Mohammad Hifz Ur, Rahman, Sajjad Ur, Rai, Rajesh Kumar, Ram, Usha, Ranabhat, Chhabi Lal, Rangaswamy, Thara, Rao, Paturi Vishnupriya, Refaat, Amany H, Remuzzi, Giuseppe, Resnikoff, Serge, Rojas-Rueda, David, Ronfani, Luca, Roshandel, Gholamreza, Roy, Ambuj, Ruhago, George Mugambage, Sagar, Rajesh, Saleh, Muhammad Muhammad, Sanabria, Juan R, Sanchez-Niño, Maria Dolores, Santos, Itamar S, Santos, Joao Vascos, Sarmiento-Suarez, Rodrigo, Sartorius, Benn, Satpathy, Maheswar, Savic, Miloje, Sawhney, Monika, Saylan, Mete I, Schneider, Ione J C, Schwebel, David C, Seedat, Soraya, Sepanlou, Sadaf G, Servan-Mori, Edson E, Setegn, Tesfaye, Shackelford, Katya A, Shaikh, Masood Ali, Shakh-Nazarova, Marina, Sharma, Rajesh, She, Jun, Sheikhbahaei, Sara, Shen, Jiabin, Shibuya, Kenji, Shin, Min-Jeong, Shiri, Rahman, Shishani, Kawkab, Shiue, Ivy, Sigfusdottir, Inga Dora, Silpakit, Naris, Silva, Diego Augusto Santos, Silveira, Dayane Gabriele Alves, Silverberg, Jonathan I, Simard, Edgar P, Sindi, Shireen, Singh, Abhishek, Singh, Jasvinder A, Singh, Om Prakash, Singh, Prashant Kumar, Singh, Virendra, Skirbekk, Vegard, Sligar, Amber, Sliwa, Karen, Smith, Jessica M, Soneji, Samir, Sorensen, Reed J D, Soriano, Joan B, Soshnikov, Sergey, Sposato, Luciano A, Sreeramareddy, Chandrashekhar T, Stathopoulou, Vasiliki, Stroumpoulis, Konstantinos, Sturua, Lela, Sunguya, Bruno F, Swaminathan, Soumya, Sykes, Bryan L, Szoeke, Cassandra E I, Tabarés-Seisdedos, Rafael, Tabb, Karen M, Talongwa, Roberto Tchio, Tavakkoli, Mohammad, Taye, Bineyam, Tedla, Bemnet Amare, Tefera, Worku Mekonnen, Tekle, Tesfaye, Shifa, Girma Temam, Terkawi, Abdullah Sulieman, Tesfay, Fisaha Haile, Tessema, Gizachew Assefa, Thomson, Alan J, Thorne-Lyman, Andrew L, Tobe-Gai, Ruoyan, Topor-Madry, Roman, Towbin, Jeffrey Allen, Tran, Bach Xuan, Dimbuene, Zacharie Tsala, Tura, Abera Kenay, Tyrovolas, Stefanos, Ukwaja, Kingsley N, Uthman, Olalekan A, Vasankari, Tommi, Venketasubramanian, Narayanaswamy, Violante, Francesco S, Vladimirov, Sergey K, Vlassov, Vasiliy Victorovich, Vollset, Stein Emil, Wagner, Joseph A, Wang, Linhong, Weichenthal, Scott, Weiderpass, Elisabete, Weintraub, Robert G, Werdecker, Andrea, Westerman, Ronny, Wijeratne, Tissa, Wilkinson, James D, Wiysonge, Charles Shey, Woldeyohannes, Solomon Meseret, Wolfe, Charles D A, Wolock, Timothy, Won, Sungho, Wubshet, Mamo, Xiao, Qingyang, Xu, Gelin, Yadav, Ajit Kumar, Yakob, Bereket, Yalew, Ayalnesh Zemene, Yano, Yuichiro, Yebyo, Henock Gebremedhin, Yip, Paul, Yonemoto, Naohiro, Yoon, Seok-Jun, Younis, Mustafa Z, Yu, Chuanhua, Yu, Shicheng, Zaidi, Zoubida, Zaki, Maysaa El Sayed, Zeeb, Hajo, Zhao, Yi, Zhao, Yong, Zhou, Maigeng, Zodpey, Sanjay, Zuhlke, Liesl Joanna, and Murray, Christopher J L

Abstract

In transitioning from the Millennium Development Goal to the Sustainable Development Goal era, it is imperative to comprehensively assess progress toward reducing maternal mortality to identify areas of success, remaining challenges, and frame policy discussions. We aimed to quantify maternal mortality throughout the world by underlying cause and age from 1990 to 2015.

Published
2016
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123. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015

Author

Vos, Theo, Allen, Christine, Arora, Megha, Barber, Ryan M, Bhutta, Zulfiqar A, Brown, Alexandria, Carter, Austin, Casey, Daniel C, Charlson, Fiona J, Chen, Alan Z, Coggeshall, Megan, Cornaby, Leslie, Dandona, Lalit, Dicker, Daniel J, Dilegge, Tina, Erskine, Holly E, Ferrari, Alize J, Fitzmaurice, Christina, Fleming, Tom, Forouzanfar, Mohammad H, Fullman, Nancy, Gething, Peter W, Goldberg, Ellen M, Graetz, Nicholas, Haagsma, Juanita A, Hay, Simon I, Johnson, Catherine O, Kassebaum, Nicholas J, Kawashima, Toana, Kemmer, Laura, Khalil, Ibrahim A, Kinfu, Yohannes, Kyu, Hmwe H, Leung, Janni, Liang, Xiaofeng, Lim, Stephen S, Lopez, Alan D, Lozano, Rafael, Marczak, Laurie, Mensah, George A, Mokdad, Ali H, Naghavi, Mohsen, Nguyen, Grant, Nsoesie, Elaine, Olsen, Helen, Pigott, David M, Pinho, Christine, Rankin, Zane, Reinig, Nikolas, Salomon, Joshua A, Sandar, Logan, Smith, Alison, Stanaway, Jeffrey, Steiner, Caitlyn, Teeple, Stephanie, Thomas, Bernadette A, Troeger, Christopher, Wagner, Joseph A, Wang, Haidong, Wanga, Valentine, Whiteford, Harvey A, Zoeckler, Leo, Abajobir, Amanuel Alemu, Abate, Kalkidan Hassen, Abbafati, Cristiana, Abbas, Kaja M, Abd-Allah, Foad, Abraham, Biju, Abubakar, Ibrahim, Abu-Raddad, Laith J, Abu-Rmeileh, Niveen M E, Ackerman, Ilana N, Adebiyi, Akindele Olupelumi, Ademi, Zanfina, Adou, Arsène Kouablan, Afanvi, Kossivi Agbelenko, Agardh, Emilie Elisabet, Agarwal, Arnav, Kiadaliri, Aliasghar Ahmad, Ahmadieh, Hamid, Ajala, Oluremi N, Akinyemi, Rufus Olusola, Akseer, Nadia, Al-Aly, Ziyad, Alam, Khurshid, Alam, Noore K M, Aldhahri, Saleh Fahed, Alegretti, Miguel Angel, Alemu, Zewdie Aderaw, Alexander, Lily T, Alhabib, Samia, Ali, Raghib, Alkerwi, Ala'a, Alla, François, Allebeck, Peter, Al-Raddadi, Rajaa, Alsharif, Ubai, Altirkawi, Khalid A, Alvis-Guzman, Nelson, Amare, Azmeraw T, Amberbir, Alemayehu, Amini, Heresh, Ammar, Walid, Amrock, Stephen Marc, Andersen, Hjalte H, Anderson, Gregory M, Anderson, Benjamin O, Antonio, Carl Abelardo T, Aregay, Atsede Fantahun, Ärnlöv, Johan, Artaman, Al, Asayesh, Hamid, Assadi, Reza, Atique, Suleman, Avokpaho, Euripide Frinel G Arthur, Awasthi, Ashish, Quintanilla, Beatriz Paulina Ayala, Azzopardi, Peter, Bacha, Umar, Badawi, Alaa, Balakrishnan, Kalpana, Banerjee, Amitava, Barac, Aleksandra, Barker-Collo, Suzanne L, Bärnighausen, Till, Barregard, Lars, Barrero, Lope H, Basu, Arindam, Bazargan-Hejazi, Shahrzad, Beghi, Ettore, Bell, Brent, Bell, Michelle L, Bennett, Derrick A, Bensenor, Isabela M, Benzian, Habib, Berhane, Adugnaw, Bernabé, Eduardo, Betsu, Balem Demtsu, Beyene, Addisu Shunu, Bhala, Neeraj, Bhatt, Samir, Biadgilign, Sibhatu, Bienhoff, Kelly, Bikbov, Boris, Biryukov, Stan, Bisanzio, Donal, Bjertness, Espen, Blore, Jed, Borschmann, Rohan, Boufous, Soufiane, Brainin, Michael, Brazinova, Alexandra, Breitborde, Nicholas J K, Brown, Jonathan, Buchbinder, Rachelle, Buckle, Geoffrey Colin, Butt, Zahid A, Calabria, Bianca, Campos-Nonato, Ismael Ricardo, Campuzano, Julio Cesar, Carabin, Hélène, Cárdenas, Rosario, Carpenter, David O, Carrero, Juan Jesus, Castañeda-Orjuela, Carlos A, Rivas, Jacqueline Castillo, Catalá-López, Ferrán, Chang, Jung-Chen, Chiang, Peggy Pei-Chia, Chibueze, Chioma Ezinne, Chisumpa, Vesper Hichilombwe, Choi, Jee-Young Jasmine, Chowdhury, Rajiv, Christensen, Hanne, Christopher, Devasahayam Jesudas, Ciobanu, Liliana G, Cirillo, Massimo, Coates, Matthew M, Colquhoun, Samantha M, Cooper, Cyrus, Cortinovis, Monica, Crump, John A, Damtew, Solomon Abrha, Dandona, Rakhi, Daoud, Farah, Dargan, Paul I, das Neves, José, Davey, Gail, Davis, Adrian C, Leo, Diego De, Degenhardt, Louisa, Gobbo, Liana C Del, Dellavalle, Robert P, Deribe, Kebede, Deribew, Amare, Derrett, Sarah, Jarlais, Don C Des, Dharmaratne, Samath D, Dhillon, Preet K, Diaz-Torné, Cesar, Ding, Eric L, Driscoll, Tim R, Duan, Leilei, Dubey, Manisha, Duncan, Bruce Bartholow, Ebrahimi, Hedyeh, Ellenbogen, Richard G, Elyazar, Iqbal, Endres, Matthias, Endries, Aman Yesuf, Ermakov, Sergey Petrovich, Eshrati, Babak, Estep, Kara, Farid, Talha A, Farinha, Carla Sofia e Sa, Faro, André, Farvid, Maryam S, Farzadfar, Farshad, Feigin, Valery L, Felson, David T, Fereshtehnejad, Seyed-Mohammad, Fernandes, Jefferson G, Fernandes, Joao C, Fischer, Florian, Fitchett, Joseph R A, Foreman, Kyle, Fowkes, F Gerry R, Fox, Jordan, Franklin, Richard C, Friedman, Joseph, Frostad, Joseph, Fürst, Thomas, Futran, Neal D, Gabbe, Belinda, Ganguly, Parthasarathi, Gankpé, Fortuné Gbètoho, Gebre, Teshome, Gebrehiwot, Tsegaye Tewelde, Gebremedhin, Amanuel Tesfay, Geleijnse, Johanna M, Gessner, Bradford D, Gibney, Katherine B, Ginawi, Ibrahim Abdelmageem Mohamed, Giref, Ababi Zergaw, Giroud, Maurice, Gishu, Melkamu Dedefo, Giussani, Giorgia, Glaser, Elizabeth, Godwin, William W, Gomez-Dantes, Hector, Gona, Philimon, Goodridge, Amador, Gopalani, Sameer Vali, Gotay, Carolyn C, Goto, Atsushi, Gouda, Hebe N, Grainger, Rebecca, Greaves, Felix, Guillemin, Francis, Guo, Yuming, Gupta, Rahul, Gupta, Rajeev, Gupta, Vipin, Gutiérrez, Reyna A, Haile, Demewoz, Hailu, Alemayehu Desalegne, Hailu, Gessessew Bugssa, Halasa, Yara A, Hamadeh, Randah Ribhi, Hamidi, Samer, Hammami, Mouhanad, Hancock, Jamie, Handal, Alexis J, Hankey, Graeme J, Hao, Yuantao, Harb, Hilda L, Harikrishnan, Sivadasanpillai, Haro, Josep Maria, Havmoeller, Rasmus, Hay, Roderick J, Heredia-Pi, Ileana Beatriz, Heydarpour, Pouria, Hoek, Hans W, Horino, Masako, Horita, Nobuyuki, Hosgood, H Dean, Hoy, Damian G, Htet, Aung Soe, Huang, Hsiang, Huang, John J, Huynh, Chantal, Iannarone, Marissa, Iburg, Kim Moesgaard, Innos, Kaire, Inoue, Manami, Iyer, Veena J, Jacobsen, Kathryn H, Jahanmehr, Nader, Jakovljevic, Mihajlo B, Javanbakht, Mehdi, Jayaraman, Sudha P, Jayatilleke, Achala Upendra, Jee, Sun Ha, Jeemon, Panniyammakal, Jensen, Paul N, Jiang, Ying, Jibat, Tariku, Jimenez-Corona, Aida, Jin, Ye, Jonas, Jost B, Kabir, Zubair, Kalkonde, Yogeshwar, Kamal, Ritul, Kan, Haidong, Karch, André, Karema, Corine Kakizi, Karimkhani, Chante, Kasaeian, 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Abstract

Non-fatal outcomes of disease and injury increasingly detract from the ability of the world's population to live in full health, a trend largely attributable to an epidemiological transition in many countries from causes affecting children, to non-communicable diseases (NCDs) more common in adults. For the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015), we estimated the incidence, prevalence, and years lived with disability for diseases and injuries at the global, regional, and national scale over the period of 1990 to 2015.

Published
2016
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124. Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015

Author

Forouzanfar, Mohammad H, Afshin, Ashkan, Alexander, Lily T, Anderson, H Ross, Bhutta, Zulfiqar A, Biryukov, Stan, Brauer, Michael, Burnett, Richard, Cercy, Kelly, Charlson, Fiona J, Cohen, Aaron J, Dandona, Lalit, Estep, Kara, Ferrari, Alize J, Frostad, Joseph J, Fullman, Nancy, Gething, Peter W, Godwin, William W, Griswold, Max, Hay, Simon I, Kinfu, Yohannes, Kyu, Hmwe H, Larson, Heidi J, Liang, Xiaofeng, Lim, Stephen S, Liu, Patrick Y, Lopez, Alan D, Lozano, Rafael, Marczak, Laurie, Mensah, George A, Mokdad, Ali H, Moradi-Lakeh, Maziar, Naghavi, Mohsen, Neal, Bruce, Reitsma, Marissa B, Roth, Gregory A, Salomon, Joshua A, Sur, Patrick J, Vos, Theo, Wagner, Joseph A, Wang, Haidong, Zhao, Yi, Zhou, Maigeng, Aasvang, Gunn Marit, Abajobir, Amanuel Alemu, Abate, Kalkidan Hassen, Abbafati, Cristiana, Abbas, Kaja M, Abd-Allah, Foad, Abdulle, Abdishakur M, Abera, Semaw Ferede, Abraham, Biju, Abu-Raddad, Laith J, Abyu, Gebre Yitayih, Adebiyi, Akindele Olupelumi, Adedeji, Isaac Akinkunmi, 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James G, Seedat, Soraya, Sepanlou, Sadaf G, Servan-Mori, Edson E, Shaddick, Gavin, Shaheen, Amira, Shahraz, Saeid, Shaikh, Masood Ali, Levy, Teresa Shamah, Sharma, Rajesh, She, Jun, Sheikhbahaei, Sara, Shen, Jiabin, Sheth, Kevin N, Shi, Peilin, Shibuya, Kenji, Shigematsu, Mika, Shin, Min-Jeong, Shiri, Rahman, Shishani, Kawkab, Shiue, Ivy, Shrime, Mark G, Sigfusdottir, Inga Dora, Silva, Diego Augusto Santos, Silveira, Dayane Gabriele Alves, Silverberg, Jonathan I, Simard, Edgar P, Sindi, Shireen, Singh, Abhishek, Singh, Jasvinder A, Singh, Prashant Kumar, Slepak, Erica Leigh, Soljak, Michael, Soneji, Samir, Sorensen, Reed J D, Sposato, Luciano A, Sreeramareddy, Chandrashekhar T, Stathopoulou, Vasiliki, Steckling, Nadine, Steel, Nicholas, Stein, Dan J, Stein, Murray B, Stöckl, Heidi, Stranges, Saverio, Stroumpoulis, Konstantinos, Sunguya, Bruno F, Swaminathan, Soumya, Sykes, Bryan L, Szoeke, Cassandra E I, Tabarés-Seisdedos, Rafael, Takahashi, Ken, Talongwa, Roberto Tchio, Tandon, Nikhil, Tanne, David, Tavakkoli, Mohammad, Taye, Belaynew Wasie, Taylor, Hugh R, Tedla, Bemnet Amare, Tefera, Worku Mekonnen, Tegegne, Teketo Kassaw, Tekle, Dejen Yemane, Terkawi, Abdullah Sulieman, Thakur, J S, Thomas, Bernadette A, Thomas, Matthew Lloyd, Thomson, Alan J, Thorne-Lyman, Andrew L, Thrift, Amanda G, Thurston, George D, Tillmann, Taavi, Tobe-Gai, Ruoyan, Tobollik, Myriam, Topor-Madry, Roman, Topouzis, Fotis, Towbin, Jeffrey Allen, Tran, Bach Xuan, Dimbuene, Zacharie Tsala, Tsilimparis, Nikolaos, Tura, Abera Kenay, Tuzcu, Emin Murat, Tyrovolas, Stefanos, Ukwaja, Kingsley N, Undurraga, Eduardo A, Uneke, Chigozie Jesse, Uthman, Olalekan A, van Donkelaar, Aaron, van Os, Jim, Varakin, Yuri Y, Vasankari, Tommi, Veerman, J Lennert, Venketasubramanian, Narayanaswamy, Violante, Francesco S, Vollset, Stein Emil, Wagner, Gregory R, Waller, Stephen G, Wang, Jian Li, Wang, Linhong, Wang, Yanping, Weichenthal, Scott, Weiderpass, Elisabete, Weintraub, Robert G, Werdecker, Andrea, Westerman, Ronny, Whiteford, Harvey A, Wijeratne, Tissa, Wiysonge, Charles Shey, Wolfe, Charles D A, Won, Sungho, Woolf, Anthony D, Wubshet, Mamo, Xavier, Denis, Xu, Gelin, Yadav, Ajit Kumar, Yakob, Bereket, Yalew, Ayalnesh Zemene, Yano, Yuichiro, Yaseri, Mehdi, Ye, Pengpeng, Yip, Paul, Yonemoto, Naohiro, Yoon, Seok-Jun, Younis, Mustafa Z, Yu, Chuanhua, Zaidi, Zoubida, Zaki, Maysaa El Sayed, Zhu, Jun, Zipkin, Ben, Zodpey, Sanjay, Zuhlke, Liesl Joanna, and Murray, Christopher J L

Abstract

The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context.

Published
2016
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125. School for sandals.

Author

Fleming, Tom

Abstract

The article focuses on art exhibition "Life with Art: Benton End and the East Anglian School of Painting and Drawing" featuring work of Cedric Morris and Arthur Lett-Haines at Firstsite in Colchester, England from December 11 2021 to April 18, 2022.

Published
2022

129. Mouse early extra-embryonic lineages activate compensatory endocytosis in response to poor maternal nutrition.

Author

Congshan Sun, Velazquez, Miguel A., Marfy-Smith, Stephanie, Sheth, Bhavwanti, Cox, Andy, Johnston, David A., Smyth, Neil, and Fleming, Tom P.

Subjects
MAMMALS, ENDOCYTOSIS, MATERNAL nutrition, BLASTOCYST, FETAL development, YOLK sac
Abstract

Mammalian extra-embryonic lineages perform the crucial role of nutrient provision during gestation to support embryonic and fetal growth. These lineages derive from outer trophectoderm (TE) and internal primitive endoderm (PE) in the blastocyst and subsequently give rise to chorio-allantoic and visceral yolk sac placentae, respectively. We have shown maternal low protein diet exclusively during mouse preimplantation development (Emb-LPD) is sufficient to cause a compensatory increase in fetal and perinatal growth that correlates positively with increased adult-onset cardiovascular, metabolic and behavioural disease. Here, to investigate early mechanisms of compensatory nutrient provision, we assessed the influence of maternal Emb-LPD on endocytosis within extraembryonic lineages using quantitative imaging and expression of markers and proteins involved. Blastocysts collected from Emb-LPD mothers within standard culture medium displayed enhanced TE endocytosis compared with embryos from control mothers with respect to the number and collective volume per cell of vesicles with endocytosed ligand and fluid and lysosomes, plus protein expression of megalin (Lrp2) LDL-family receptor. Endocytosis was also stimulated using similar criteria in the outer PE-like lineage of embryoid bodies formed from embryonic stem cell lines generated from Emb-LPD blastocysts. Using an in vitro model replicating the depleted amino acid (AA) composition found within the Emb-LPD uterine luminal fluid, we show TE endocytosis response is activated through reduced branched-chain AAs (leucine, isoleucine, valine). Moreover, activation appears mediated through RhoA GTPase signalling. Our data indicate early embryos regulate and stabilise endocytosis as a mechanism to compensate for poor maternal nutrient provision. [ABSTRACT FROM AUTHOR]

Published
2014
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133. Mouse embryo culture induces changes in postnatal phenotype including raised systolic blood pressure.

Author

Adam J. Watkins, Platt, Duncan, Papenbrock, Tom, Wilkins, Adrin, Eckert, Judith J., Wing Yee Kwong, Osmond, Clive, Hanson, Mark, and Fleming, Tom P.

Subjects
HUMAN cell culture, EMBRYO transfer, ARTIFICIAL insemination of domestic animals, REPRODUCTIVE technology, BLASTOCYST, EMBRYOLOGY
Abstract

A key factor in the use of assisted reproductive technologies (ART) for diverse species is the safety of procedures for long-term health. By using a mouse model, we have investigated the effect of in vitro culture and embryo transfer (ET) of superovulated embryos on postnatal growth and physiological activity compared with that of embryos developing in vivo. Embryo culture from two-cell to blastocyst stages in T6 medium either with or without a protein source reduced blastocyst trophectoderm and inner cell mass cell number compared with that of embryos developing in vivo. Embryo culture and ET had minimal effects on postnatal growth when compared with in vivo development with an equivalent litter size. However, embryo culture, and to a lesser extent ET, led to an enhanced systolic blood pressure at 21 weeks compared with in vivo development independent of litter size, maternal origin, or body weight. Moreover, activity of enzymatic regulators of cardiovascular and metabolic physiology, namely, serum angiotensin-converting enzyme and the gluconeogenesis controller, hepatic phosphoenolpyruvate carboxykinase, were significantly elevated in response to embryo culture and/or ET in female offspring at 27 weeks, independent of maternal factors and postnatal growth. These animal data indicate that postnatal physiological criteria important in cardiovascular and metabolic health may be more sensitive to routine ART procedures than growth. [ABSTRACT FROM AUTHOR]

Published
2007
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135. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013

Author

Ng, Marie, Fleming, Tom, Robinson, Margaret, Thomson, Blake, Graetz, Nicholas, Margono, Christopher, Mullany, Erin C, Biryukov, Stan, Abbafati, Cristiana, Abera, Semaw Ferede, Abraham, Jerry P, Abu-Rmeileh, Niveen M E, Achoki, Tom, AlBuhairan, Fadia S, Alemu, Zewdie A, Alfonso, Rafael, Ali, Mohammed K, Ali, Raghib, Guzman, Nelson Alvis, Ammar, Walid, Anwari, Palwasha, Banerjee, Amitava, Barquera, Simon, Basu, Sanjay, Bennett, Derrick A, Bhutta, Zulfiqar, Blore, Jed, Cabral, Norberto, Nonato, Ismael Campos, Chang, Jung-Chen, Chowdhury, Rajiv, Courville, Karen J, Criqui, Michael H, Cundiff, David K, Dabhadkar, Kaustubh C, Dandona, Lalit, Davis, Adrian, Dayama, Anand, Dharmaratne, Samath D, Ding, Eric L, Durrani, Adnan M, Esteghamati, Alireza, Farzadfar, Farshad, Fay, Derek F J, Feigin, Valery L, Flaxman, Abraham, Forouzanfar, Mohammad H, Goto, Atsushi, Green, Mark A, Gupta, Rajeev, Hafezi-Nejad, Nima, Hankey, Graeme J, Harewood, Heather C, Havmoeller, Rasmus, Hay, Simon, Hernandez, Lucia, Husseini, Abdullatif, Idrisov, Bulat T, Ikeda, Nayu, Islami, Farhad, Jahangir, Eiman, Jassal, Simerjot K, Jee, Sun Ha, Jeffreys, Mona, Jonas, Jost B, Kabagambe, Edmond K, Khalifa, Shams Eldin Ali Hassan, Kengne, Andre Pascal, Khader, Yousef Saleh, Khang, Young-Ho, Kim, Daniel, Kimokoti, Ruth W, Kinge, Jonas M, Kokubo, Yoshihiro, Kosen, Soewarta, Kwan, Gene, Lai, Taavi, Leinsalu, Mall, Li, Yichong, Liang, Xiaofeng, Liu, Shiwei, Logroscino, Giancarlo, Lotufo, Paulo A, Lu, Yuan, Ma, Jixiang, Mainoo, Nana Kwaku, Mensah, George A, Merriman, Tony R, Mokdad, Ali H, Moschandreas, Joanna, Naghavi, Mohsen, Naheed, Aliya, Nand, Devina, Narayan, K M Venkat, Nelson, Erica Leigh, Neuhouser, Marian L, Nisar, Muhammad Imran, Ohkubo, Takayoshi, Oti, Samuel O, Pedroza, Andrea, Prabhakaran, Dorairaj, Roy, Nobhojit, Sampson, Uchechukwu, Seo, Hyeyoung, Sepanlou, Sadaf G, Shibuya, Kenji, Shiri, Rahman, Shiue, Ivy, Singh, Gitanjali M, Singh, Jasvinder A, Skirbekk, Vegard, Stapelberg, Nicolas J C, Sturua, Lela, Sykes, Bryan L, Tobias, Martin, Tran, Bach X, Trasande, Leonardo, Toyoshima, Hideaki, van de Vijver, Steven, Vasankari, Tommi J, Veerman, J Lennert, Velasquez-Melendez, Gustavo, Vlassov, Vasiliy Victorovich, Vollset, Stein Emil, Vos, Theo, Wang, Claire, Wang, XiaoRong, Weiderpass, Elisabete, Werdecker, Andrea, Wright, Jonathan L, Yang, Y Claire, Yatsuya, Hiroshi, Yoon, Jihyun, Yoon, Seok-Jun, Zhao, Yong, Zhou, Maigeng, Zhu, Shankuan, Lopez, Alan D, Murray, Christopher J L, and Gakidou, Emmanuela

Abstract

In 2010, overweight and obesity were estimated to cause 3·4 million deaths, 3·9% of years of life lost, and 3·8% of disability-adjusted life-years (DALYs) worldwide. The rise in obesity has led to widespread calls for regular monitoring of changes in overweight and obesity prevalence in all populations. Comparable, up-to-date information about levels and trends is essential to quantify population health effects and to prompt decision makers to prioritise action. We estimate the global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013.

Published
2014
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136. Estimating distributions of health state severity for the global burden of disease study

Author

Burstein, Roy, Fleming, Tom, Haagsma, Juanita, Salomon, Joshua A., Vos, Theo, and Murray, Christopher JL.

Subjects
Global burden of disease, Non-fatal outcomes, Medical expenditures panel survey (MEPS), Functional health status, Disability weights, 12-item short form health survey (SF-12)
Abstract

Background: Many major causes of disability in the Global Burden of Disease (GBD) study present with a range of severity, and for most causes finding population distributions of severity can be difficult due to issues of sparse data, inconsistent measurement, and need to account for comorbidities. We developed an indirect approach to obtain severity distributions empirically from survey data. Methods: Individual-level data were used from three large population surveys from the US and Australia that included self-reported prevalence of major diseases and injuries as well as generic health status assessments using the 12-Item Short Form Health Survey (SF-12). We developed a mapping function from SF-12 scores to GBD disability weights. Mapped scores for each individual respondent were regressed against the reported diseases and injuries using a mixed-effects model with a logit-transformed response variable. The regression outputs were used to predict comorbidity-corrected health-state weights for the group of individuals with each condition. The distribution of these comorbidity-corrected weights were used to estimate the fraction of individuals with each condition falling into different GBD severity categories, including asymptomatic (implying disability weight of zero). Results: After correcting for comorbid conditions, all causes analyzed had some proportion of the population in the asymptomatic category. For less severe conditions, such as alopecia areata, we estimated that 44.1 % [95 % CI: 38.7 %-49.4 %] were asymptomatic while 28.3 % [26.8 %-29.6 %] of anxiety disorders had asymptomatic cases. For 152 conditions, full distributions of severity were estimated. For anxiety disorders for example, we estimated the mean population proportions in the mild, moderate, and severe states to be 40.9 %, 18.5 %, and 12.3 % respectively. Thirty-seven of the analyzed conditions were used in the GBD 2013 estimates and are reported here. Conclusion: There is large heterogeneity in the disabling severity of conditions among individuals. The GBD 2013 approach allows explicit accounting for this heterogeneity in GBD estimates. Existing survey data that have collected health status together with information on the presence of a series of comorbid conditions can be used to fill critical gaps in the information on condition severity while correcting for effects of comorbidity. Our ability to make these estimates may be limited by lack of geographic variation in the data and by the current methodology for disability weights, which implies that severity must be binned rather than expressed in as a full distribution. Future country-specific data collection efforts will be needed to advance this research. Electronic supplementary material The online version of this article (doi:10.1186/s12963-015-0064-y) contains supplementary material, which is available to authorized users.

Published
2015
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137. UK health performance: findings of the Global Burden of Disease Study 2010

Author

Murray, Christopher JL, Richards, Michael A, Newton, John N, Fenton, Kevin A, Anderson, H Ross, Atkinson, Charles, Bennett, Derrick, Bernabé, Eduardo, Blencowe, Hannah, Bourne, Rupert, Braithwaite, Tasanee, Brayne, Carol, Bruce, Nigel G, Brugha, Traolach S, Burney, Peter, Dherani, Mukesh, Dolk, Helen, Edmond, Karen, Ezzati, Majid, Flaxman, Abraham D, Fleming, Tom D, Freedman, Greg, Gunnell, David, Hay, Roderick J, Hutchings, Sally J, Ohno, Summer Lockett, Lozano, Rafael, Lyons, Ronan A, Marcenes, Wagner, Naghavi, Mohsen, Newton, Charles R, Pearce, Neil, Pope, Dan, Rushton, Lesley, Salomon, Joshua A, Shibuya, Kenji, Vos, Theo, Wang, Haidong, Williams, Hywel C, Woolf, Anthony D, Lopez, Alan D, and Davis, Adrian

Abstract

The UK has had universal free health care and public health programmes for more than six decades. Several policy initiatives and structural reforms of the health system have been undertaken. Health expenditure has increased substantially since 1990, albeit from relatively low levels compared with other countries. We used data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) to examine the patterns of health loss in the UK, the leading preventable risks that explain some of these patterns, and how UK outcomes compare with a set of comparable countries in the European Union and elsewhere in 1990 and 2010.

Published
2013
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140. Report on the 2ndWorld Congress on Fetal Origins of Adult Disease, Brighton, U.K., June 7–10, 2003

Author

Hanson, Mark, Gluckman, Peter, Bier, Dennis, Challis, John, Fleming, Tom, Forrester, Terrence, Godfrey, Keith, Nestel, Penelope, and Yajnik, Chittaranjan

Abstract

In 1989, reports suggested that the fetal environment, as reflected in birth size, was related to the risk of noncommunicable diseases in adult life. This association was first described for coronary heart disease but rapidly extended to include type 2 diabetes, osteoporosis, and metabolic and endocrine homeostasis. This led to the development of the fetal origins of adult disease paradigm, which resulted in a refocusing of research effort over the next 10 y to consider the lifelong consequences of perinatal influences on chronic diseases. Previously, perinatal influences had largely been seen in terms of teratogenic effects or acute birth injury rather than whether trajectories and responses made during early development had lifelong consequences. Indeed, in developmental biology, it is widely recognized that adaptive plastic responses during early development often have consequences for function in later adulthood. Although the relative importance of this newly recognized set of phenomena to the burden of human disease has been controversial, the research precipitated by those early observations has confirmed their robustness and started to provide a mechanistic basis to this biology. Two world congresses have been held to review progress in this research. Both have been characterized by a unique multidisciplinary attendance ranging from molecular, experimental, and developmental biologists to epidemiologists and health economists.

Published
2004
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141. Occludin TM4(-): an isoform of the tight junction protein present in primates lacking the fourth transmembrane domain.

Author

Reza, Ghassemifar M, Bhavwanti, Sheth, Tom, Papenbrock, J, Leese Henry, D, Houghton Franchesca, and P, Fleming Tom

Abstract

The tight junction protein occludin possesses four transmembrane domains, two extracellular loops, and cytoplasmic N- and C-termini. Reverse transcription-PCR analysis of human tissues, embryos and cells using primers spanning the fourth transmembrane domain (TM4) and adjacent C-terminal region revealed two products. The larger and predominant product corresponded in sequence to canonical occludin (TM4(+)), while the smaller product exhibited a 162 bp deletion encoding the entire TM4 and immediate C-terminal flanking region (TM4(-)). Examination of the genomic occludin sequence identified that the 162 bp sequence deleted in TM4(-) coincided precisely with occludin exon 4, strongly suggesting that TM4(-) is an alternative splice isoform generated by skipping of exon 4. Indeed, the reading frame of downstream exons is not affected by exclusion of exon 4. The presence of both TM4(+) and TM4(-) occludin isoforms was also identified in monkey epithelial cells but TM4(-) was undetected in murine and canine tissue and cells, indicating a late evolutionary origin for this alternative splicing event. Conceptual translation of TM4(-) isoform predicts extracellular localisation of the C-terminus. Immunocytochemical processing of living human Caco-2 cells using a C-terminal occludin antibody revealed weak, discontinuous staining restricted to the periphery of subconfluent islands of cells, or islands generated by wounding confluent layers. In occludin immunoblots, a weak band at approximately 58 kDa, smaller than the predominant band at 65 kDa and corresponding to the predicted mass of TM4(-) isoform, is evident and upregulated in subconfluent cells. These data suggest that the TM4(-) isoform may be translated at low levels in specific conditions and may contribute to regulation of occludin function.

Published
2002

142. Maternal undernutrition during the preimplantation period of rat development causes blastocyst abnormalities and programming of postnatal hypertension

Author

Kwong, Wing Yee, Wild, Arthur E., Roberts, Paul, Willis, Antony C., and Fleming, Tom P.

Abstract

Epidemiological studies have indicated that susceptibility of human adults to hypertension and cardiovascular disease may result from intrauterine growth restriction and low birth weight induced by maternal undernutrition. Although the ‘foetal origins of adult disease’ hypothesis has significant relevance to preventative healthcare, the origin and biological mechanisms of foetal programming are largely unknown. Here, we investigate the origin, embryonic phenotype and potential maternal mechanisms of programming within an established rat model. Maternal low protein diet (LPD) fed during only the preimplantation period of development (0-4.25 days after mating), before return to control diet for the remainder of gestation, induced programming of altered birthweight, postnatal growth rate, hypertension and organ/body-weight ratios in either male or female offspring at up to 12 weeks of age. Preimplantation embryos collected from dams after 0-4.25 days of maternal LPD displayed significantly reduced cell numbers, first within the inner cell mass (ICM; early blastocyst), and later within both ICM and trophectoderm lineages (mid/late blastocyst), apparently induced by a slower rate of cellular proliferation rather than by increased apoptosis. The LPD regimen significantly reduced insulin and essential amino acid levels, and increased glucose levels within maternal serum by day 4 of development. Our data indicate that long-term programming of postnatal growth and physiology can be induced irreversibly during the preimplantation period of development by maternal protein undernutrition. Further, we propose that the mildly hyperglycaemic and amino acid-depleted maternal environment generated by undernutrition may act as an early mechanism of programming and initiate conditions of ‘metabolic stress’, restricting early embryonic proliferation and the generation of appropriately sized stem-cell lineages.

Published
2000
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143. Tissue-specific control of expression of the tight junction polypeptide ZO-1 in the mouse early embryo

Author

Fleming, Tom P. and Hay, Mark J.

Abstract

The processes governing differential protein expression in preimplantation lineages were investigated using a monoclonal antibody recognising the tight junction polypeptide, ZO-1. ZO-1 localises to the maturing tight junction membrane domain in the polarised trophectoderm lineage from compaction (8-cell stage) onwards, ultimately forming a zonular belt around each trophectoderm cell of the blastocyst (32- to 64-cell stage). The protein is usually undetectable within the inner cell mass (ICM) although, in a minority of embryos, punctate ZO-1 sites are present on the surface of one or more ICM cells. Since ICM cells derive from the differentiative division of polarised 8- and 16-cell blastomeres, the distribution of ZO-1 following differentiative division in isolated, synchronised cell clusters of varying size, was examined. In contrast to the apical cytocortical pole, ZO-1 was found to be inherited by nonpolar (prospective ICM) as well as polar (prospective trophectoderm) daughter cells. Following division, polar cells adhere to and gradually envelop nonpolar cells. Prior to envelopment, ZO-1 localises to the boundary between the contact area and free membrane of daughter cells, irrespective of their phenotype. After envelopment, polar cells retain these ZO-1 contact sites whilst nonpolar cells lose them, in which case ZO-1 transiently appears as randomly-distributed punctate sites on the membrane before disappearing. Thus, symmetrical cell contact appears to initiate ZO-1 down-regulation in the ICM lineage. The biosynthetic level at which ZO-1 down-regulation occurs was investigated in immunosurgically isolated ICMs undergoing trophectoderm regeneration. By 6 h in culture, isolated ICMs generated a zonular network of ZO-1 at the contact area between outer cells, thereby demonstrating the reversibility of down-regulation. This assembly process was unaffected by alpha-amanitin treatment but was inhibited by cycloheximide. These results indicate that the ICM inherits and stabilises ZO-1 transcripts which can be utilised for rapid synthesis and assembly of the protein, a capacity that may have significance both in maintaining lineage integrity within the blastocyst and in the subsequent development of the ICM.

Published
1991
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144. Do trophectoderm and inner cell mass cells in the mouse blastocyst maintain discrete lineages?

Author

Dyce, Jonathan, George, Martin, Goodall, Harry, and Fleming, Tom P.

Abstract

The extent to which trophectoderm (TE) and inner cell mass (ICM) lineages in the mouse blastocyst remain distinct during the period from the commencement of cavitation up until 48 h later in culture was investigated. Fluorescent latex microparticles were used to label exclusively all TE cells in nascent blastocysts and the position of labelled progeny in cultured blastocysts was examined by disaggregation, by serial sectioning and by whole-mount analyses. The results indicate that, in most blastocysts (80–90 %), TE and ICM lineages are entirely separate during this period while in the remainder lineage crossing is limited usually to only one or two cells of either tissue.

Published
1987
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145. Tight junction protein cingulin is expressed by maternal and embryonic genomes during early mouse development

Author

Javed, Qamar, Fleming, Tom P., Hay, Mark, and Citi, Sandra

Abstract

The expression of the tight junction peripheral membrane protein, cingulin (140 103Mr), was investigated in mouse eggs and staged preimplantation embryos by immunoblotting and immunoprecipitation. Polyclonal antibody to chicken brush border cingulin detected a single 140 103Mr protein in immunoblots of unfertilised eggs and all preimplantation stages. Relative protein levels were high in eggs and early cleavage stages, declined during later cleavage and increased again in expanding blastocysts. Quantitative immunoprecipitation of metabolically labelled eggs and staged embryos also revealed a biphasic pattern for cingulin synthesis with relative net levels being high in unfertilised eggs, minimal during early cleavage, rising 2.3-fold specifically at the onset of compaction (8-cell stage, when tight junction formation begins), and increasing further at a linear rate during morula and blastocyst stages. Cingulin synthesis in eggs is not influenced by fertilisation (or aging, if unfertilised), but this level declines sharply after first cleavage. These results indicate that cingulin is expressed by both maternal and embryonic genomes. The turnover of maternal cingulin (unfertilised eggs) and embryonic cingulin at a stage before tight junction formation begins (4-cell stage) is higher (t ∼4 hours) than cingulin synthesised after tight junction formation (blastocysts; t ∼10 hours). This increase in cingulin stability is reversed in the absence of extracellular calcium. Cingulin synthesis is also tissue-specific in blastocysts, being up-regulated in trophectoderm and down-regulated in the inner cell mass. Taken together, the results suggest that (i) cingulin may have a role during oogenesis and (ii) cell-cell contact patterns regulate cingulin biosynthesis during early morphogenesis, contributing to lineage-specific epithelial maturation.

Published
1993
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146. Localisation of tight junction protein cingulin is temporally and spatially regulated during early mouse development

Author

Fleming, Tom P., Hay, Mark, Javed, Qamar, and Citi, Sandra

Abstract

The molecular maturation of the tight junction in the mouse early embryo has been investigated by monitoring the distribution of cingulin, a 140 103Mr peripheral (cytoplasmic) membrane constituent of the junction, at different stages of development and in different experimental situations. Although tight junction formation does not begin until compaction at the 8-cell stage, cingulin is detectable in oocytes and all stages of cleavage, a factor consistent with our biochemical analysis of cingulin expression (Javed et al., 1992, Development 117, 1145-1151). Using synchronised egg and embryo stages and isolated cell clusters, we have identified three sites where cingulin is localised, the cytocortex, punctate cytoplasmic foci and tight junctions themselves. Cytocortical cingulin is present at the cumulus-oocyte contact site (both cell types), in unfertilised and fertilised eggs and in cleavage stages up to 16-cell morulae, particularly at microvillous domains on the embryo outer surface (eg. apical poles at compaction). Embryo manipulation experiments indicate that cortical cingulin is labile and dependent upon cell interactions and therefore is not merely an inheritance from the egg. Cingulin cytoplasmic foci are evident only in outer cells (prospective trophectoderm) from the 32-cell stage, just prior to cavitation, and decline from approx. 8 hours after cavitation has initiated. The appearance of these foci is insensitive to cycloheximide treatment and they colocalise with apically derived endocytic vesicles visualised by FITC-dextran, indicating that the foci represent the degradation of cytocortical cingulin by endocytic turnover. Cingulin is detectable at the tight junction site between blastomeres usually from the 16-cell stage, although earlier assembly occurs in a minority (up to 20%) of specimens. Cingulin assembly at the tight junction is sensitive to cycloheximide and is identifiable approx. 10 hours after cell adhesion is initiated and ZO-1 protein assembles. Collectively, our results indicate that (i) cingulin from nonjunctional sites does not contribute to tight junction assembly and (ii) the molecular maturation of the junction appears to occur progressively over at least two cell cycles.

Published
1993
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147. Desmosome biogenesis in the mouse preimplantation embryo

Author

Fleming, Tom P., Garrod, David R., and Elsmore, Andrew J.

Abstract

The molecular processes underlying the formation of the first desmosomes in the mouse early embryo have been examined by immunocytochemical and biochemical techniques using antibody probes recognising desmosomal proteins 1 and 2 (dp1+2, desmoplakins), dp3 (plakoglobin), desmosomal glycoprotein 1 (dgl, desmoglein) and dg2+3 (desmocollins). Immunofluorescence labelling of staged intact embryos and synchronised cell clusters indicates that dp1+2, dgl and dg2+3 are first detectable on the lateral membrane contact sites between trophectoderm cells in early cavitating blastocysts, coincident with the onset of desmosome formation as seen in ultrastructural preparations. Membrane localisation of these antigens is predominantly punctate in appearance, occurs after division to the 32-cell stage and appears to be coincident with blastocoele formation since non-cavitated embryos/cell clusters of equivalent age/ cell cycle are usually unlabelled. In contrast, dp3 is first detectable at the 32-cell stage at all internal membrane contact sites (including those with inner cell mass cells) in a continuous linear pattern, and appears in both cavitated and non-cavitated specimens. Subsequently during blastocyst expansion, dp3 localisation becomes punctate and restricted to trophectodermal membranes. Immunoprecipitation of desmosomal antigens following metabolic labelling indicates that synthesis of dp3 is underway from at least compaction in the 8-cell embryo, while dp1 + 2 synthesis is first evident in 16-cell morulae. Synthesis of dgl and dg2+3 is not detectable until the early blastocyst stage. These results suggest that desmosome biogenesis in the preimplantation embryo might be regulated by transcription or translation of desmosomal glycoproteins and by maturational changes in the trophectoderm layer associated with blastocoele formation. The earlier expression and wider distribution of dp3 at cell contact areas may reflect non-desmosomal sites (eg, adherens junctions) for this protein and a possible role for dp3 in the development of intercellular junctions.

Published
1991
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148. Maturation and polarization of the endocytotic system in outside blastomeres during mouse preimplantation development

Author

Fleming, Tom P. and Pickering, Susan J.

Abstract

The maturation and distribution of the endocytotic apparatus in outside cells of cleavage-stage mouse embryos have been studied to determine the nature and sequence of changes associated with the differentiation of the polarized trophectoderm epithelium of the blastocyst. Various quantitative and qualitative techniques used at the light and electron microscopic levels have revealed an incremental pattern of endocytotic maturation and polarization. Oocytes, eggs and blastomeres within embryos up to the early 8-cell stage contain clusters of prelysosomal endocytotic vesicles (endosomes) distributed randomly in the cortical cytoplasm. During the 8-cell stage and continuing into the early 16-cell stage, endosomes become progressively localized in the apical cytoplasm beneath the microvillous pole. Endosome polarization is initiated prior to overt polarization of the surface membrane. Concomitant with endosome polarization, pinocytotic activity at the cell surface, revealed by horseradish peroxidase labelling, becomes segregated preferentially to the apical rather than the basolateral membrane. The final maturation phase occurs at the late 16-cell stage when secondary lysosomes, characterized by trimetaphosphatase reactivity, form and polarize in the basal cytoplasm.

Published
1985
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149. Are human spermatozoa separated on a Percoll*density gradient safe for therapeutic use?*Pharmacia Fine Chemicals (AB), Uppsala, Sweden.††Supported by a grant to P.R.B. from the Medical Research Council of Great Britain.

Author

Pickering, Susan J., Fleming, Tom P., Braude, Peter R., Bolton, Virginia N., and Gresham, G. Austin G.

Abstract

Motile morphologically normal human spermatozoa can be separated from semen by bouyant density centrifugation on Percoll (Pharmacia Fine Chemicals AB, Uppsala, Sweden) gradients. In this study, the authors have examined (1) the efficiency of washing procedures to remove contaminating Percoll particles from the separated spermatozoa, and (2) the potential of Percoll particles, which contain silica, to cause an inflammatory response when used for intrauterine insemination, or when introduced into the fallopian tube during gamete intrafallopian transfer (GIFT) procedures, as assessed by an intraperitoneal injection into mice. Although Percoll was phagocytosed at the injection site, and therefore cannot be presumed to be totally inert, no generalized inflammatory response was detected. A double spin and wash technique was found to remove most residual Percoll from the spermatozoa, as assessed by scanning electron microscopy. These results suggest that procedures involving the use of Percoll for the separation of human spermatozoa for in vitro fertilization, GIFT, or intrauterine insemination should include stringent washing protocols that will remove most, if not all, contaminating Percoll from the sample.

Published
1989
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150. Developmental variability within and between mouse expanding blastocysts and their ICMs

Author

Chisholm, Julia C., Johnson, Martin H., Warren, Paul D., Fleming, Tom P., and Pickering, Susan J.

Abstract

We have attempted to reduce the developmental heterogeneity amongst populations of mouse blastocysts by synchronizing embryos to the first visible signs of blastocoel formation. Using embryos timed in this way, we have examined the extent of variation of inside and outside cell number and of inside cell size, nuclear DNA content and developmental potential, between and within embryos of a similar age postcavitation. The overall impression gained is one of wide heterogeneity in inside: outside cell number ratios and in cell cycling and its relation to cavitation among embryos of similar age postcavitation. However, the simplest explanation of our results suggests that cavitation generally begins at a time when most outside cells are in their sixth developmental cell cycle and that outside cells, as a population, are a little ahead of inside cells in their cell cycling. Additionally we present evidence that, within at least some individual inner cell masses (ICM), there is intraembryo variation in the time at which inside cell developmental potential becomes restricted.

Published
1985
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