83 results on '"Koshizaka M"'
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2. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes
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Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, Josse R, Kaufman KD, Koglin J, Korn S, Lachin JM, McGuire DK, Pencina MJ, Standl E, Stein PP, Suryawanshi S, Van de Werf F, Peterson ED, Holman RR, Josse RG, Califf RM, Goldstein BJ, Shapiro DR, Silverman R, Bethel A, Green J, Hayden S, Hannan K, Quintero K, Rorick T, Berdan L, Leloudis D, Califf S, Wilson M, McFarron D, Trollinger K, Pesarchick J, Eskenazi L, Campbell C, Townes O, Tolsma D, Keenan J, Milton J, Athwal R, Darbyshire J, Doran Z, Kennedy I, Gregory V, Lokhnygina Y, Prather K, Wolfley A, Usman M, Tajjar A, Gray R, Pfeffer MA, Gerstein HC, Groop L, McMurray JJ, Pocock SJ, Clayton T, Sinay I, Brieger D, Stranks S, Scheen A, Lopes R, Tankova T, Hramiak I, Grado CR, Wenying Y, Ge J, Aschner P, Skrha J, Ambos A, Strandberg T, Travert F, Hanefeld M, Riefflin A, Chan JC, Ofner P, Reddy NK, Christopher J, Mathur A, Arambam P, Mittal S, Manchanda M, Wainstein J, Ambrosio G, Pirags V, Jakuboniene N, Mohamed M, Scott R, White H, Cornel J, Halvorsen S, Tykarski A, Veresiu IA, Dreval AV, Misinkova I, Tai E, Krahulec B, Distiller L, Park Y, Rovira A, Alversson M, Chuang LM, Delibasi T, Adler A, Rodbard HW, Marre M, Goff D, Chacra A, DeVore A, Beaven A, Shah B, Hirsch B, Batch B, Bushnell C, Patel C, Melloni C, Henshaw C, Kong D, Bernecki G, Tillman H, Kang HJ, Hawes J, Strickler J, Piccini J, Wilder J, Alexander K, Mahaffey K, Patel K, Hyland K, Newby K, Jackson L, Cooper L, Armaganijan L, Szczeh L, Koshizaka M, Roe M, Morse M, Guimaraes P, Hess P, Tricoci P, Mehta R, Mathews R, Kociol R, Harrison R, Mentz R, Pokorney S, Leblanc T, Lazzarini V, Eapen Z, Truffa A, Fosbol E, Brito F, Katz M, Bahit M, Santos M, Barros P, Bernardez S, Alvarisqueta AF, Arias P, Cagide AL, Calella PR, Cantero MC, Canella JP, Cipullo MA, de Loredo L, Gelersztein ES, Gorban de Lapertosa SB, Klyver MI, Maffei LE, Maldonado N, Oviedo AI, Piskorz DL, Ridruejo MC, Saavedra SS, Sessa HA, Sinay IR, Sposetti GD, Ulla MR, Vico ML, Waitman JN, Binnekamp M, Carroll P, Cheung W, Colman P, Davis T, De Looze F, dEmden M, Fulcher G, Gerstman M, Hamilton A, Lehman S, Moses R, Proietto J, Roberts A, Shaw J, Simpson R, Sinha A, Tan Y, Topliss D, Vora P, Waites J, Crenier L, Descamps O, Keymeulen B, Mathieu C, Nobels F, Van den Bruel A, Van Gaal L, Borges JL, Costa e Forti A, Eliaschewitz FG, Felício JS, Griz LH, Hissa MN, Leite S, Panarotto D, Pimentel Filho P, Rassi N, Saraiva JK, Sgarbi JA, Silva RP, Tambascia M, Weber Silva DM, Bobeva R, Bostandzhieva R, Cinlikov I, Georgieva M, Iliev D, Ilieva E, Kovacheva S, Liubenova L, Nikitov Z, SHeinikova G, Slavcheva A, Spasova V, Temelkova-Kurktschiev T, Velichka D, Yakov A, Carpentier A, Chiasson JL, Constance C, Dumas R, Filteau P, Garceau C, Huynh T, Kaiser S, Kornder J, Leiter L, Mereu L, Miller D, Pandey S, Punthakee Z, Rabasa-Lhoret R, Robitaille Y, Saunders K, Sigal R, Sigalas J, Vizel S, Weisnagel S, Woo V, Yale JF, Yared K, Zinman B, Bunster Balocchi LB, Escobar Cerda EE, Garces Flores EE, Lanas Zanetti FT, Larrazabal Miranda Adel P, Morales Alvarado JM, Olivares Cañon CM, Potthoff Cárdenas SH, Raffo Grado CA, Rodriguez Venegas ME, Saavedra Gajardo VA, Westerberg Maldonado BH, Chen LL, Dong J, Guo X, Li QM, Shi B, Tang XL, Yang T, Yang WY, Zheng SX, Aschner Montoya P, Botero Lopez R, Coronel Arroyo JA, Cure CA, Gómez Medina AM, Molina DI, Perez Amador GA, Reyes Rincon A, Urina Triana MA, Valenzuela Rincon A, Vélez Pelaez S, Yupanqui Lozno H, Brabec T, Brychta T, Hasalova Zapletalova J, Havelkova J, Hejnicova K, Hola O, Hornackova M, Hrdina T, Kafkova D, Kellnerova I, Krystl T, Kutejova V, Mikulkova I, Nevrla J, Pantlikova C, Petr M, Racicka E, Sarbochova R, Smolenakova K, Turcinek R, Urbancova K, Vejvodova J, Vondrakova M, Zachoval R, Alt I, Kaasik Ü, Kiiroja K, Lanno R, Märtsin K, Past M, Vides H, Viitas L, Kantola I, Nieminen S, Perhonen M, Strand J, Valle T, Clergeot A, Couffinhal T, Courreges JP, Gouet D, Moulin P, Ziegler O, Badenhoop K, Behnke T, Bender G, Braun M, Dshabrailov J, Hamann A, Himpel-Boenninghoff A, Kamke W, Kasperk C, Luedemann J, Mayr P, Merkel M, Oerter EM, Ohlow MA, Ott P, Overhoff U, Paschen B, Remppis R, Rose L, Schumm-Draeger PM, Segiet T, Strotmann HJ, Stuchlik G, Stürmer W, Thinesse-Mallwitz M, Tytko A, Wendisch U, Wurziger J, Ho AY, Kam G, Kong AP, Lam YY, Lau EY, Lee S, Siu SC, Tomlinson B, Tsang CC, Yeung VT, Dezső E, Dudás M, Földesi I, Fülöp T, Késmárki N, Koranyi L, Nagy K, Oroszlán T, Pécsvárady Z, Ples Z, Taller A, Agarwal P, Ambulkar S, Aravind S, Balaji V, Kalra S, Kesavadev J, Kudalkar H, Kumar A, Misra A, Mithal A, Mohan V, Pitale S, Ramu M, Reddy N, Shah S, Shamanna P, Sharda A, Sharma A, Shunmugavelu M, Srikanta S, Suryaprakash G, Abramov G, Adawi F, Bashkin A, Darawsha M, Fuchs S, Harman-Boehm I, Hayek T, Jaffe A, Knobler H, Minuchin O, Mosseri M, Shechter M, Shimon I, Stern N, Tsur A, Vishlitzky V, Alfonsi F, Cavalot F, Del Vecchio L, Frisinghelli A, Gambardella S, Lauro D, Lembo G, Leotta S, Mondillo S, Novo S, Pedrinelli R, Piatti P, Salvioni A, Tritto I, Zavaroni DZ, Ahn KJ, Choi KM, Chung C, Han SJ, Kim DM, Kim IJ, Kim MH, Lee IK, Nam M, Park IeB, Park KS, Park TS, Rhee EJ, Yoo SJ, Andersone I, Balode A, Eglite R, Gersamija A, Kakurina N, Jegere B, Leitane I, Pastare S, Stalte V, Teterovska D, Baltramonaitiene K, Barsiene L, Ceponis J, Lasiene J, Levinger A, Sirutaviciene A, Sulskiene M, Urbanaviciene L, Valius L, Varanauskiene E, Velickiene D, Mahendran KA, Abu Hassan MR, Aziz NA, Hussein Z, Ismail IS, Kamaruddin NA, Nordin Z, Nayar SK, Ramanathan GR, Sothiratnam R, Beijerbacht H, Breedveld R, Cornel JH, Den Hartog F, Hermans W, Kietselaer B, Kooy A, Lenderink T, Nierop P, Remmen J, Rojas Lingan G, Ronner E, Van der Heijden R, Van Hessen M, van Kempen W, Voors-Pette C, Westendorp I, Baker J, Benatar J, Cutfield R, Krebs J, Leikis R, Lunt H, Manning P, Williams M, Birkeland K, Claudi T, Istad H, Karlsson T, Ossum Gronert J, Arciszewska M, Artemiuk E, Blach E, Blicharski T, Cypryk K, Dabrowska M, Górny G, Górska M, Jakubowska I, Jazwinska-Tarnawska E, Karczmarczyk A, Kitowska-Koterla J, Koltowski L, Krzyzagorska E, Pasternak D, Pentela-Nowicka J, Piesiewicz W, Przekwas-Jaruchowska M, Rajzer M, Salamon-Ferenc A, Sawicki A, Skowron T, Śmiałowski A, Albota A, Alexandru C, Crisan C, Dumitrescu A, Ferariu IE, Lupusoru DA, Munteanu M, Negru D, Nicolau A, Pintiliei E, Popescu A, Serban G, Voitec M, Babenko A, Barbarash O, Bondar I, Chizhov P, Demin A, Dora S, Dreval A, Ershova O, Gratsiansky N, Ketova G, Kotelnikov M, Levashov S, Morugova T, Mustafina S, Pekarskiy S, Raskina T, Rechkova E, Samoylova Y, Sazonova O, Sherenkov A, Shilkina N, Stetsyuk O, Tretyakova T, Turova E, Valeeva F, Zadionchenko V, Dalan R, Tan RS, Tay L, Buganova I, Fabry J, Jan C, Toserova E, Zak R, Zimanova J, Badat A, Bester F, Burgess L, De Jong D, Ellis G, Fouche L, Govender P, Govind U, Naidoo V, Nieuwoudt G, Nortje H, Rheeder P, Robertson L, Siddique N, Stapelberg AM, Trinder Y, Van Der Merwe A, Van Zyl L, Viljoen M, Wilhase A, Botella M, Civeira Murillo F, de Teresa L, Del Cañizo FJ, Extremera BG, Gimeno EJ, Martin-Hidalgo A, Morales C, Nubiola A, Tinahones Madueño F, Tranche S, Trescolí Serrano C, Alvarsson M, Eizyk E, Gillblad A, Johansson P, Löndahl M, Ohlsson-Önerud Å, Rautio A, Sundström U, Torstensson I, Chen JF, Chou CW, Ho LT, Hsieh IC, Huang BH, Huang CL, Huang CN, Lai WT, Lo PH, Pei D, Sheu WH, Wang SY, Araz M, Bakiner O, Comlekci A, Guler S, Sahin I, Sarac F, Tarkun I, Ukinc K, Yilmaz M, Abdulhakim E, Abraham P, Adamson K, Blagden M, Bundy C, Daly M, Davies M, Deshpande M, Gillings S, Harvey P, Horvathova V, Hristova D, Jaap A, Johnson A, Jones H, Kerrane J, Kilvert A, Ko T, Kumar J, Lindsay R, Litchfield J, McCrimmon R, McKnight J, Millward B, Oyesile B, Purewal T, Ravikumar C, Robinson A, Sathyapalan T, Simpson H, Thomas H, Turner W, Weaver J, Wilding J, Wiles P, Adkins K, Akpunonu B, Albu J, Anagnostis G, Anastasi L, Argoud G, Aroda V, Azizad M, Banerji MA, Bartkowiak A Jr, Bays H, Behn P, Bergenstal R, Bhargava A, Bias D, Bolster E, Buchanan P, Busch R, Chadha C, Chang M, Cheng C, Cohen A, Cohen J, Cole B, Connery L, Cooperman M, Cushman W, DAgostino R, Dayamani P, De Lemos J, De Meireles M, Dean J, DeHart D, Detweiler R, Donovan D, Dugano-Daphnis P, Dulin M, Dunn F, Eaton C, Erickson B, Estevez R, Feinglos M, Fonseca V, Force R, Forker A, Fox D, Gabriel J, Garcia R, Garvey T, Gaudiani L, Getaneh A, Goldberg A, Goldman S, Hairston K, Harris R, Haught W, Hidalgo H Jr, Higgins A, Houchin V, Ison R, Jacobs G, Jaffrani N, Jafry B, Kapsner P, Kaye W, Labroo A, Levinson L, Lewis S, Lillestol M, Luttrell L, Madu I, McNeill R, Merrick B, Metzger F, Nadar V, Nagelberg S, Nash S, Oparil S, Osei K, Papademetriou V, Patel N, Pedley C, Prentiss A, Radbill M, Raisinghani A, Rassouli N, Reddy R, Rees P, Rendell M, Robbins D, Rodbard H, Rohlf J, Roseman H, Rudolph L, Sadler L, Schnall A, Schramm R, Schubart U, Seneviratne T, Shanik M, Snyder H, Sorli C, Stich M, Sweeney ME, Tsao J, Ukwade P, Viswanath D, Vo A, Vogel C, Voyce S, Weintraub H, White J, Wood M, Wu P, Wysham C, Zimmerman R, Pathology/molecular and cellular medicine, Diabetes Pathology & Therapy, and Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, Josse R, Kaufman KD, Koglin J, Korn S, Lachin JM, McGuire DK, Pencina MJ, Standl E, Stein PP, Suryawanshi S, Van de Werf F, Peterson ED, Holman RR, Holman RR, Peterson ED, Holman RR, Peterson ED, Armstrong PW, Buse JB, Josse RG, Kaufman KD, Koglin J, Korn S, Lachin JM, McGuire DK, Standl E, Stein PP, Suryawanshi S, Van de Werf F, Engel SS, Califf RM, Goldstein BJ, Shapiro DR, Silverman R, Bethel A, Green J, Hayden S, Hannan K, Quintero K, Rorick T, Berdan L, Leloudis D, Califf S, Wilson M, McFarron D, Trollinger K, Pesarchick J, Eskenazi L, Campbell C, Townes O, Tolsma D, Keenan J, Milton J, Athwal R, Darbyshire J, Doran Z, Kennedy I, Gregory V, Garg J, Lokhnygina Y, Prather K, Wolfley A, Usman M, Tajjar A, Gray R, Pfeffer MA, Gerstein HC, Groop L, McMurray JJ, Pocock SJ, Clayton T, Sinay I, Brieger D, Stranks S, Scheen A, Lopes R, Tankova T, Hramiak I, Grado CR, Wenying Y, Ge J, Aschner P, Skrha J, Ambos A, Strandberg T, Travert F, Hanefeld M, Riefflin A, Chan JC, Ofner P, Reddy NK, Christopher J, Mathur A, Arambam P, Mittal S, Manchanda M, Wainstein J, Ambrosio G, Pirags V, Jakuboniene N, Mohamed M, Scott R, White H, Cornel J, Halvorsen S, Tykarski A, Veresiu IA, Dreval AV, Misinkova I, Tai E, Krahulec B, Distiller L, Park Y, Rovira A, Alversson M, Chuang LM, Delibasi T, Adler A, Rodbard HW, Marre M, Goff D, Chacra A, DeVore A, Beaven A, Shah B, Hirsch B, Batch B, Bushnell C, Patel C, Melloni C, Henshaw C, Kong D, McFarron D, Bernecki G, Tillman H, Kang HJ, Green J, Hawes J, Strickler J, Piccini J, Wilder J, Alexander K, Mahaffey K, Patel K, Hyland K, Newby K, Jackson L, Cooper L, Armaganijan L, Szczeh L, Koshizaka M, Roe M, Morse M, Guimaraes P, Hess P, Tricoci P, Mehta R, Lopes R, Mathews R, Kociol R, Harrison R, Mentz R, Pokorney S, Leblanc T, Lazzarini V, Eapen Z, Truffa A, Fosbol E, Brito F, Katz M, Bahit M, Santos M, Barros P, Bernardez S, Alvarisqueta AF, Arias P, Cagide AL, Calella PR, Cantero MC, Canella JP, Cipullo MA, de Loredo L, Gelersztein ES, Gorban de Lapertosa SB, Klyver MI, Maffei LE, Maldonado N, Oviedo AI, Piskorz DL, Ridruejo MC, Saavedra SS, Sessa HA, Sinay IR, Sposetti GD, Ulla MR, Vico ML, Waitman JN, Binnekamp M, Carroll P, Cheung W, Colman P, Davis T, De Looze F, dEmden M, Fulcher G, Gerstman M, Hamilton A, Lehman S, Moses R, Proietto J, Roberts A, Shaw J, Simpson R, Sinha A, Stranks S, Tan Y, Topliss D, Vora P, Waites J, Crenier L, Descamps O, Keymeulen B, Mathieu C, Nobels F, Scheen A, Van den Bruel A, Van Gaal L, Borges JL, Costa e Forti A, Eliaschewitz FG, Felício JS, Griz LH, Hissa MN, Leite S, Panarotto D, Pimentel Filho P, Rassi N, Saraiva JK, Sgarbi JA, Silva RP, Tambascia M, Weber Silva DM, Bobeva R, Bostandzhieva R, Cinlikov I, Georgieva M, Iliev D, Ilieva E, Kovacheva S, Liubenova L, Nikitov Z, SHeinikova G, Slavcheva A, Spasova V, Tankova T, Temelkova-Kurktschiev T, Velichka D, Yakov A, Carpentier A, Chiasson JL, Constance C, Dumas R, Filteau P, Garceau C, Hramiak I, Huynh T, Kaiser S, Kornder J, Leiter L, Mereu L, Miller D, Pandey S, Punthakee Z, Rabasa-Lhoret R, Robitaille Y, Saunders K, Sigal R, Sigalas J, Vizel S, Weisnagel S, Woo V, Yale JF, Yared K, Zinman B, Bunster Balocchi LB, Escobar Cerda EE, Garces Flores EE, Lanas Zanetti FT, Larrazabal Miranda Adel P, Morales Alvarado JM, Olivares Cañon CM, Potthoff Cárdenas SH, Raffo Grado CA, Rodriguez Venegas ME, Saavedra Gajardo VA, Westerberg Maldonado BH, Chen LL, Dong J, Guo X, Li QM, Shi B, Tang XL, Yang T, Yang WY, Zheng SX, Aschner Montoya P, Botero Lopez R, Coronel Arroyo JA, Cure CA, Gómez Medina AM, Molina DI, Perez Amador GA, Reyes Rincon A, Urina Triana MA, Valenzuela Rincon A, Vélez Pelaez S, Yupanqui Lozno H, Brabec T, Brychta T, Hasalova Zapletalova J, Havelkova J, Hejnicova K, Hola O, Hornackova M, Hrdina T, Kafkova D, Kellnerova I, Krystl T, Kutejova V, Mikulkova I, Nevrla J, Pantlikova C, Petr M, Racicka E, Sarbochova R, Skrha J, Smolenakova K, Turcinek R, Urbancova K, Vejvodova J, Vondrakova M, Zachoval R, Alt I, Ambos A, Kaasik Ü, Kiiroja K, Lanno R, Märtsin K, Past M, Vides H, Viitas L, Kantola I, Nieminen S, Perhonen M, Strand J, Strandberg T, Valle T, Clergeot A, Couffinhal T, Courreges JP, Gouet D, Moulin P, Travert F, Ziegler O, Badenhoop K, Behnke T, Bender G, Braun M, Dshabrailov J, Hamann A, Hanefeld M, Himpel-Boenninghoff A, Kamke W, Kasperk C, Luedemann J, Mayr P, Merkel M, Oerter EM, Ohlow MA, Ott P, Overhoff U, Paschen B, Remppis R, Riefflin A, Rose L, Schumm-Draeger PM, Segiet T, Strotmann HJ, Stuchlik G, Stürmer W, Thinesse-Mallwitz M, Tytko A, Wendisch U, Wurziger J, Ho AY, Kam G, Kong AP, Lam YY, Lau EY, Lee S, Siu SC, Tomlinson B, Tsang CC, Yeung VT, Dezső E, Dudás M, Földesi I, Fülöp T, Késmárki N, Koranyi L, Nagy K, Ofner P, Oroszlán T, Pécsvárady Z, Ples Z, Taller A, Agarwal P, Ambulkar S, Aravind S, Balaji V, Christopher J, Kalra S, Kesavadev J, Kudalkar H, Kumar A, Misra A, Mithal A, Mohan V, Pitale S, Ramu M, Reddy N, Shah S, Shamanna P, Sharda A, Sharma A, Shunmugavelu M, Srikanta S, Suryaprakash G, Abramov G, Adawi F, Bashkin A, Darawsha M, Fuchs S, Harman-Boehm I, Hayek T, Jaffe A, Knobler H, Minuchin O, Mosseri M, Shechter M, Shimon I, Stern N, Tsur A, Vishlitzky V, Wainstein J, Alfonsi F, Cavalot F, Del Vecchio L, Frisinghelli A, Gambardella S, Lauro D, Lembo G, Leotta S, Mondillo S, Novo S, Pedrinelli R, Piatti P, Salvioni A, Tritto I, Zavaroni DZ, Ahn KJ, Choi KM, Chung C, Han SJ, Kim DM, Kim IJ, Kim MH, Lee IK, Nam M, Park IeB, Park KS, Park TS, Park Y, Rhee EJ, Yoo SJ, Andersone I, Balode A, Eglite R, Gersamija A, Kakurina N, Jegere B, Leitane I, Pastare S, Pirags V, Stalte V, Teterovska D, Baltramonaitiene K, Barsiene L, Ceponis J, Jakuboniene N, Lasiene J, Levinger A, Sirutaviciene A, Sulskiene M, Urbanaviciene L, Valius L, Varanauskiene E, Velickiene D, Mahendran KA, Abu Hassan MR, Aziz NA, Hussein Z, Ismail IS, Kamaruddin NA, Mohamed M, Nordin Z, Nayar SK, Ramanathan GR, Sothiratnam R, Beijerbacht H, Breedveld R, Cornel JH, Den Hartog F, Hermans W, Kietselaer B, Kooy A, Lenderink T, Nierop P, Remmen J, Rojas Lingan G, Ronner E, Van der Heijden R, Van Hessen M, van Kempen W, Voors-Pette C, Westendorp I, Baker J, Benatar J, Cutfield R, Krebs J, Leikis R, Lunt H, Manning P, Scott R, Williams M, Birkeland K, Claudi T, Halvorsen S, Istad H, Karlsson T, Ossum Gronert J, Arciszewska M, Artemiuk E, Blach E, Blicharski T, Cypryk K, Dabrowska M, Górny G, Górska M, Jakubowska I, Jazwinska-Tarnawska E, Karczmarczyk A, Kitowska-Koterla J, Koltowski L, Krzyzagorska E, Pasternak D, Pentela-Nowicka J, Piesiewicz W, Przekwas-Jaruchowska M, Rajzer M, Salamon-Ferenc A, Sawicki A, Skowron T, Śmiałowski A, Tykarski A, Albota A, Alexandru C, Crisan C, Dumitrescu A, Ferariu IE, Lupusoru DA, Munteanu M, Negru D, Nicolau A, Pintiliei E, Popescu A, Serban G, Veresiu IA, Voitec M, Babenko A, Barbarash O, Bondar I, Chizhov P, Demin A, Dora S, Dreval A, Ershova O, Gratsiansky N, Ketova G, Kotelnikov M, Levashov S, Morugova T, Mustafina S, Pekarskiy S, Raskina T, Rechkova E, Samoylova Y, Sazonova O, Sherenkov A, Shilkina N, Stetsyuk O, Tretyakova T, Turova E, Valeeva F, Zadionchenko V, Dalan R, Tan RS, Tay L, Buganova I, Fabry J, Jan C, Krahulec B, Toserova E, Zak R, Zimanova J, Badat A, Bester F, Burgess L, De Jong D, Distiller L, Ellis G, Fouche L, Govender P, Govind U, Naidoo V, Nieuwoudt G, Nortje H, Rheeder P, Robertson L, Siddique N, Stapelberg AM, Trinder Y, Van Der Merwe A, Van Zyl L, Viljoen M, Wilhase A, Botella M, Civeira Murillo F, de Teresa L, Del Cañizo FJ, Extremera BG, Gimeno EJ, Martin-Hidalgo A, Morales C, Nubiola A, Rovira A, Tinahones Madueño F, Tranche S, Trescolí Serrano C, Alvarsson M, Eizyk E, Gillblad A, Johansson P, Löndahl M, Ohlsson-Önerud Å, Rautio A, Sundström U, Torstensson I, Chen JF, Chou CW, Chuang LM, Ho LT, Hsieh IC, Huang BH, Huang CL, Huang CN, Lai WT, Lo PH, Pei D, Sheu WH, Wang SY, Araz M, Bakiner O, Comlekci A, Delibasi T, Guler S, Sahin I, Sarac F, Tarkun I, Ukinc K, Yilmaz M, Abdulhakim E, Abraham P, Adamson K, Adler A, Blagden M, Bundy C, Daly M, Davies M, Deshpande M, Gillings S, Harvey P, Horvathova V, Horvathova V, Hristova D, Jaap A, Johnson A, Jones H, Kerrane J, Kilvert A, Ko T, Kumar J, Lindsay R, Litchfield J, McCrimmon R, McKnight J, Millward B, Oyesile B, Purewal T, Ravikumar C, Robinson A, Sathyapalan T, Simpson H, Thomas H, Turner W, Weaver J, Wilding J, Wiles P, Adkins K, Akpunonu B, Albu J, Anagnostis G, Anastasi L, Argoud G, Aroda V, Azizad M, Banerji MA, Bartkowiak A Jr, Bays H, Behn P, Bergenstal R, Bhargava A, Bias D, Bolster E, Buchanan P, Busch R, Chadha C, Chang M, Cheng C, Cohen A, Cohen J, Cole B, Connery L, Cooperman M, Cushman W, DAgostino R, Davies M, Dayamani P, De Lemos J, De Meireles M, Dean J, DeHart D, Detweiler R, Donovan D, Dugano-Daphnis P, Dulin M, Dunn F, Eaton C, Erickson B, Estevez R, Feinglos M, Fonseca V, Force R, Forker A, Fox D, Gabriel J, Garcia R, Garvey T, Gaudiani L, Getaneh A, Goff D, Goldberg A, Goldman S, Hairston K, Harris R, Haught W, Hidalgo H Jr, Higgins A, Houchin V, Ison R, Jacobs G, Jaffrani N, Jafry B, Kapsner P, Kaye W, Labroo A, Levinson L, Lewis S, Lillestol M, Luttrell L, Madu I, McNeill R, Merrick B, Metzger F, Nadar V, Nagelberg S, Nash S, Oparil S, Osei K, Papademetriou V, Patel N, Pedley C, Prentiss A, Radbill M, Raisinghani A, Rassouli N, Reddy R, Rees P, Rendell M, Robbins D, Rodbard H, Rohlf J, Roseman H, Rudolph L, Sadler L, Schnall A, Schramm R, Schubart U, Seneviratne T, Shanik M, Snyder H, Sorli C, Stich M, Sweeney ME, Tsao J, Ukwade P, Viswanath D, Vo A, Vogel C, Voyce S, Weintraub H, White J, Wood M, Wu P, Wysham C, Zimmerman R
- Subjects
Oral ,medicine.medical_specialty ,Heart diseases ,Glycosylated ,Administration, Oral ,heart failure ,Type 2 diabetes ,Dipeptidyl peptidase-4 inhibitor ,Kaplan-Meier Estimate ,Placebo ,Sitagliptin Phosphate ,Sitagliptin, Cardiovascular Outcomes ,chemistry.chemical_compound ,Drug Therapy ,Double-Blind Method ,Internal medicine ,Diabetes Mellitus ,medicine ,Humans ,Hypoglycemic Agents ,Glycated Hemoglobin ,Hemoglobin A, Glycosylated ,Cardiovascular Diseases ,Diabetes Mellitus, Type 2 ,Drug Therapy, Combination ,Follow-Up Studies ,Heart Diseases ,Heart Failure ,Hospitalization ,Pyrazines ,Triazoles ,Medicine (all) ,business.industry ,Semaglutide ,Hemoglobin A ,General Medicine ,ta3121 ,medicine.disease ,Surgery ,Cardiovascular diseases ,chemistry ,Sitagliptin ,Administration ,Combination ,Glycated hemoglobin ,business ,Type 2 ,Alogliptin ,medicine.drug - Abstract
BACKGROUND: Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS: During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to-0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P
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- 2015
3. Metabolic effects of glabridin in healthy volunteers and patients with type 2 diabetes: A pilot study
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Hattori, A., primary, Takemoto, M., additional, Ishikawa, T., additional, Maezawa, Y., additional, Koshizaka, M., additional, Tokuyama, H., additional, He, P., additional, Kawamura, H., additional, Kobayashi, K, additional, and Yokote, K., additional
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- 2019
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4. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes
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Holman, Rr, Bethel, Ma, Mentz, Rj, Thompson, Vp, Lokhnygina, Y, Buse, Jb, Chan, Jc, Choi, J, Gustavson, Sm, Iqbal, N, Maggioni, Ap, Marso, Sp, Öhman, P, Pagidipati, Nj, Poulter, N, Ramachandran, A, Zinman, B, Hernandez, Af, EXSCEL Study Group, : Califf RM, Patel, R, George, J, Sourij, H, Wong, Yw, Hannan, K, Sellers, Ma, Gottlieb, P, Lavender, P, Leloudis, D, Meadows, Y, Larson, D, Anderson, H, Elkins, M, Stone, A, Tisch, A, Perkins, L, Sanders, K, Campbell, C, Kennedy, I, Heal, P, Masterson, M, Darbyshire, J, Mumtaz, L, Athwal, R, Ferch, A, Batra, P, Durborow, L, Vincent, J, Woodall, A, Flanagan, T, Katona, B, Reicher, B, Pozzi, E, Oulhaj, A, Coleman, R, Rouleau, Jl, Pocock, Sj, Gorelick, F, Mcmurray, J, Riddle, M, Gagel, R, Collier, T, Markovic, T, Kong, Aps, Hian, Sk, Scott, R, Panelo, A, Yoon, Kh, Sheu, W, Sritara, P, Linong, J, Pan, C, Yong, H, Schernthaner, G, Mathieu, C, Tankova, T, Widimsky, P, Hanefeld, M, Keltai, M, Wainstein, J, del Prato, S, Pirags, V, Jakuboniene, N, Kooy, A, Dziemidok, P, Veresiu, Ia, Dreval, Av, Murin, J, Torello, Al, Sattar, N, Parkhomenko, O, Omar, M, Diaz, R, Lopes, R, Lanas, F, Urina Triana, M, Leiva-Pons, Jl, Aguliera, D, Bergenstal, R, Goodman, S, Yale, Jf, Caterson, I, Weng, J, Hu, D, Junbo, G, Zannad, F, Anoop, M, Ambrish, M, Gallegos, Ja, Green, Jb, Akerblom, A, Alexander, K, Al-Khatib, S, Armaganijan, L, Barros, P, Batit, M, Bernacki, G, Bernandez, S, Bloomfield, G, Clausen, E, De Souza Brito, F, Devore, A, Dombrowski, K, Eapen, Z, Gellad, Z, George, D, Guimaraes, P, Halim, S, Harrison, R, Hawes, J, Hess, C, Hyland, K, Jackson, L, Jones, S, Jordan, D, Katz, M, Kong, D, Koshizaka, M, Lakey, W, Leblanc, T, Leonardi, S, Luo, N, Mahaffey, K, Mandawat, A, Mehta, R, Melloni, C, Morse, M, Pagidpati, N, Patel, C, Patel, K, Pokorney, S, Posvic, T, Rao, M, Roe, M, Shah, B, Tillmann, H, Truffa, A, Zazula, A, Zeitler, E, Sicer, M, Ulla, Mr, Maffei, L, Klyver, Mi, Calella, P, Alvarisqueta, A, De La Fuente RL, Aizenberg, D, Roque, F, Cruciani, A, Frechtel, G, Gelersztein, E, Villarino, A, Mallagray, M, Nardone, L, Zaidman, C, Novaretto, L, Bartolacci, I, de Salvo, M, Delcourt, C, Crimmins, D, Jackson, R, O’Neal, D, Colman, P, Jeffries, W, Mah, Pm, Wittert, G, Proietto, J, Amerena, J, Marks, S, Tan, R, Colquhoun, D, Pieber, T, Drexel, H, Prager, R, Schnack, C, Hoppichler, F, Fasching, P, Francesconi, C, Luger, A, Schoenherr, Hr, Ebenbichler, C, Paulweber, B, Shernthaner, G, Verhaegen, A, Vanuytsel, J, Thissen, Jp, e Silva P, Barros, Gonzaga, C, Borges, J, Hissa, M, Rea, R, Rossi, P, Chacra, A, Eliaschewitz, F, Garbelini, B, Felicio, J, Rassi, N, Rossi, F, Nunes dos Santos, M, e Farias F, Bandeira, Lisboa, H, e Forti A, Costa, Saraiva, Jk, Kovacheva, S, Levterov, G, Sheinkova, G, Ilieva, E, Lyubenova, L, Damyanova, V, Gushterova, V, Mincheva, L, Illiev, D, Ivanov, V, Bobeva, R, Nikitov, Z, Shumkova, R, Lefterov, In, Zaharieva, S, Videva, V, Yakov, A, Cheung, S, Elliott, T, Mehta, P, Ross, S, Sigal, R, Woo, V, Jaffer, S, Kuritsky, R, Bell, A, Dumas, R, Gosselin, G, Robitaille, Y, Greenspoon, A, Lochnan, H, Tytus, R, Leiter, L, Pandey, A, Punthakee, Z, Dube, F, Sigalas, J, Pearce, M, Woodford, T, Paul, P, Bourgeois, R, Conway, R, Mazza, G, Hatheway, R, Misterski, J, Raffo, C, Olivares, C, Godoy, J, Potthoff, S, Santibañez, C, Larenas Yanez GJ, Gu, W, Shen, F, Ma, J, Guo, X, Li, Q, Du, Y, Hu, J, Ji, L, Li, Y, Deng, H, Feng, Y, Liu, L, Mu, Y, Ma, C, Qu, S, Wang, J, Wang, Y, Yuan, Z, Zhang, L, Zhou, S, Yang, T, Dong, Y, Liu, D, Coronel Arroyo, J, Perez Amador, G, Botero Lopes, R, Jaramilo, C, Orozco Linares, A, Cure Cure CA, Hernandez Triana, E, Molina de Salazar DI, Marin, Cr, Jaramilo Gomez CJ, Kellinerova, I, Adamkova, V, Krami, P, Brychta, T, Havelkova, J, Pantikova, K, Schoper, F, Pohl, W, Schumm-Draeger, Pm, Julius, U, Tschöpe, D, Hamann, A, Seissler, J, Schellong, S, Rose, L, Becker, B, Linn, T, Oerter, Em, Strotmann, Hj, Mölle, A, Pfutzner, A, Forst, T, Schäufele, T, Mugge, A, Lehrke, M, Meyer-Pannwitt, U, Mehling, H, Simon-Wagner, I, Schenkenberger, I, Busch, K, Hermes, S, Milek, K, Landers, B, Grueneberg, M, Braun, M, Nothroff, J, Kamke, W, Hergdt, G, Duengen, Hd, Kleinertz, K, Kuesters, D, Boenninghoff, Ah, Appel, Kf, Schaefer, A, Bieler, T, Ozaki, R, Luk, Aoy, Chu, Dw, Cheung-Wong, Mm, Siu, Dc, Yan, Bpy, Kung, K, Wong, Sys, Tsang, Cc, Yeung, Vt, Cheung, Bm, Tse, Hf, Hodi, G, Nagy, K, Lippai, J, Takacs, J, Fulop, T, Gaal, Z, Pauker, Z, Foldesi, I, Simon, J, Oroszan, T, Futo, L, Bezzegh, K, Nagy, A, Vandorfi, G, Kiss, J, Kesmarki, N, Kis, E, Papp, A, Kovacs, A, Szakal, I, Palinkas, A, Czegany, Z, Voros, P, Reiber, I, Kerenyi, Z, Dezso, E, Wittman, I, Penzes, J, Ples, Z, Taller, A, Farago, K, Kis, Jt, Zilahi, Z, Molnar, M, Barkai, L, Mileder, M, Szentpeteri, I, Peterfai, E, Lovasz, O, Mosenzon, O, Minuchin, O, Jaffe, A, Vishlitsky, V, Shimon, I, Bashkin, A, Stern, N, Elias, N, Bental, T, Butnaru, A, Lewis, B, Adawi, F, Nseir, W, Klainman, E, Herskovits, T, Cignarelli, M, Rotella, Cm, Ambrosio, G, Pozzilli, P, Genovese, S, Cavarape, A, Salvioni, A, Sokolova, J, Strautina, I, Teterovska, D, Stalte, V, Pastare, S, Leitane, I, Lagzdina, L, Andersone, I, Eglite, R, Stelmane, I, Levinger, A, Barsiene, L, Sulskiene, M, Varanauskiene, E, Danyte, E, Urbanaviciene, E, Urbanavicius, V, Zabuliene, L, Juskiene, R, Velaviciene, A, Kakariekiene, V, Augusteniene, A, Velickiene, D, Lasiene, J, Dauksiene, D, Caponis, J, Tan, At, Ramanathan, L, Hassan, Mra, Tan, F, Ong, Tk, Foo, Sh, Ghani, Ra, Cheah, Wk, Sanchez Mijangos JH, Cabrera Jardines, R, Barrientos Perez, M, Sauque Reyna, L, Alcocer Gamba MA, Villeda Espinosa, E, Tamez Perez HE, De La Garza Hernandez NE, Lopes, Sm, Ramirez Diaz SP, Reyes Sanchez, R, Márquez-Rodriguez, E, Köse, V, Voors-Pette, C, Oldenburg-Ligtenberg, Pc, van Kempen WW, Cox, K, Hoogendyk, J, Swinkels-Diepenmaat, L, Rojas-Lingan, G, Kentgens, S, Schipperen, S, de Valk HW, Swart, H, van Bemmel, B, Hoogslag, Pam, Diamant, M, Serné, Eh, Hamer, A, Wilson, S, Fisher, N, Dixon, P, Chaudhri, O, Crawford, V, Quinn, D, Nirmalaraj, K, Dunn, P, Gillies, J, Cutfield, R, Krebs, J, Helm, C, Kerr, J, Pryke, J, Ebo, G, Denopol, M, Ang, E, Uy, N, Jimeno, C, Mirasoi, R, Paz Pacheco, E, Custodio, M, Nicodemus, N Jr, Catindig, Ea, Magno, M, Tirador, L, Cylkowska, B, Stasinksa, T, Silwinska, T, Sroka, M, Piepiorka, M, Korzeniak, R, Mirecka, H, Zaluska, R, Pupek-Musialik, D, Homenda, W, Grabowska, A, Okopien, B, Niegowska, J, Pogorzelska, H, Mikolajczyk-Swatko, A, Sikorski, M, Sowinski, D, Tahk, Sj, Kim, Yn, Nam, Cw, Rim, Sj, Kim, Cj, Choi, Km, Lee, Ik, Kim, Ij, Namgung, J, Moon, Kw, Kim, Ks, Oh, Bh, Lee, Wy, Choi, Sh, Kim, Es, Moon, S, Mindrescu, Nm, Aron, G, Graur, M, Hancu, N, Mlitaru, C, Nafornita, V, Szilagyi, I, Popa, Ar, Angelescu, Lm, Negrisanu, Gd, Zaharie, Dg, Culman, Mi, Vacaru, G, Munteanu, M, Constantinescu, S, Tivadar, S, Dreval, A, Barbarash, O, Strongin, L, Dogadin, S, Suplotova, L, Izmozherova, N, Marasaev, V, Khokhlov, A, Repin, A, Turova, E, Bondar, I, Samoylova, Y, Sherenkov, A, Smolenskaya, O, Zrahevskiy, K, Koshelskaya, O, Obrezan, A, Dzupina, A, Stevlik, J, Buganova, I, Pella, D, Vinanska, D, Jascur, J, Micko, K, Sosovec, D, Philippiova, A, Olexa, P, Fedacko, J, Selecky, J, Nicolau, J, Mediavilla Garcia, J, Botella Serrano, M, Lecube, A, Arguelles, I, Sabán, J, Gómez Cerezo, F, Soto, A, Bellido, D, Sucunza Alfonso, N, Vendrell Ortega, J, Alvarez, L, Garcia Puig, J, Angustias Quesada, M, Contreras Gilbert, J, Almeida, Ca, Tinahones, Fj, Garcia Ortiz, L, Gómez Marcos MA, Aomar, I, Fernández Balsells, M, Distiller, L, Padayachee, T, Badat, A, Ebrahim, I, Naiker, P, Ranjith, N, Kelfkens, Y, Makan, H, Mogashoa, S, Fulat, M, Carim-Ganey, N, Coetzee, K, Govender, T, Nortje, H, Wilhase, A, Seedat, S, Gani, M, Ellis, G, Rheeder, P, Wing, J, Blignaut, S, Kaplan, H, Lottering, H, Pillai, P, Louw, C, Coetzer, T, Sheu, Whh, Chen, Jf, Yang, Cy, Tseng, St, Wang, Cy, Lai, Wt, Hung, Yj, Hsieh, Ic, Su, Sl, Pei, D, Benjasuratwong, Y, Purewal, T, Milward, A, Dimitropoulos, I, Kumar, S, Barber, T, Wiles, P, Dang, C, Adler, A, Philip, S, Bellary, S, Price, D, Oelbaum, R, Heller, S, Sathayapalan, T, Clark, J, Leese, G, Simpson, H, Kilvert, A, Dawson, A, Hall, T, Takhar, A, Bundy, C, Harvey, P, Maxwell, S, Asamoah-Owusu, Nj, Mcknight, J, Chatterjee, S, Calvert, J, Wright, A, Macrury, S, Macfarlane, D, Johnson, A, Litchfield, J, Field, B, Koval, O, Larin, O, Levchenko, O, Martynyuk, L, Maslyanko, V, Rudyk, I, Suprun, Y, Tseluyko, V, Botsyurko, V, Vatutin, M, Fushtey, I, Grishyna, O, Kuskalo, P, Panina, S, Pererva, L, Prysupa, L, Teliatnikova, Z, Sokolova, L, Vlasenko, M, Berenfus, V, Gyrina, O, Kopytsya, M, Vizir, V, Vayda, M, Shanik, M, Headapohl, D, Pahl, J, Aronoff, S, Bartkowiak, A Jr, Chang, A, Gaudiani, L, Kayne, D, Look, M, Patel, N, Moran, J, Stout, E, Tsao, J, Struble, R, Fishman, N, Rodbard, H, Lucas, K, Dugano-Daphnis, P, Merrick, B, Nadar, V, Severa, L, Sorli, C, Chang, M, Reed, J III, Grunberger, G, Bain, C, Bestermann, W Jr, Morawski, E, White, J, Azizad, M, Ukwade, P, Anekwe, A, Jimenez, A, Weiss, D, Green, S, Overcash, J, Eaton, C, Roseman, H, Soler, N, Mikell, F, Manos, P, Levinson, L, Claxton, E Jr, Weiss, R, Argoud, G, Bickel, L, Wilson, J, Short, B, Webster, B, Mcneill, R, Schnall, A, Force, R, Phillips, L, Bybee, K, Forker, A, Denham, D, Vonderhaar, T, Pullman, J, Kruger, D, Whitehouse, F, Wysham, C, Baron, M, Kravitz, A, Dushkin, H, Manning, Mb, Wine, A, Jaffrani, N, Chadha, C, Sperl-Hillen, J, Busch, R, Estevez, R, Robbins, D, Rassouli, N, Garvey, T, Oparil, S, Eckel, R, Mcdermott, M, Rasouli, N, Mcgill, J, Corder, C, Klonoff, D, Mills, R, Earl, J, Kessel, J, Cuddihy, R, Zimmerman, R, Dayamani, P, Oral, E, Zimering, M, Marks, J, Farnsworth, K, Sugimoto, D, Toth, P, Bhargava, A, Mcguire, D, Rohatgi, A, Davies, M, Peden, E, Wyne, K, Alfonso, L, Seyoum, B, Akpunonu, B, Feinglos, M, Reaven, P, Soule, J, Luttrell, L, Schactman, B, Canadas, R, Boggs, B, Abbott, L, Herring, C, Roberts, L, Hage-Korban, E, Schubart, U, Taylon, A, Tannenbaum, A, Kingsley, J, Lenhard, J, Biscoveanu, M, Cohen, J, Donovan, D, Laferrere, B, Thompson, N, Wade, T, Detweiler, R, Henson, B, White, A, Cavale, A, Ravi, C, Thomas, A, Goodman, H, Kalen, V, Fox, D, Dauber, I, Rizvi, S, Marcus, A, Mulford, M, Higgins, A, Chane, M, Bland, V, Osunkoya, A, Suresh, D, Khan, S, Anastasi, L, Bajaj, M, Eisen, H, Mudaliar, Sr, Powell, S, Carr, K, Tripathy, D, Azad, N, Wakefield, P, Acheatel, R, Bressler, P, Dean, J, El Shahawy, M, Gilbert, J, Haque, I, Humiston, D, Ison, R, Karounos, D, Lillestol, M, Ferrier, N, Labroo, A, Vo, A, D’Agostino, R, Dulin, M, Mcwilliams, A, Hargrove, J, Blumberg, E, Jackson, B, Staniloae, C, Salacata, A, Hidalgo, H Jr, Nicol, P, Digiovanna, M, Soufer, J, Mahabadi, V, Akinboboye, O, Arauz-Pacheco, C, Neutel, J, Dungan, K, Benson, M, Powell, T, Gandy, W, Rovner, S, Berk, M, Khan, A, Ledesma, G, Madu, I, Erickson, B, Radbill, M, Graves, M, Kaczmarek, G, Giep, S, Baldauf, C, Golden, G, Lesh, K, Davis, C, Godbole, N, Kirby, W, Razzaque, N, Bhatt, B, Wilson, M., Internal medicine, ACS - Diabetes & metabolism, and ACS - Microcirculation
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Male ,medicine.medical_specialty ,EXSCEL Study Group ,Injections, Subcutaneous ,030209 endocrinology & metabolism ,Type 2 diabetes ,Kaplan-Meier Estimate ,030204 cardiovascular system & hematology ,Placebo ,Article ,Drug Administration Schedule ,GLP1-agonists ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Interquartile range ,Internal medicine ,Diabetes mellitus ,General & Internal Medicine ,medicine ,Humans ,Hypoglycemic Agents ,Least-Squares Analysis ,Aged ,Glycated Hemoglobin ,business.industry ,Venoms ,Semaglutide ,Incidence ,Type 2 diabetes, GLP1-agonists, exenatide, cardiovascular effects ,General Medicine ,11 Medical And Health Sciences ,Middle Aged ,medicine.disease ,Surgery ,Albiglutide ,Editorial ,Diabetes Mellitus, Type 2 ,Cardiovascular Diseases ,Exenatide ,Dulaglutide ,Female ,business ,Peptides ,cardiovascular effects ,medicine.drug - Abstract
BACKGROUND: The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown. METHODS: We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. RESULTS: In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P
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- 2017
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5. RELATIONSHIP BETWEEN SILENT HYPOGLYCEMIA AND TREATMENTS, OR HBA1C IN ELDERLY PATIENTS WITH DIABETES
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Koshizaka, M., primary, Ishikawa, T., additional, Maezawa, Y., additional, Takemoto, M., additional, Tokuyama, Y., additional, Saito, T., additional, and Yokote, K., additional
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- 2017
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6. Relationship between diabetes, race, obesity and outcomes in patients with acute coronary syndrome: a pool analysis from randomized trials
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Koshizaka, M., primary, Lopes, R. D., additional, Newby, L. K., additional, Schulte, P. J., additional, Clare, R. M., additional, Tricoci, P., additional, Mahaffey, K. W., additional, Ogawa, H., additional, Harrington, R. A., additional, and Alexander, J. H., additional
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- 2013
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7. Sodium-glucose cotransporter 2 inhibitor therapy reduces the administration frequency of steroid injection in patients with diabetic macular edema: A cohort study using the Japanese health insurance claims database.
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Ishibashi R, Koshizaka M, Takatsuna Y, Tatsumi T, Maezawa Y, Shiko Y, Inaba Y, Kawasaki Y, Kashiwagi Y, Kawakami E, Yamamoto S, and Yokote K
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- Humans, Male, Female, Japan epidemiology, Retrospective Studies, Middle Aged, Aged, Databases, Factual, Triamcinolone Acetonide administration & dosage, Triamcinolone Acetonide therapeutic use, Follow-Up Studies, Cohort Studies, Insurance, Health statistics & numerical data, East Asian People, Sodium-Glucose Transporter 2 Inhibitors therapeutic use, Sodium-Glucose Transporter 2 Inhibitors administration & dosage, Macular Edema drug therapy, Macular Edema epidemiology, Macular Edema etiology, Diabetic Retinopathy drug therapy, Diabetic Retinopathy epidemiology
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Aims/introduction: Severe diabetic macular edema (DME) is often resistant to anti-vascular endothelial growth factor therapy. Steroids are particularly effective at reducing edema by suppressing inflammation; they are also used as an alternative to expensive anti-vascular endothelial growth factor therapy in some patients. Therefore, the use of steroids in DME reflects an unmet need for anti-vascular endothelial growth factor therapy. Notably, triamcinolone acetonide (TA) injections are widely used in Japan. Here, we evaluated the frequency of TA as an indicator of the efficacy of sodium-glucose cotransporter 2 inhibitors (SGLT2is) in DME treatment using a health insurance claims database., Materials and Methods: In this cohort study, we retrospectively analyzed the health insurance claims data of 11 million Japanese individuals from 2005 to 2019. The frequency and duration of TA injection after the initiation of SGLT2is or other antidiabetic drugs were analyzed., Results: Among the 2,412 matched patients with DME, the incidence rate of TA injection was 63.8 times per 1,000 person-years in SGLT2i users and 94.9 times per 1,000 person-years in non-users. SGLT2is reduced the risk for the first (P = 0.0024, hazard ratio 0.66, 95% confidence interval 0.50-0.87), second (P = 0.0019, hazard ratio 0.53, 95% confidence interval 0.35-0.80) and third TA (P = 0.0053, hazard ratio 0.44, 95% confidence interval 0.25-0.80) injections. A subanalysis of each baseline characteristic of the patients showed that SGLT2is were effective regardless of the background factors., Conclusions: The use of SGLT2is reduced the frequency of TA injection in patients with DME. Therefore, SGLT2i therapy might be a novel, noninvasive and low-cost adjunctive therapy for DME., (© 2024 The Author(s). Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)
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- 2024
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8. Recommendations for cancer screening and surveillance in patients with Werner syndrome.
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Aono K, Maezawa Y, Kato H, Kaneko H, Kubota Y, Taniguchi T, Oshitari T, Motegi SI, Nakagami H, Taniguchi A, Watanabe K, Takemoto M, Koshizaka M, and Yokote K
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- 2024
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9. Sodium-glucose co-transporter 2 inhibitor therapy reduces the administration frequency of anti-vascular endothelial growth factor agents in patients with diabetic macular oedema with a history of anti-vascular endothelial growth factor agent use: A cohort study using the Japanese health insurance claims database.
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Ishibashi R, Inaba Y, Koshizaka M, Takatsuna Y, Tatsumi T, Shiko Y, Kashiwagi Y, Maezawa Y, Kawasaki Y, Kawakami E, Yamamoto S, and Yokote K
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- Humans, Ranibizumab adverse effects, Bevacizumab adverse effects, Angiogenesis Inhibitors therapeutic use, Angiogenesis Inhibitors adverse effects, Endothelial Growth Factors therapeutic use, Vascular Endothelial Growth Factor A therapeutic use, Cohort Studies, Retrospective Studies, Japan epidemiology, Glucose therapeutic use, Sodium, Intravitreal Injections, Macular Edema drug therapy, Macular Edema epidemiology, Macular Edema chemically induced, Sodium-Glucose Transporter 2 Inhibitors therapeutic use, Diabetic Retinopathy complications, Diabetic Retinopathy drug therapy, Diabetic Retinopathy epidemiology, Symporters therapeutic use
- Abstract
Aim: We assessed the effectiveness of sodium-glucose co-transporter 2 inhibitors (SGLT2is) in reducing the administration frequency of anti-vascular endothelial growth factor (VEGF) agents in patients with diabetic macular oedema (DMO) using a health insurance claims database., Materials and Methods: This retrospective cohort study analysed health insurance claims data covering 11 million Japanese patients between 2005 and 2019. We analysed the frequency and duration of intravitreal injection of anti-VEGF agents after initiating SGLT2is or other antidiabetic drugs., Results: Among 2412 matched patients with DMO, the incidence rates of anti-VEGF agent injections were 230.1 per 1000 person-year in SGLT2i users and 228.4 times per 1000 person-year in non-users, respectively, and the risk ratio for events was unchanged in both groups. Sub-analysis of each baseline characteristic of the patients showed that SGLT2is were particularly effective in patients with a history of anti-VEGF agent use [p = .027, hazard ratio (HR): 0.44, 95% confidence interval (CI): 0.22-0.91]. SGLT2is reduced the risk for the first (p = .023, HR: 0.45, 95% CI: 0.22-0.91) and second (p = .021, HR: 0.39, 95% CI: 0.17-0.89) anti-VEGF agent injections., Conclusions: There was no difference in the risk ratio for the addition of anti-VEGF therapy between the two treatment groups. However, the use of SGLT2is reduced the frequency of anti-VEGF agent administration in patients with DMO requiring anti-VEGF therapy. Therefore, SGLT2i therapy may be a novel, non-invasive, low-cost adjunctive therapy for DMO requiring anti-VEGF therapy., (© 2024 John Wiley & Sons Ltd.)
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- 2024
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10. A Japanese Case of Familial Hypercholesterolemia with a Protein-truncating Variant in LDLR and a PCSK9 Variant without Significant Atherosclerosis but Showing Remarkable Achilles Tendon Thickening.
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Minamizuka T, Kobayashi J, Tada H, Koshizaka M, Maezawa Y, Ono H, and Yokote K
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- Humans, Female, Middle Aged, Rosuvastatin Calcium therapeutic use, Atherosclerosis genetics, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Cholesterol, LDL blood, Mutation, Missense, Japan, East Asian People, Achilles Tendon diagnostic imaging, Achilles Tendon pathology, Hyperlipoproteinemia Type II genetics, Hyperlipoproteinemia Type II drug therapy, Hyperlipoproteinemia Type II blood, Hyperlipoproteinemia Type II complications, Hyperlipoproteinemia Type II diagnosis, Receptors, LDL genetics, Proprotein Convertase 9 genetics
- Abstract
The patient was a 54-year-old woman with familial hypercholesterolemia and remarkable Achilles tendon thickening. At 20 years old, the patient had a total cholesterol level of approximately 300 mg/dL. She started receiving rosuvastatin (5 mg/day) for low-density lipoprotein cholesterol (LDL-C) 235 mg/dL at 42 years old, which was increased to 10 mg/day at 54 years old, decreasing her serum LDL-C level to approximately 90 mg/dL. The serum Lp (a) level was 9 mg/dL. A computed tomography coronary angiogram showed no significant stenosis. Next-generation sequencing revealed a frameshift variant in LDL receptor (LDLR) (heterozygous) and a missense variant in proprotein convertase subtilisin/kaxin type 9 (PCSK9) (heterozygous). Continued statin therapy, in addition to low Lp (a) and female sex, can help prevent cardiovascular disease.
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- 2024
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11. Case of Werner syndrome complicated with Sjögren's syndrome and Hashimoto's thyroiditis presenting sclerosing panniculitis-like symptoms.
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Nishino A, Adachi A, Koshizaka M, Maezawa Y, Yokote K, and Sawada Y
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- Humans, Male, Adult, Hashimoto Disease complications, Hashimoto Disease diagnosis, Panniculitis complications, Sjogren's Syndrome complications, Sjogren's Syndrome diagnosis, Werner Syndrome complications, Werner Syndrome diagnosis
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- 2024
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12. Sex differences in symptom presentation and their impact on diagnostic accuracy in Werner syndrome.
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Kaneko H, Maezawa Y, Tsukagoshi-Yamaguchi A, Koshizaka M, Takada-Watanabe A, Nakamura R, Funayama S, Aono K, Teramoto N, Sawada D, Maeda Y, Minamizuka T, Hayashi A, Ide K, Ide S, Shoji M, Kitamoto T, Takemoto M, Kato H, and Yokote K
- Subjects
- Humans, Male, Female, Retrospective Studies, Sex Characteristics, Werner Syndrome Helicase genetics, Mutation, Werner Syndrome diagnosis, Werner Syndrome genetics
- Abstract
Aim: Whether sex differences exist in hereditary progeroid syndromes remains unclear. In this study, we investigated sex differences in patients with Werner syndrome (WS), a model of human aging, using patient data at the time of diagnosis., Methods: The presence of six cardinal signs in the diagnostic criteria was retrospectively evaluated., Results: We found that the percentage of patients with all cardinal signs was higher in males than in females (54.2% vs. 21.2%). By the age of 40 years, 57.1% of male patients with WS presented with all the cardinal signs, whereas none of the female patients developed all of them. In particular, the frequency of having a high-pitched, hoarse voice, a characteristic of WS, was lower in female patients. The positive and negative predictive values for clinical diagnosis were 100% for males and females, indicating the helpfulness of diagnostic criteria regardless of sex. More female patients than male (86.7% vs. 64%) required genetic testing for their diagnosis because their clinical symptoms were insufficient, suggesting the importance of genetic testing for females even if they do not show typical symptoms of WS. Finally, the frequency of abnormal voice was lower in patients with WS harboring the c.3139-1G > C homozygous mutation., Conclusion: These results indicate, for the first time, that there are sex differences in the phenotypes of hereditary progeroid syndromes. The analysis of this mechanism in this human model of aging may lead to the elucidation of sex differences in the various symptoms of normal human aging. Geriatr Gerontol Int 2024; 24: 161-167., (© 2023 The Authors. Geriatrics & Gerontology International published by John Wiley & Sons Australia, Ltd on behalf of Japan Geriatrics Society.)
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- 2024
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13. Imeglimin-mediated glycemic control in maternally inherited deafness and diabetes.
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Ishibashi R, Hirayama K, Watanabe S, Okano K, Kuroda Y, Baba Y, Kanayama T, Ito C, Kasahara K, Aiba S, Iga R, Ohtani R, Inaba Y, Koshizaka M, Maezawa Y, and Yokote K
- Subjects
- Female, Humans, Middle Aged, Blood Glucose analysis, Glucagon, Glycemic Control, Maternal Inheritance, Hypoglycemic Agents therapeutic use, Diabetes Mellitus, Type 2, Deafness drug therapy, Deafness chemically induced, Dipeptidyl-Peptidase IV Inhibitors adverse effects, Sodium-Glucose Transporter 2 Inhibitors adverse effects
- Abstract
Mitochondrial dysfunction causes maternally inherited deafness and diabetes (MIDD). Herein, we report improved glycemic control in a 47-year-old Japanese woman with MIDD using imeglimin without major adverse effects. Biochemical tests and metabolome analysis were performed before and after imeglimin administration. Blood glucose level fluctuations were determined. Sulfonylureas, dipeptidyl peptidase-4 inhibitors (DPP4is), and sodium glucose transporter-2 inhibitors (SGLT2i) were administered to evaluate the efficacy of their combination with imeglimin. Imeglimin decreased the HbA1c and ammonia levels and increased the time-in-range, C-peptide reactivity, and glucagon level. Elevated citrulline and histamine levels were decreased by imeglimin. The hypoglycemic effect was not enhanced by imeglimin when combined with sulfonylurea or DPP4i, but the blood glucose level was improved when combined with SGLT2i. Imeglimin improved glucose concentration-dependent insulin secretion and maximized the insulin secretory capacity by improving mitochondrial function and glutamine metabolism and urea circuit abnormalities by promoting glucagon secretion. Imeglimin could improve glycemic control in MIDD., (© 2023 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)
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- 2023
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14. Metabolomic analysis of serum samples from a clinical study on ipragliflozin and metformin treatment in Japanese patients with type 2 diabetes: Exploring human metabolites associated with visceral fat reduction.
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Tsukagoshi-Yamaguchi A, Koshizaka M, Ishibashi R, Ishikawa K, Ishikawa T, Shoji M, Ide S, Ide K, Baba Y, Terayama R, Hattori A, Takemoto M, Ouchi Y, Maezawa Y, and Yokote K
- Subjects
- Humans, Hypoglycemic Agents adverse effects, Japan, Glycated Hemoglobin, Intra-Abdominal Fat metabolism, Blood Glucose, Drug Therapy, Combination, Diabetes Mellitus, Type 2 drug therapy, Metformin therapeutic use, Sodium-Glucose Transporter 2 Inhibitors therapeutic use
- Abstract
Study Objective: The effects of the sodium-dependent glucose transporter-2 inhibitor ipragliflozin were compared with metformin in a previous study, which revealed that ipragliflozin reduced visceral fat content by 12%; however, the underlying mechanism was unclear. Therefore, this sub-analysis aimed to compare metabolomic changes associated with ipragliflozin and metformin that may contribute to their biological effects., Design: A sub-analysis of a randomized controlled study., Setting: Chiba University Hospital and ten hospitals in Japan., Patients: Fifteen patients with type 2 diabetes in the ipragliflozin group and 15 patients with type 2 diabetes in the metformin group with matching characteristics, such as age, sex, baseline A1C, baseline visceral fat area, smoking status, and concomitant medication., Interventions: Ipragliflozin 50 mg or metformin 1000 mg daily., Measurements: The clinical data were reanalyzed, and metabolomic analysis of serum samples collected before and 24 weeks after drug administration was performed using capillary electrophoresis time-of-flight mass spectrometry., Main Results: The reduction in the mean visceral fat area after 24 weeks of treatment was significantly larger (p = 0.002) in the ipragliflozin group (-19.8%) than in the metformin group (-2.5%), as were the subcutaneous fat area and body weight. The A1C and blood glucose levels decreased in both groups. Glutamic pyruvic oxaloacetic transaminase, γ-glutamyl transferase, uric acid, and triglyceride levels decreased in the ipragliflozin group. Low-density lipoprotein cholesterol levels decreased in the metformin group. After ipragliflozin administration, N2-phenylacetylglutamine, inosine, guanosine, and 1-methyladenosine levels increased, whereas galactosamine, glucosamine, 11-aminoundecanoic acid, morpholine, and choline levels decreased. After metformin administration, metformin, hypotaurine, methionine, methyl-2-oxovaleric acid, 3-nitrotyrosine, and cyclohexylamine levels increased, whereas citrulline, octanoic acid, indole-3-acetaldehyde, and hexanoic acid levels decreased., Conclusions: Metabolites that may affect visceral fat reduction were detected in the ipragliflozin group. Studies are required to further elucidate the underlying mechanisms., (© 2023 Pharmacotherapy Publications, Inc.)
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- 2023
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15. Senescence-associated inflammation and inhibition of adipogenesis in subcutaneous fat in Werner syndrome.
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Sawada D, Kato H, Kaneko H, Kinoshita D, Funayama S, Minamizuka T, Takasaki A, Igarashi K, Koshizaka M, Takada-Watanabe A, Nakamura R, Aono K, Yamaguchi A, Teramoto N, Maeda Y, Ohno T, Hayashi A, Ide K, Ide S, Shoji M, Kitamoto T, Endo Y, Ogata H, Kubota Y, Mitsukawa N, Iwama A, Ouchi Y, Takayama N, Eto K, Fujii K, Takatani T, Shiohama T, Hamada H, Maezawa Y, and Yokote K
- Subjects
- Animals, Humans, Adipogenesis genetics, Caenorhabditis elegans, Cellular Senescence genetics, Subcutaneous Fat metabolism, Inflammation, Sirolimus, Mammals, Werner Syndrome genetics, Insulin Resistance, Lipodystrophy, Insulins
- Abstract
Werner syndrome (WS) is a hereditary premature aging disorder characterized by visceral fat accumulation and subcutaneous lipoatrophy, resulting in severe insulin resistance. However, its underlying mechanism remains unclear. In this study, we show that senescence-associated inflammation and suppressed adipogenesis play a role in subcutaneous adipose tissue reduction and dysfunction in WS. Clinical data from four Japanese patients with WS revealed significant associations between the decrease of areas of subcutaneous fat and increased insulin resistance measured by the glucose clamp. Adipose-derived stem cells from the stromal vascular fraction derived from WS subcutaneous adipose tissues (WSVF) showed early replicative senescence and a significant increase in the expression of senescence-associated secretory phenotype (SASP) markers. Additionally, adipogenesis and insulin signaling were suppressed in WSVF, and the expression of adipogenesis suppressor genes and SASP-related genes was increased. Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), alleviated premature cellular senescence, rescued the decrease in insulin signaling, and extended the lifespan of WS model of C. elegans . To the best of our knowledge, this study is the first to reveal the critical role of cellular senescence in subcutaneous lipoatrophy and severe insulin resistance in WS, highlighting the therapeutic potential of rapamycin for this disease.
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- 2023
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16. Urinary α1 microglobulin level is useful for selecting sodium-glucose transporter 2 inhibitor or metformin for visceral fat reduction in patients with type 2 diabetes.
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Koshizaka M, Ishibashi R, Ishikawa K, Shoji M, Ide K, Ide S, Kato H, Teramoto N, Terayama R, Maezawa Y, and Yokote K
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- Humans, Intra-Abdominal Fat, Hypoglycemic Agents therapeutic use, Hypoglycemic Agents pharmacology, Metformin therapeutic use, Diabetes Mellitus, Type 2 drug therapy, Sodium-Glucose Transporter 2 Inhibitors therapeutic use
- Published
- 2023
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17. Weight loss improves inflammation by T helper 17 cells in an obese patient with psoriasis at high risk for cardiovascular events.
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Maezawa Y, Endo Y, Kono S, Ohno T, Nakamura Y, Teramoto N, Yamaguchi A, Aono K, Minamizuka T, Kato H, Ishikawa T, Koshizaka M, Takemoto M, Nakayama T, and Yokote K
- Subjects
- Humans, Th17 Cells metabolism, Inflammation complications, Inflammation metabolism, Obesity complications, Obesity metabolism, Weight Loss, Diabetes Mellitus, Type 2 metabolism, Psoriasis complications, Atherosclerosis
- Abstract
Psoriasis is a chronic inflammatory skin disease that is associated with obesity and myocardial infarction. Obesity-induced changes in lipid metabolism promote T helper 17 (Th17) cell differentiation, which in turn promotes chronic inflammation. Th17 cells have central roles in many inflammatory diseases, including psoriasis and atherosclerosis; however, whether treatment of obesity attenuates Th17 cells and chronic inflammatory diseases has been unknown. In this study, we found an increase in Th17 cells in a patient with obesity, type 2 diabetes and psoriasis. Furthermore, weight loss with diet and exercise resulted in a decrease in Th17 cells and improvement of psoriasis. This case supports the hypothesis that obesity leads to an increase in Th17 cells and chronic inflammation of the skin and blood vessel walls, thereby promoting psoriasis and atherosclerosis., (© 2023 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)
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- 2023
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18. Renal dysfunction, malignant neoplasms, atherosclerotic cardiovascular diseases, and sarcopenia as key outcomes observed in a three-year follow-up study using the Werner Syndrome Registry.
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Maeda Y, Koshizaka M, Shoji M, Kaneko H, Kato H, Maezawa Y, Kawashima J, Yoshinaga K, Ishikawa M, Sekiguchi A, Motegi SI, Nakagami H, Yamada Y, Tsukamoto S, Taniguchi A, Sugimoto K, Takami Y, Shoda Y, Hashimoto K, Yoshimura T, Kogure A, Suzuki D, Okubo N, Yoshida T, Watanabe K, Kuzuya M, Takemoto M, Oshima J, and Yokote K
- Subjects
- Humans, Kidney, Follow-Up Studies, Cross-Sectional Studies, Creatinine, Werner Syndrome complications, Werner Syndrome epidemiology, Sarcopenia, Cardiovascular Diseases, Kidney Diseases, Neoplasms complications, Neoplasms epidemiology
- Abstract
Werner syndrome is an adult-onset progeria syndrome that results in various complications. This study aimed to clarify the profile and secular variation of the disease. Fifty-one patients were enrolled and registered in the Werner Syndrome Registry. Their data were collected annually following registration. A cross-sectional analysis at registration and a longitudinal analysis between the baseline and each subsequent year was performed. Pearson's chi-squared and Wilcoxon signed-rank tests were used. Malignant neoplasms were observed from the fifth decade of life (mean onset: 49.7 years) and were observed in approximately 30% of patients during the 3-year survey period. Regarding renal function, the mean estimated glomerular filtration rate calculated from serum creatinine (eGFRcre) and eGFRcys, which were calculated from cystatin C in the first year, were 98.3 and 83.2 mL/min/1.73 m
2 , respectively, and differed depending on the index used. In longitudinal analysis, the average eGFRcre for the first and fourth years was 74.8 and 63.4 mL/min/1.73 m2 , showing a rapid decline. Secular changes in Werner syndrome in multiple patients were identified. The prevalence of malignant neoplasms is high, and renal function may decline rapidly. It is, therefore, necessary to carry out active and detailed examinations and pay attention to the type and dose of the drugs used.- Published
- 2023
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19. Association of high proprotein convertase subtilisin/kexin type 9 antibody level with poor prognosis in patients with diabetes: a prospective study.
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Yamagata H, Hayashi A, Yoshida Y, Koshizaka M, Onishi S, Yoshida T, Hiwasa T, and Takemoto M
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- Humans, Prospective Studies, Prognosis, Autoantibodies, Subtilisins, Proprotein Convertase 9, Diabetes Mellitus, Type 2 complications
- Abstract
In addition to pathogenic autoantibodies, polyclonal autoantibodies with unknown physiological roles and pathogenicity are produced in the body. Moreover, serum antibodies against the proprotein convertase subtilisin/kexin type 9 (PCSK9) protein, which is integral to cholesterol metabolism, have also been observed. PCSK9 was also reported to be associated with insulin secretion and diabetes mellitus (DM). Therefore, we aimed to examine the clinical significance of PCSK9 antibodies (PCSK9-Abs) levels. We measured blood PCSK9-Abs and PCSK9 protein levels in 109 healthy donors (HDs) and 274 patients with DM (type 2 DM: 89.8%) using an amplified luminescence proximity homogeneous assay-linked immunosorbent assay. Subsequently, patients with DM were followed up (mean: 4.93 years, standard deviation: 2.77 years, maximum: 9.58 years, minimum: 0.07 years) to examine associations between antibody titers and mortality, myocardial infarction, stroke onset, and cancer. The primary endpoint of this study was to examine whether PCSK9-Abs can be a prognostic marker for overall mortality among the patients with diabetes. The secondary endpoint was to examine the relationship between PCSK9-Abs and clinical parameters. Although both PCSK9-Abs and PCSK9 protein levels were significantly higher in the DM group than in the HD group (p < 0.008), PCSK9-Abs and PCSK9 protein levels showed no correlation in either group. Mortality was significantly associated with higher PCSK9-Ab levels, but unrelated to PCSK9 protein levels. After investigating for potential confounding factors, higher PCSK9-Ab levels were still associated with increased mortality among the patients with DM. PCSK9-Abs may be a novel prognostic marker for overall mortality in patients with diabetes, and further studies are warranted to verify its usefulness., (© 2023. The Author(s).)
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- 2023
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20. Case of Werner syndrome with significant improvement of refractory skin ulcer despite fibroblast cellular senescence.
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Kinoshita D, Kato H, Kaneko H, Ishikawa T, Teramoto N, Tsukagoshi A, Maeda Y, Minamizuka T, Hayashi A, Shoji M, Sawada D, Funayama S, Koshizaka M, Ogata H, Kubota Y, Mitsukawa N, Takemoto M, Yokote K, and Maezawa Y
- Subjects
- Humans, Cellular Senescence, Fibroblasts, Skin, Werner Syndrome Helicase, Skin Ulcer, Werner Syndrome
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- 2023
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21. Quality of life in Werner syndrome and associated subjective foot/ankle symptoms: A cross-sectional survey.
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Kitagawa Y, Amemiya A, Ogata H, Koshizaka M, Shoji M, Maezawa Y, Akita S, Mitsukawa N, and Yokote K
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- Male, Humans, Cross-Sectional Studies, Ankle, Surveys and Questionnaires, Pain, Quality of Life psychology, Werner Syndrome
- Abstract
Aim: The aims of this study were to assess the general quality of life and foot/ankle health-related quality of life among subjects with Werner syndrome (WS) and to determine subjective foot/ankle symptoms associated with quality of life., Methods: Using a questionnaire survey, patients were asked to provide information on age, sex and presence of subjective symptoms and complete both the 36-Item Short Form Health Survey (SF-36) questionnaire and the Self-Administered Foot Evaluation Questionnaire (SAFE-Q). Statistical analyses were performed using Student's t-test, the Mann-Whitney U test, Fisher's exact test and Spearman's rank correlation., Results: Data from 12 patients with an average age of 54 ± 8.6 years were analyzed. The mean SF-36 score for the domain of physical functioning was 21.2; for role-physical function, 32.6; for bodily pain, 38.5; for general health, 34.4; for vitality, 44.8; for social function, 38.5; for role-emotional function and for mental health, 46.7. The mean mental component summary was as high as the national standard, but it was low in men. The mean SAFE-Q scores were also low. Patients with ulcers had significantly more pain and low general health perception. As compared with the national standard, the role/social component score was not low, and there was a correlation in most domains of the SAFE-Q., Conclusion: In WS, the general health-related quality of life was low overall in the physical domain and low only in men for the mental domain, whereas it was low in the social domain when foot/ankle health-related quality of life was low. Geriatr Gerontol Int 2023; 23: 188-193., (© 2023 Japan Geriatrics Society.)
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- 2023
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22. Antihypertensive Effects of Esaxerenone in Older Patients with Primary Aldosteronism.
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Fujimoto M, Watanabe S, Igarashi K, Ruike Y, Ishiwata K, Naito K, Ishida A, Koshizaka M, Suzuki S, Shiko Y, Koide H, and Yokote K
- Abstract
Design: Retrospective cohort study. Patients . The data was obtained from a total of 87 PA patients treated with esaxerenone. The treatment group comprised 33 patients who received esaxerenone as first-line therapy and 54 patients that switched from another MRA to esaxerenone. Measurements . Blood pressure (BP), plasma aldosterone concentration (PAC), plasma renin activity (PRA), serum potassium level, estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (UACR), and brain natriuretic peptide (BNP) were assessed before and after treatment with esaxerenone. Patients with overall reductions in their systolic or diastolic BP by 10 mmHg, or more, were considered responders. Unpaired t -tests of the biochemical and personal parameters between responders and nonresponders were run to find the most influencing characteristic for treatment success., Results: BP overall decreased after treatment with esaxerenone (systolic BP: P =0.025, diastolic BP: P =0.096). Serum potassium levels increased, while eGFR decreased ( P =0.047 and 0.043, respectively). No patients needed a dose reduction or treatment discontinuation of esaxerenone based on the serum potassium and eGFR criteria. UACR and BNP decreased insignificantly. The responders were significantly older than the nonresponders of the esaxerenone treatment ( P =0.0035)., Conclusions: Esaxerenone was effective in older patients with primary aldosteronism., Competing Interests: The authors declare that there are no conflicts of interest. K.Y. received honorarium from Daiichi Sankyo., (Copyright © 2023 Masanori Fujimoto et al.)
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- 2023
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23. Optical coherence tomography findings in three patients with Werner syndrome.
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Nagai T, Yokouchi H, Miura G, Koshizaka M, Maezawa Y, Oshitari T, Yokote K, and Baba T
- Subjects
- Humans, Tomography, Optical Coherence methods, Choroid, Retina, Werner Syndrome diagnosis, Cataract diagnosis
- Abstract
Background: Werner syndrome is a rare, autosomal recessive disorder characterised by premature aging. It is a typical hereditary progeroid syndrome that can be difficult to diagnose owing to its rarity and the similarity of some of its symptoms, such as juvenile cataracts, to other common ophthalmologic conditions. Early onset of bilateral cataracts is currently used as the ophthalmological feature for Werner syndrome; however, ophthalmologists often find performing a detailed examination of the medical history and genetic testing for Werner syndrome at the time of an ophthalmologic consultation challenging. If a unique ocular finding was observed on ocular examinations in cases of juvenile bilateral cataracts, we could consider Werner syndrome as a differential diagnosis. CASE PRESENTATION: We documented the cases of three patients with Werner syndrome in whom thinning of the retina in the retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) were observed using optical coherence tomography (OCT). Visual field tests revealed the loss of visual field mainly owing to glaucoma. The thinnig of the choroidal thickness (CT) in three patients was also observed using enhanced depth imaging (EDI)-OCT., Conclusions: Three patients have thinning of the RNFL, GCC, and choroidal thickness and the loss of visual field. These findings suggest the need for including Werner syndrome in the differential diagnosis when patients presenting with juvenile cataracts of unknown cause also show abnormal retinal and choroidal thinning in the OCT images., (© 2022. The Author(s).)
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- 2022
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24. Correction of Hypercortisolemia with an Improved Cognitive Function and Muscle Mass after Transsphenoidal Surgery in an Older Patient with Cushing's Disease.
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Terayama R, Ishikawa T, Ishiwata K, Sato A, Minamizuka T, Ohno T, Kono S, Yamamoto M, Yokoh H, Nagano H, Koshizaka M, Suzuki S, Koide H, Maezawa Y, and Yokote K
- Abstract
Cushing's disease causes numerous metabolic disorders, cognitive decline, and sarcopenia, leading to deterioration of the general health in older individuals. Cushing's disease can be treated with transsphenoidal surgery, but thus far, surgery has often been avoided in older patients. We herein report an older woman with Cushing's disease whose cognitive impairment and sarcopenia improved after transsphenoidal surgery. Although cognitive impairment and sarcopenia in most older patients show resistance to treatment, our case indicates that normalization of the cortisol level by transsphenoidal surgery can be effective in improving the cognitive impairment and muscle mass loss caused by Cushing's disease.
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- 2022
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25. Homozygous familial lipoprotein lipase deficiency without obvious coronary artery stenosis.
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Minamizuka T, Kobayashi J, Tada H, Koshizaka M, Maezawa Y, and Yokote K
- Subjects
- Aged, Arteries, Cholesterol, Codon, Nonsense, Constriction, Pathologic, Female, Fibric Acids, Humans, Lipoprotein Lipase genetics, Lipoproteins, HDL genetics, Triglycerides, Coronary Stenosis diagnostic imaging, Coronary Stenosis genetics, Hyperlipoproteinemia Type I diagnosis, Hyperlipoproteinemia Type I genetics, Hypertriglyceridemia
- Abstract
The prevalence of familial lipoprotein lipase deficiency (LPLD) is approximately one in 1,000,000 in the general population. There are conflicting reports on whether or not LPLD is atherogenic. We conducted coronary computed tomographic (CT) angiography on two patients in their 70 s who had genetically confirmed LPLD. Patient 1 was a 73 year old woman with a body mass index (BMI) of 27.5 kg/m
2 , no history of diabetes mellitus and no history of drinking alcohol or smoking. At the time of her first visit, her serum total cholesterol, triglycerides and high-density lipoprotein cholesterol levels were 4.8 mmol/L, 17.3 mmol/L, and 0.5 mmol/L, respectively. She was treated with a lipid-restricted diet and fibrate but her serum TG levels remained extremely high. Next-generation sequencing analysis revealed a missense mutation (homo) in the LPL gene, c.662T>C (p. Ile221Thr), leading to the diagnosis of homozygous familial LPL deficiency (LPLD). Patient 2 was another 73- year- old woman. She also had marked hypertriglyceridemia with no history of diabetes mellitus, drinking alcohol, or smoking. Previous genetic studies showed she had a nonsense mutation (homozygous) in the LPL gene, c.1277G>A (p.Trp409Ter). To clarify the degree of coronary artery stenosis in these two cases, we conducted coronary CT angiography and found that no coronary artery stenosis in either the right or left coronary arteries. Based on the findings in these two elderly women along with previous reports on patients in their 60 s with LPLD and hypertriglyceridemia, we suggest that LPLD may not be associated with the development or progression of coronary artery disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
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26. Lifetime extension and the recent cause of death in Werner syndrome: a retrospective study from 2011 to 2020.
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Kato H, Koshizaka M, Kaneko H, Maezawa Y, and Yokote K
- Subjects
- Aged, Cause of Death, Humans, Longevity, Middle Aged, Retrospective Studies, Werner Syndrome Helicase, Neoplasms, Werner Syndrome diagnosis
- Abstract
Background: Werner syndrome (WS) is an autosomal recessive premature ageing disease that causes accelerated ageing-like symptoms after puberty. Previous studies conducted in the late 2000s reported that malignant neoplasms and atherosclerotic diseases were the two leading causes of death, with life expectancies in the mid-50 s. However, the recent lifespan and cause of death in patients with WS remain unclear., Objective: To clarify the latest lifespan and causes of death in patients with WS., Method: We conducted a questionnaire-based survey in 2020 among the primary doctors of WS patients who were identified in previous nationwide surveys in Japan and clarified the following: the age of WS patients (age of death, if the patient had already died), sex, and cause of death. Patients who died in 2010 or earlier were excluded from the analysis., Results: A total of 123 living patients were identified at the time of the survey in 2020. Fourteen WS patients died between 2011 and 2020, with a mean age of 59.0 ± 8.9 years (mean ± SD). The most common cause of death was non-epithelial tumours, accounting for eight deaths, while no patient died of atherosclerotic diseases., Conclusions: Compared to previous studies, this study suggests that the lifespan of patients with WS has been extended. Although there were no deaths due to atherosclerotic diseases, non-epithelial tumours were still the leading cause of death. Further development of screening and treatment methods for these tumours is required., (© 2022. The Author(s).)
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- 2022
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27. Predictive model and risk engine web application for surgical site infection risk in perioperative patients with type 2 diabetes.
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Koshizaka M, Ishibashi R, Maeda Y, Ishikawa T, Maezawa Y, Takemoto M, and Yokote K
- Abstract
Aim: To identify predictive factors for surgical site infection (SSI) in patients with type 2 diabetes and develop a prediction tool., Materials and Methods: We retrospectively analyzed the perioperative blood glucose management of 105 patients with type 2 diabetes treated from 2016 to 2018 at Chiba University Hospital. The primary outcome was SSI onset within 30 postoperative days; moreover, predictive factors were identified using univariate analysis. Principal component analysis and logistic regression analysis were performed to prepare SSI predictive model using the identified predictive factors. The area under the receiver operating characteristic curve (AUC) was evaluated. Based on the predictive model, we developed a risk engine for SSI prediction., Results: Compared with patients without SSI ( n = 70), those with SSI ( n = 35) had significantly higher fasting blood glucose levels at referral (169.1 ± 61.8 mg/dL vs. 140.1 ± 56.6, P = 0.036), preoperative mean blood glucose levels (178.3 ± 48.4 mg/dL vs. 155.2 ± 39.7, P = 0.009), preoperative maximum blood glucose levels (280.4 ± 87.3 mg/dL vs. 230.3 ± 92.4, P = 0.009), preoperative blood glucose fluctuations (54.9 ± 24.1 mg/dL vs. 37.7 ± 23.1, P = 0.001), percentage of hospitalization at referral (54.3% vs. 20.0, P < 0.001); longer operation time (432.5 ± 179.6 min vs. 282.5 ± 178.3, P < 0.001); and greater bleeding volume (972.3 ± 920.1 mg/dL vs. 436.4 ± 795.8, P < 0.001). Logistic regression analysis revealed preoperative blood glucose fluctuation and operation time as the most reliable predictive factors. The predictive model had high prediction accuracy (AUC of 0.801). The risk engine prototype for SSI prediction can be accessed at https://www.dm-ope-riskengine.org/., Conclusions: The predictive model developed in this study could screen high-risk patients. It may be useful to prevent SSI in such patients., Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-022-00587-w., Competing Interests: Conflict of interestNone., (© The Japan Diabetes Society 2022.)
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- 2022
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28. Sodium-Glucose Co-Transporter 2 Inhibitors Reduce Macular Edema in Patients with Diabetes mellitus .
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Tatsumi T, Oshitari T, Takatsuna Y, Ishibashi R, Koshizaka M, Shiko Y, Baba T, Yokote K, and Yamamoto S
- Abstract
Purpose: To determine the efficacy of systemic sodium-glucose co-transporter 2 inhibitors (SGLT2i) on diabetic macular edema (DME)., Methods: The medical records of patients with DME with a central retinal thickness (CRT) ≥320 µm in men and 305 µm in women, more than 6 months after the initiation of diabetes mellitus treatment, were reviewed. The CRT and best-corrected visual acuity (BCVA) were evaluated before and after the initiation of systemic SGLT2i and non-SGLT2i treatments., Results: There were 24 eyes of 19 patients with DME that were treatment naïve or had not received treatments for the DME within four months before the initiation of SGLT2i. In these patients, the BCVA had a 0.31 ± 0.39 logarithm of the minimum angle of resolution (logMAR) units at the baseline, and it did not improve significantly at 0.26 ± 0.29 logMAR units after the initiation of SGLT2i ( p = 0.56). However, the SGLT2i treatment significantly reduced the CRT from 423.3 ± 79.8 µm to 379.6 ± 69.5 µm ( p = 0.0001). In the same evaluation of 19 eyes of 14 patients with DME that were initiated with non-SGLT2i agents, there was no significant difference between the baseline BCVA and the BCVA after the initiation of non-SGLT2i ( p = 0.47). The CRT increased significantly after the initiation of non-SGLT2i ( p = 0.0011). In three eyes in which the SGLT2i treatments were administered at the time of anti-vascular endothelial growth factor (VEGF) treatments, the anti-VEGF treatment alone had only a limited effect on the DME, but the reduction in the DME was enhanced after the addition of SGLT2i., Conclusions: These findings indicate that systemic SGLT2i can reduce DMEs, and they suggest that SGLT2i may be an additional treatment option to anti-VEGF treatments for eyes with DMEs.
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- 2022
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29. A high prevalence of myeloid malignancies in progeria with Werner syndrome is associated with p53 insufficiency.
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Kato H, Maezawa Y, Nishijima D, Iwamoto E, Takeda J, Kanamori T, Yamaga M, Mishina T, Takeda Y, Izumi S, Hino Y, Nishi H, Ishiko J, Takeuchi M, Kaneko H, Koshizaka M, Mimura N, Kuzuya M, Sakaida E, Takemoto M, Shiraishi Y, Miyano S, Ogawa S, Iwama A, Sanada M, and Yokote K
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- Chromosome Aberrations, Humans, Mutation, Prevalence, Tumor Suppressor Protein p53 genetics, Hematologic Neoplasms, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Myeloproliferative Disorders, Progeria genetics, Werner Syndrome complications, Werner Syndrome genetics
- Abstract
Werner syndrome (WS) is a progeroid syndrome caused by mutations in the WRN gene, which encodes the RecQ type DNA helicase for the unwinding of unusual DNA structures and is implicated in DNA replication, DNA repair, and telomere maintenance. patients with WS are prone to develop malignant neoplasms, including hematological malignancies. However, the pathogenesis of WS-associated hematological malignancies remains uncharacterized. Here we investigated the somatic gene mutations in WS-associated myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). Whole-exome sequencing (WES) of 4 patients with WS with MDS/AML revealed that all patients had somatic mutations in TP53 but no other recurrent mutations in MDS/AML. TP53 mutations were identified at low allele frequencies at more than one year before the MDS/AML stage. All 4 patients had complex chromosomal abnormalities including those that involved TP53. Targeted sequencing of nine patients with WS without apparent blood abnormalities did not detect recurrent mutations in MDS/AML except for a PPM1D mutation. These results suggest that patients with WS are apt to acquire TP53 mutations and/or chromosomal abnormalities involving TP53, rather than other MDS/AML-related mutations. TP53 mutations are frequently associated with prior exposure to chemotherapy; however, all four patients with WS with TP53 mutations/deletions had not received any prior chemotherapy, suggesting a pathogenic link between WRN mutations and p53 insufficiency. These results indicate that WS hematopoietic stem cells with WRN insufficiency acquire competitive fitness by inactivating p53, which may cause complex chromosomal abnormalities and the subsequent development of myeloid malignancies. These findings promote our understanding of the pathogenesis of myeloid malignancies associated with progeria., (Copyright © 2022 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)
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- 2022
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30. Rothmund-Thomson syndrome investigated by two nationwide surveys in Japan.
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Kaneko H, Takemoto M, Murakami H, Ihara K, Kosaki R, Motegi SI, Taniguchi A, Matsuo M, Yamazaki N, Nishigori C, Takita J, Koshizaka M, Maezawa Y, and Yokote K
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- Humans, Japan epidemiology, Mutation, Quality of Life, Surveys and Questionnaires, Rothmund-Thomson Syndrome diagnosis, Rothmund-Thomson Syndrome epidemiology, Rothmund-Thomson Syndrome genetics
- Abstract
Background: Rothmund-Thomson syndrome (RTS) is an autosomal recessive genetic disorder characterized by poikiloderma of the face, small stature, sparse scalp hair, juvenile cataract, radial aplasia, and predisposition to cancers. Due to the rarity of RTS, the situation of patients with RTS in Japan has not been elucidated., Methods: In 2010 and 2020, following the results of a primary questionnaire survey, a secondary questionnaire survey on RTS was conducted nationwide to investigate the number of RTS cases and their associated skin lesions, bone lesions, other clinical features, and quality of life in Japan., Results: In 2010 and 2020, 10 and eight patients with RTS were recruited, respectively. Skin lesions such as poikiloderma, erythema, pigmentation, and abnormal scalp hair were observed in almost all cases. Bone lesions were observed in four cases in the 2010 and 2020 surveys, respectively. Two cases had mutations in the RECQL4 gene in the 2020 survey., Conclusions: Two nationwide surveys have shown the actual situation of patients with RTS in Japan. Cutaneous and bone manifestations are important for the diagnosis of RTS. However, many patients have no RECQL4 mutations. The novel causative gene of RTS should be further elucidated., (© 2022 Japan Pediatric Society.)
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- 2022
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31. Serum HDL-C values: An extremely useful marker for differentiating homozygous lipoprotein lipase deficiency from severe hypertriglyceridemia with other causes in Japan: A meta-analysis based on literatures on Japanese homozygous lipoprotein lipase deficiency.
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Kobayashi J, Minamizuka T, Koshizaka M, Maezawa Y, Ono H, and Yokote K
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- Homozygote, Humans, Japan, Lipoprotein Lipase genetics, Triglycerides, Hyperlipoproteinemia Type I genetics, Hypertriglyceridemia diagnosis, Hypertriglyceridemia genetics
- Abstract
Backgrounds and Aim: Lipoprotein lipase (LPL) deficiency is a genetic disorder with a defective gene for lipoprotein lipase, leading to very high triglycerides. In the daily practice it is much more common to come across severely hypertriglyceridemia without homozygous or compound heterozygous LPL deficiency (SHTG)., Methods: We investigated on how to screen homozygous or compound heterozygous LPL deficiency using lipid parameters by meta-analyzing past 20 subjects on this genetic disease reported by Japanese investigators. As a comparison with LPL deficiency, 21 subjects with SHTG from recent two studies were included in this study., Results: Serum HDL-C levels were significantly lower in LPL deficiency than in SHTG (0.38 ± 0.13 vs 0.94 ± 0.28 mmol/L (mean ± SD), p < 0.001), whereas other serum lipids did not differ between the two groups. The ROC curve ± standard error for serum HDL-C for discriminating the two groups was 0.97 ± 0.019. Sensitivity and specificity for distinguishing the two groups were 90% and 95%, respectively when serum HDL-C 0.62 mmol/L was adopted as cut point., Conclusion: We found for the first time that serum HDL-C is an extremely useful marker for discriminating LPL deficiency from SHTG in Japanese population., (Copyright © 2021 Elsevier B.V. All rights reserved.)
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- 2021
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32. Low dose red yeast rice with monacolin K lowers LDL cholesterol and blood pressure in Japanese with mild dyslipidemia: A multicenter, randomized trial.
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Minamizuka T, Koshizaka M, Shoji M, Yamaga M, Hayashi A, Ide K, Ide S, Kitamoto T, Sakamoto K, Hattori A, Ishikawa T, Kobayashi J, Maezawa Y, Kobayashi K, Takemoto M, Inagaki M, Endo A, and Yokote K
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- Biological Products, Blood Pressure, Cholesterol, LDL, Dietary Supplements, Humans, Japan, Lovastatin, Dyslipidemias drug therapy, Hypercholesterolemia
- Abstract
Background and Objectives: Red yeast rice contains monacolin K, an inhibitor of cholesterol synthesis, and gamma-aminobutyric acid, a neurotransmitter. The daily dose of red yeast rice and monacolin K in previous studies was relatively high; therefore, there were safety concerns. We aimed to examine the effects of low daily dose red yeast rice on arteriosclerosis in patients with mild dyslipidemia., Methods and Study Design: Eighteen patients without known cardiovascular disease and unsatisfactory low-density lipoprotein cholesterol (3.96±0.19 mmol/L) controlled only by diet therapy were randomly allocated to receive low dose red yeast rice (200 mg/day) containing 2 mg monacolin K or diet therapy alone for 8 weeks. The primary outcome was the absolute change in low-density lipoprotein cholesterol. Secondary outcomes included total cholesterol, apolipoprotein B, and blood pressure., Results: Low-density lipoprotein cholesterol decreased significantly in the red yeast rice group than in the diet therapy group (median [interquartile range]: control -0.20 [-0.62, 1.19] mmol/L vs. red yeast rice -0.96 [-1.05, -0.34] mmol/L, p=0.030). The red yeast rice group also exhibited significant decreases in total cholesterol, apolipoprotein B, and blood pressure. No severe treatment-related adverse effects on muscles, liver, or renal function were observed., Conclusions: We found that patients in the red yeast rice group exhibited significant reductions in lowdensity lipoprotein cholesterol, total cholesterol, apolipoprotein B, and blood pressure without any recognised adverse effect. This suggests that low daily dose red yeast rice could reduce cardiovascular risk in patients with dyslipidemia.
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- 2021
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33. Generation of disease-specific and CRISPR/Cas9-mediated gene-corrected iPS cells from a patient with adult progeria Werner syndrome.
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Kato H, Maezawa Y, Ouchi Y, Takayama N, Sone M, Sone K, Takada-Watanabe A, Tsujimura K, Koshizaka M, Nagasawa S, Saitoh H, Ohtaka M, Nakanishi M, Tahara H, Shimamoto A, Iwama A, Eto K, and Yokote K
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- Adult, CRISPR-Cas Systems genetics, Exodeoxyribonucleases genetics, Humans, Werner Syndrome Helicase genetics, Werner Syndrome Helicase metabolism, Induced Pluripotent Stem Cells metabolism, Werner Syndrome genetics
- Abstract
Adult progeria Werner syndrome (WS), a rare autosomal recessive disorder, is characterized by accelerated aging symptoms after puberty. The causative gene, WRN, is a member of the RecQ DNA helicase family and is predominantly involved in DNA replication, repair, and telomere maintenance. Here, we report the generation of iPS cells from a patient with WS and correction of the WRN gene by the CRISPR/Cas9-mediated method. These iPSC lines would be a valuable resource for deciphering the pathogenesis of WS., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)
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- 2021
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34. Effects of Sodium Glucose Co-Transporter 2 Inhibitors in Type 1 Diabetes Mellitus on Body Composition and Glucose Variabilities: Single-Arm, Exploratory Trial.
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Baba Y, Ishibashi R, Takasaki A, Ito C, Watanabe A, Tokita M, Meguro M, Harama T, Hirayama K, Yamamoto T, Nakamura S, Koshizaka M, Maezawa Y, Uchida D, and Okajima F
- Abstract
Introduction: Sodium glucose co-transporter 2 (SGLT2) inhibitors are widely used in the management of type 2 diabetes mellitus; they prevent cardiovascular events and reduce fat mass. However, little is known about the effects of SGLT2 inhibitors on type 1 diabetes mellitus as an adjuvant to insulin therapy. Therefore, we aimed to elucidate the effects of SGLT2 inhibitors on body composition of patients with type 1 diabetes mellitus and assess blood glucose variability., Methods: A single-center, single-arm, prospective, interventional study was performed on Japanese patients with type 1 diabetes mellitus who were not administered SGLT2 inhibitors prior to this study. These patients were equipped with flash glucose monitoring (FGM) and administered ipragliflozin 50 mg daily. Body composition was evaluated using bioelectrical impedance analysis, and glycemic variabilities were assessed using FGM before and after SGLT2 inhibitor treatment., Results: After 52 weeks of treatment, the total fat mass tended to be reduced (- 9.10% from baseline, P = 0.098). In addition, skeletal muscle mass also decreased (- 2.98% from baseline, P = 0.023). Although the basal insulin dose was reduced, SGLT2 inhibitors decreased HbA1c levels. FGM revealed that glycemic variabilities were also reduced, and time within the target glucose range increased (51.7% vs. 62.5%, P = 0.004)., Conclusion: SGLT2 inhibitors have beneficial effects on glycemic variabilities and fat mass reductions in patients with type 1 diabetes mellitus. However, loss of skeletal muscle is a major concern; therefore, caution is required when using SGLT2 inhibitors in lean patients with type 1 diabetes mellitus., Trial Registration: University Hospital Medical Information Network Clinical Trial Registry (UMIN000042407).
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- 2021
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35. Fibroblasts from different body parts exhibit distinct phenotypes in adult progeria Werner syndrome.
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Kato H, Maezawa Y, Takayama N, Ouchi Y, Kaneko H, Kinoshita D, Takada-Watanabe A, Oshima M, Koshizaka M, Ogata H, Kubota Y, Mitsukawa N, Eto K, Iwama A, and Yokote K
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- Cellular Senescence, Gene Expression Profiling, Humans, Osteogenesis, Werner Syndrome Helicase genetics, Abdomen physiology, Aging genetics, Fibroblasts pathology, Foot physiopathology, Human Body, Phenotype, Werner Syndrome genetics
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Werner syndrome (WS), also known as adult progeria, is characterized by accelerated aging symptoms from a young age. Patients with WS experience painful intractable skin ulcers with calcifications in their extremities, subcutaneous lipoatrophy, and sarcopenia. However, there is no significant abnormality in the trunk skin, where the subcutaneous fat relatively accumulates. The cause of such differences between the limbs and trunk is unknown. To investigate the underlying mechanism behind these phenomena, we established and analyzed dermal fibroblasts from the foot and trunk of two WS patients. As a result, WS foot-derived fibroblasts showed decreased proliferative potential compared to that from the trunk, which correlated with the telomere shortening. Transcriptome analysis showed increased expression of genes involved in osteogenesis in the foot fibroblasts, while adipogenic and chondrogenic genes were downregulated in comparison with the trunk. Consistent with these findings, the adipogenic and chondrogenic differentiation capacity was significantly decreased in the foot fibroblasts in vitro . On the other hand, the osteogenic potential was mutually maintained and comparable in the foot and trunk fibroblasts. These distinct phenotypes in the foot and trunk fibroblasts are consistent with the clinical symptoms of WS and may partially explain the underlying mechanism of this disease phenotype.
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- 2021
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36. Management guideline for Werner syndrome 2020. 4. Osteoporosis associated with Werner syndrome.
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Mori S, Takemoto M, Kubota Y, Taniguchi T, Motegi SI, Taniguchi A, Nakagami H, Maezawa Y, Koshizaka M, Kato H, Tsukamoto K, Kuzuya M, and Yokote K
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- Female, Humans, Male, Middle Aged, Osteogenesis, Patient Care Management methods, Polymorphism, Single Nucleotide, Absorptiometry, Photon methods, Diphosphonates therapeutic use, Femoral Fractures diagnosis, Femoral Fractures etiology, Femoral Fractures prevention & control, Osteoporosis complications, Osteoporosis diagnosis, Osteoporosis drug therapy, Osteoporosis etiology, Werner Syndrome complications, Werner Syndrome genetics, Werner Syndrome therapy, Werner Syndrome Helicase genetics
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- 2021
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37. Management guideline for Werner syndrome 2020. 3. Diabetes associated with Werner syndrome.
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Takemoto M, Kubota Y, Taniguchi T, Motegi SI, Taniguchi A, Nakagami H, Maezawa Y, Koshizaka M, Kato H, Tsukamoto K, Mori S, Kuzuya M, and Yokote K
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- Humans, Hypoglycemic Agents therapeutic use, Diabetes Mellitus, Type 2, Dipeptidyl-Peptidase IV Inhibitors, Metformin therapeutic use, Werner Syndrome
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Aims: To evaluate the characteristics of diabetes associated with Werner syndrome., Methods: A literature search was done with search term "Werner syndrome" and "Diabetes"., Results and Conclusions: Prevalence of diabetes is extremely high in Werner syndrome. Diabetes associated with Werner syndrome is classified as "accompanied with other diseases and conditions and the one occurring mainly in association with other genetic syndromes." This type of diabetes is marked by accumulated visceral fat and high insulin resistance, despite low body mass index. Thiazolidine derivatives and metformin are effective for glycemic control. New antidiabetic drugs, such as dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists, could be potentially beneficial for patients with Werner syndrome. Furthermore, the establishment of diet therapy as well as exercise therapy is warranted. Geriatr Gerontol Int 2021; 21: 142-145., (© 2020 Japan Geriatrics Society.)
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- 2021
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38. Management guideline for Werner syndrome 2020 8. Calcification in tendons associated with Werner syndrome.
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Taniguchi A, Tanaka Y, Takemoto M, Kubota Y, Taniguchi T, Motegi SI, Nakagami H, Maezawa Y, Koshizaka M, Kato H, Tsukamoto K, Mori S, Kuzuya M, and Yokote K
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- Humans, Achilles Tendon diagnostic imaging, Achilles Tendon surgery, Calcinosis diagnostic imaging, Calcinosis epidemiology, Orthopedic Procedures, Werner Syndrome
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Aim: To clarify the diagnostic value of the calcification in the Achilles tendon for Werner syndrome., Methods: Calcification of the Achilles tendon in the plain radiograph was investigated in 92 patients with Werner syndrome provided from the nationwide secondary survey in 2010. And the same investigation was performed for 2151 feet in 1853 patients without Werner syndrome, who underwent foot and ankle surgeries at the department of orthopaedic surgery in Nara Medical University from 2004 to 2015., Result and Conclusion: Achilles tendon calcification was observed in 70 (76.1%) out of 92 patients with Werner syndrome, whereas that was observed only in 19 feet (0.88%) without Werner syndrome, accompanied by 1 to 4 calcified masses with a maximum diameter ranging from 9.7mm to 63.2mm. The frequency of Achilles tendon calcification in patients with Werner syndrome is far higher than that of patients without Werner syndrome. Achilles tendon calcification could be included in the diagnostic criteria for Werner syndrome. Geriatr Gerontol Int 2021; 21: 163-165., (© 2020 Japan Geriatrics Society.)
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- 2021
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39. Management guideline for Werner syndrome 2020. 7. Skin ulcer associated with Werner syndrome: Dermatological treatment.
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Motegi SI, Takemoto M, Taniguchi T, Kubota Y, Taniguchi A, Nakagami H, Maezawa Y, Koshizaka M, Kato H, Mori S, Tsukamoto K, Kuzuya M, and Yokote K
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- Bandages, Humans, Wound Healing, Pressure Ulcer, Skin Ulcer diagnosis, Skin Ulcer etiology, Skin Ulcer therapy, Werner Syndrome
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Skin ulcers in Werner's syndrome often arise from hyperkeratotic lesions and trauma to pressure points such as the plantar region, and are more difficult to treat than wound healing in healthy individuals. Multiple factors contribute to the intractable skin ulcers in Werner's syndrome, including skin thinning, sclerosis, fatty tissue loss, impaired blood flow, calcification, and excessive pressure due to osteoarticular deformity. Treatment includes topical application of a keratolytic agent for keratosis around the ulcer. Treatment of ulcers is the same as for normal ulcers, and if the ulcer is associated with infection and necrotic tissue, surgical debridement with a scalpel or scissors should be performed as much as possible after washing with saline or mildly warm water or with an antibacterial agent. Topical medications that promote softening and debridement of the necrotic tissue are used with careful control of moisture in the wound. Topical agents that promote granulation should be used in wounds where necrotic tissue has been removed without infection. Dressings to maintain a moist environment in the wound may also be useful. If the wound does not improve with conservative treatment, surgical treatment should be considered. Geriatr Gerontol Int 2021; 21: 160-162., (© 2020 Japan Geriatrics Society.)
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- 2021
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40. Management guideline for Werner syndrome 2020. 5. Infection associated with Werner syndrome.
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Taniguchi T, Takemoto M, Kubota Y, Motegi SI, Taniguchi A, Nakagami H, Maezawa Y, Koshizaka M, Kato H, Mori S, Tsukamoto K, Kuzuya M, and Yokote K
- Subjects
- Debridement methods, Humans, Microbial Sensitivity Tests methods, Skin blood supply, Skin microbiology, Wound Healing, Anti-Bacterial Agents administration & dosage, Anti-Bacterial Agents classification, Patient Care Management methods, Patient Care Management standards, Skin Diseases, Bacterial etiology, Skin Diseases, Bacterial therapy, Skin Ulcer etiology, Skin Ulcer microbiology, Skin Ulcer physiopathology, Skin Ulcer therapy, Soft Tissue Infections etiology, Soft Tissue Infections therapy, Werner Syndrome complications
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- 2021
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41. Management guideline for Werner syndrome 2020. 2. Sarcopenia associated with Werner syndrome.
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Kuzuya M, Takemoto M, Kubota Y, Taniguchi T, Motegi SI, Taniguchi A, Nakagami H, Maezawa Y, Koshizaka M, Kato H, Mori S, Tsukamoto K, and Yokote K
- Subjects
- Aged, Exercise, Humans, Male, Muscle Strength, Muscle, Skeletal, Frailty, Sarcopenia diagnosis, Sarcopenia epidemiology, Werner Syndrome
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Aim: Sarcopenia is defined as a condition that combines decreased skeletal muscle mass with weakness or decreased physical function. It is well known that in older adults, the presence of sarcopenia is a risk of frailty, falls and physical dysfunction. Patients with Werner syndrome are characterized by visceral fat accumulation and thin limbs, but the prevalence of sarcopenia in patients with Werner syndrome has not been investigated., Methods: A literature search was conducted using Werner syndrome and skeletal muscle as keywords. We also analyzed data from our 7 Werner syndrome patients., Results: A literature search on the relationship between Werner syndrome and skeletal muscle yielded only one article reported from Japan. According to this paper, a decrease in skeletal muscle mass (appendicular skeletal muscle index) was observed in all 9 Werner syndromes investigated. On the other hand, in our 7 Werner syndrome patients, their appendicular skeletal muscle indexes were below the standard value except for one male patient who had continued resistance exercise., Conclusion: The decrease in skeletal muscle mass frequently occurs in patients with Werner syndrome. However, resistance exercise may prevent the appearance of sarcopenia and requires early intervention in patients with Werner syndrome. Geriatr Gerontol Int 2021; 21: 139-141., (© 2020 Japan Geriatrics Society.)
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- 2021
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42. Management guideline for Werner syndrome 2020. 6. Skin ulcers associated with Werner syndrome: Prevention and non-surgical and surgical treatment.
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Kubota Y, Takemoto M, Taniguchi T, Motegi SI, Taniguchi A, Nakagami H, Maezawa Y, Koshizaka M, Kato H, Mori S, Tsukamoto K, Kuzuya M, and Yokote K
- Subjects
- Humans, Quality of Life, Wound Healing, Diabetic Foot, Skin Ulcer diagnosis, Skin Ulcer etiology, Skin Ulcer prevention & control, Werner Syndrome genetics
- Abstract
Aim: To provide guidelines on the diagnosis, treatment, and prevention of skin ulcers in Werner syndrome., Methods: This article was based on literature from 1996, when WRN was identified as a gene responsible for Werner syndrome, and we evaluated several authentic clinical cases of genetically diagnosed patients. There were 63 patients with Werner syndrome in the Japanese reports retrieved from Medical Online between January 1996 and December 2017. There were 56 patients with Werner syndrome in English reports written by Japanese authors and retrieved from PubMed during the same period., Results: Records on skin ulcers were found in 27 (43%) out of 63 patients and 22 (40%) out of 56 patients from the Japanese and English reports, respectively. The reported ulcers were often located at the distal one-third of the lower legs. There were 8 patients with callosities in the foot in the Japanese reports and 9 patients in the English reports. A skin ulcer in Werner syndrome is generally intractable. Weight-bearing ulcers or callosity should be critically assessed in surgical procedures because they have effects on patient pain and gait. By adopting a recently advanced technique to facilitate wound healing, the cases of ulcers that were difficult to treat and those requiring major operations can be closed with minimally invasive surgery., Conclusions: Skin ulcers in Werner syndrome are refractory, and they lead to reduced quality of life of patients. A callosity in Werner syndrome is an important therapeutic target for the prevention of ulcers. Geriatr Gerontol Int 2021; 21: 153-159., (© 2020 Japan Geriatrics Society.)
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- 2021
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43. Management guideline for Werner syndrome 2020 1. Dyslipidemia and fatty liver associated with Werner syndrome.
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Tsukamoto K, Takemoto M, Kubota Y, Taniguchi T, Motegi SI, Taniguchi A, Nakagami H, Maezawa Y, Koshizaka M, Kato H, Mori S, Kuzuya M, and Yokote K
- Subjects
- Humans, Japan, Werner Syndrome Helicase, Dyslipidemias diagnosis, Fatty Liver, Werner Syndrome
- Abstract
For the purpose of examining the characteristics of dyslipidemia and fatty liver in patients with Werner syndrome in Japan in recent years, we searched all case reports of Japanese Werner syndrome reported on Medical Online and PubMed since 1996, and collected and examined the data and clinical features described in these reports. In addition, as there are few descriptions of treatment methods in these reports from Medical Online and PubMed, we analyzed 12 cases for which detailed data on treatment methods are available at Chiba University. Geriatr Gerontol Int 2021; 21: 133-138., (© 2020 Japan Geriatrics Society.)
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- 2021
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44. Effects of ipragliflozin versus metformin in combination with sitagliptin on bone and muscle in Japanese patients with type 2 diabetes mellitus: Subanalysis of a prospective, randomized, controlled study (PRIME-V study).
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Koshizaka M, Ishikawa K, Ishibashi R, Maezawa Y, Sakamoto K, Uchida D, Nakamura S, Yamaga M, Yokoh H, Kobayashi A, Onishi S, Kobayashi K, Ogino J, Hashimoto N, Tokuyama H, Shimada F, Ohara E, Ishikawa T, Shoji M, Ide S, Ide K, Baba Y, Hattori A, Kitamoto T, Horikoshi T, Shimofusa R, Takahashi S, Nagashima K, Sato Y, Takemoto M, Newby LK, and Yokote K
- Subjects
- Adult, Aged, Biomarkers analysis, Blood Glucose analysis, Bone and Bones pathology, Cross-Sectional Studies, Drug Therapy, Combination, Female, Follow-Up Studies, Humans, Hypoglycemic Agents therapeutic use, Male, Middle Aged, Muscles pathology, Prognosis, Prospective Studies, Sodium-Glucose Transporter 2 Inhibitors therapeutic use, Young Adult, Bone and Bones drug effects, Diabetes Mellitus, Type 2 drug therapy, Glucosides therapeutic use, Metformin therapeutic use, Muscles drug effects, Sitagliptin Phosphate therapeutic use, Thiophenes therapeutic use
- Abstract
Aims/introduction: Recent randomized clinical trials have suggested that sodium-glucose cotransporter 2 inhibitors might reduce cardiovascular events and heart failure, and have renal protective effects. Despite these remarkable benefits, the effects of sodium-glucose cotransporter 2 inhibitors on bone and muscle are unclear., Materials and Methods: A subanalysis of a randomized controlled study was carried out to evaluate the effects of the sodium-glucose cotransporter 2 inhibitor, ipragliflozin, versus metformin on bone and muscle in Japanese patients with type 2 diabetes mellitus (baseline body mass index ≥22 kg/m
2 and hemoglobin A1c 7-10%) who were already receiving sitagliptin. These patients were randomly administered ipragliflozin 50 mg or metformin 1,000-1,500 mg daily. The effects of these medications on the bone formation marker, bone alkali phosphatase; the bone resorption marker, tartrate-resistant acid phosphatase 5b (TRACP-5b); handgrip strength; abdominal cross-sectional muscle area; and bone density of the fourth lumbar vertebra were evaluated., Results: After 24 weeks of treatment, the changes in bone density of the fourth lumbar vertebra, handgrip strength and abdominal cross-sectional muscle area were not significantly different between the two groups. However, TRACP-5b levels increased in patients treated with ipragliflozin compared with patients treated with metformin (median 11.94 vs -10.30%, P < 0.0001), showing that ipragliflozin can promote bone resorption., Conclusions: There were no adverse effects on bone or muscle when sitagliptin was used in combination with either ipragliflozin or metformin. However, ipragliflozin combination increased the levels of TRACP-5b. A long-term study is required to further understand the effects of this TRACP-5b increase caused by ipragliflozin., (© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)- Published
- 2021
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45. Assessing Patient Satisfaction Following Sodium Glucose Co-Transporter 2 Inhibitor Treatment for Type 1 Diabetes Mellitus: A Prospective Study in Japan.
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Ishibashi R, Baba Y, Kakinuma K, Takasaki A, Hiraga C, Harama T, Yamamoto T, Nakamura S, Koshizaka M, Maezawa Y, Uchida D, and Okajima F
- Abstract
Introduction: In Japan, several sodium glucose co-transporter 2 (SGLT2) inhibitors have been used for type 1 diabetes mellitus as an adjuvant therapy to insulin therapy; however, there are no clinical reports regarding the satisfaction of its use. Therefore, we conducted a survey among patients with type 1 diabetes undergoing treatment using an SGLT2 inhibitor., Methods: This is a single-arm open-label prospective study including 24 patients with type 1 diabetes who were to be initiated on ipragliflozin treatment between March and August 2019. All participants provided written informed consent. They completed the Diabetes Treatment Satisfaction Questionnaire (DTSQ) for the survey and 3 months of observation after the administration of an SGLT2 inhibitor (50 mg of ipragliflozin), and changes from baseline diabetes treatment satisfaction were evaluated using modified DTSQ scores (five-step evaluation) and were analyzed., Results: The average score for each question on DTSQ significantly increased [mean (standard deviation); 0.25 (0.25) vs 0.83 (0.77), P = 0.004]. Approximately 75% of the patients perceived an improvement in glycemic control over short periods of time. Finally, 54.2% of patients were highly satisfied and would recommend the SGLT2 inhibitor treatment [0.0 (0.0) vs. 0.92 (1.32), P < 0.001]. After the administration of ipragliflozin, reductions in body weight [24.0 (2.9) vs. 23.4 (2.9) kg/m
2 , P = 0.002], total insulin [39.1 (12.9) vs. 34.3 (12.5) units, P = 0.013], and glycated hemoglobin [7.77 (0.97) vs. 7.40 (0.86) %, P = 0.013] were observed, without any severe side effects. Improvements in glycemic variability indexes were observed through flash glucose monitoring., Conclusions: SGLT2 inhibitors may improve clinical treatment satisfaction by improving glycemic variability in patients with type 1 diabetes mellitus, while not inducing severe side effects with careful use., Trial Registration: This study is registered with the University Hospital Medical Information Network Clinical Trial Registry (UMIN000040487).- Published
- 2021
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46. Comparison of Visceral Fat Reduction by Ipragliflozin and Metformin in Elderly Type 2 Diabetes Patients: Sub-Analysis of a Randomized-Controlled Study.
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Koshizaka M, Ishikawa K, Ishibashi R, Takahashi S, Sakamoto K, Yokoh H, Baba Y, Ide S, Ide K, Ishikawa T, Onishi S, Kobayashi K, Takemoto M, Horikoshi T, Shimofusa R, Maezawa Y, and Yokote K
- Abstract
Introduction: To compare the effects of ipragliflozin, a sodium-glucose transporter 2 inhibitor, with those of metformin on visceral fat (as well as muscles and bones) in Japanese elderly patients with type 2 diabetes (T2D), we conducted a sub-analysis of a prospective, multicenter, blinded-endpoint randomized-controlled study., Methods: In total, 103 patients with T2D (body mass index ≥ 22 kg/m
2 ; glycated hemoglobin, 7-10%) and being treated with sitagliptin (a dipeptidyl peptidase-4 inhibitor) were included and randomized to receive ipragliflozin or metformin. The primary outcome was the change in visceral fat area measured using computed tomography 24 weeks following treatment. The secondary outcomes included changes in subcutaneous and total fat area, muscle volume, bone density measured using computed tomography, handgrip strength, bone markers, plasma glucose, insulin, homeostasis model assessment (HOMA)2-beta, HOMA2-R, glycated hemoglobin, lipid panel, uric acid, blood pressure, adiponectin, and high-sensitivity C-reactive protein. All patients aged 65-74 years were selected for sub-analysis., Results: The sub-analysis included 15 and 14 patients in the ipragliflozin and metformin groups, respectively. The patients' backgrounds were well balanced. Visceral fat area reduction was greater in the ipragliflozin group than in the metformin group (- 10.58% vs. - 6.93%; P = 0.034). There were significant differences in the changes in bone absorption markers, uric acid, and total cholesterol levels between the groups., Conclusion: Ipragliflozin significantly reduced the visceral fat area compared with metformin when added to sitagliptin in elderly patients with T2D. Long-term and large-scale studies are required to elucidate whether ipragliflozin is suitable for elderly patients., Trial Registration: The study was registered at https://www.umin.ac.jp/ctr/ (UMIN-ID: UMIN 000015170).- Published
- 2021
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47. Time gap between the onset and diagnosis in Werner syndrome: a nationwide survey and the 2020 registry in Japan.
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Koshizaka M, Maezawa Y, Maeda Y, Shoji M, Kato H, Kaneko H, Ishikawa T, Kinoshita D, Kobayashi K, Kawashima J, Sekiguchi A, Motegi SI, Nakagami H, Yamada Y, Tsukamoto S, Taniguchi A, Sugimoto K, Shoda Y, Hashimoto K, Yoshimura T, Suzuki D, Kuzuya M, Takemoto M, and Yokote K
- Subjects
- Adolescent, Adult, Age of Onset, Alopecia physiopathology, Calcinosis physiopathology, Cataract physiopathology, Consanguinity, Diabetes Mellitus, Dyslipidemias, Early Diagnosis, Early Medical Intervention, Fatty Liver, Female, Hair Color, Hand Strength, Humans, Japan, Male, Middle Aged, Pigmentation Disorders physiopathology, Sarcopenia physiopathology, Skin Ulcer physiopathology, Walking Speed, Werner Syndrome physiopathology, Young Adult, Delayed Diagnosis statistics & numerical data, Werner Syndrome diagnosis
- Abstract
Patients with Werner syndrome present with diverse signs of aging that begin in adolescence. A Japanese nationwide survey was conducted to establish a registry that could clarify the disease profile of patients with Werner syndrome. The questionnaires were sent to 7888 doctors. The survey identified 116 patients diagnosed with Werner syndrome based on the diagnosis criteria. Forty patients were enrolled in the registry. Data on clinical symptoms, treatment information, and laboratory examination from patients who provided informed consent were collected. The data at enrollment were analyzed. The patients' average age at enrollment was 50.1±7.5 years. The mean onset age was 26.1±9.5 years, but the mean age at diagnosis was 42.5±8.6 years. Average height and weight of the study patients were lower than those of Japanese individuals. Almost all patients experienced hair change and cataracts. More than 60% of patients presented with glycolipid abnormalities. Overall, 15% of patients had a history of foot amputation. Approximately 30% of the patients' parents had a consanguineous marriage. The average grip strength, walking speed, and skeletal muscle mass index met the diagnostic criteria for sarcopenia. The registry revealed that there are opportunities for early diagnosis and intervention; therefore, sensitization about the disease is needed.
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- 2020
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48. Evaluation of glucose tolerance and effect of dietary management on increased visceral fat in a patient with Werner syndrome.
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Yamamoto R, Akasaki K, Horita M, Yonezawa M, Asakura H, Kanamori T, Maezawa Y, Koshizaka M, Yokote K, and Kurita S
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- Female, Glucose Intolerance blood, Glucose Intolerance diagnostic imaging, Glucose Tolerance Test, Humans, Insulin Secretion physiology, Intra-Abdominal Fat diagnostic imaging, Middle Aged, Obesity blood, Obesity diagnostic imaging, Ultrasonography, Werner Syndrome blood, Werner Syndrome diagnostic imaging, Diet, Glucose Intolerance complications, Insulin Resistance physiology, Obesity complications, Werner Syndrome complications
- Abstract
Werner syndrome (WS), a type of progeria, is a hereditary condition caused by a mutation in the WRN gene. A 62-year-old Japanese woman was diagnosed with WS at the age of 32 and has been visiting the hospital for follow-up since the last 30 years. The patient developed diabetes at the age of 46, and at the age of 60, her body mass index increased from 20.1 to 22.7 kg/m
2 owing to her unhealthy eating habits; her visceral fat area at the age of 61 was 233 cm2 . With dietary control, her body weight, including the visceral fat and subcutaneous fat, decreased at the age of 62, and her insulin secretion, obesity, and fatty liver improved. We conducted the oral glucose challenge test four times, including at the prediabetic stage, to evaluate the insulin-secretion ability. The patient's insulin resistance gradually increased for more than 14 years, and her insulin secretion ability began to decrease 14 years after her diabetes diagnosis. Despite a remarkable decrease in body weight and fat mass with dietary management, the psoas muscle index did not decrease significantly in proportion to the body weight or fat mass. However, muscle mass monitoring is important for preventing the progression of sarcopenia. Hence, gradual reduction of visceral fat and weight by dietary management may be useful in treating diabetes in patients with WS, particularly in those whose visceral fat is significantly increased.- Published
- 2020
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49. Sodium-Glucose Cotransporter 2 Inhibitors Improve Chronic Diabetic Macular Edema.
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Takatsuna Y, Ishibashi R, Tatsumi T, Koshizaka M, Baba T, Yamamoto S, and Yokote K
- Abstract
Purpose: Diabetic macular edema (DME) is a vision-threatening condition that develops in diabetic patients. The first-line therapy for DME is intravitreal injections of antivascular endothelial growth factor (anti-VEGF) agents; however, the high frequency of repeat injections, invasiveness of the procedure, and high cost are drawbacks for this treatment. The purpose of this report is to present our findings in 3 patients with chronic DME whose edema was resolved soon after oral doses of sodium-glucose cotransporter-2 (SGLT2) inhibitors were used. Case Presentation . Case 1 was a 66-year-old woman diagnosed with moderate nonproliferative diabetic retinopathy (DR) with DME that had developed a decade earlier. The DME persisted for 4 years in the left eye. The addition of oral empagliflozin, a SGLT2 inhibitor, led to a marked improvement of the DME after one month, and this improvement continued over two years. Case 2 was a 68-year-old woman who was diagnosed with preproliferative DR with bilateral DME. The addition of oral dapagliflozin led to the improvement of the DME after two months, and this improvement continued over one year. Case 3 was a 61-year-old woman who was diagnosed with moderate nonproliferative DR with DME. Oral luseogliflozin was given which led to better glycemic control, and her left central retinal thickness (CRT) was markedly reduced after only two weeks. This reduction was maintained in her left eye for six months without any additional ophthalmic procedures., Conclusions: Although this study involved only three cases, our findings indicate that SGLT2 inhibitors might have possible efficacy for chronic DME., Competing Interests: None of the authors has conflicts of interest with this submission., (Copyright © 2020 Yoko Takatsuna et al.)
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- 2020
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50. Detailed analysis of lipolytic enzymes in a Japanese woman of familial lipoprotein lipase deficiency - Effects of pemafibrate treatment.
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Minamizuka T, Kobayashi J, Tada H, Miyashita K, Koshizaka M, Maezawa Y, Ono H, and Yokote K
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- Acute Disease, Benzoxazoles, Butyrates, Female, Humans, Japan, Lipoprotein Lipase genetics, Liver, Triglycerides, Hyperlipoproteinemia Type I genetics, Pancreatitis
- Abstract
Background: We present here a 72-y-old Japanese woman with lipoprotein lipase (LPL) deficiency and analyzed her lipolytic enzymes in detail before and after pemafibrate treatment., Methods: She had a serum triglycerides (TG) of 22.6 mmol/l at a medical checkup at the age of 52 y. She was referred to our hospital at the age of 61 y. Her serum lipoprotein lipase (LPL) concentration was extremely low, suggesting the clinical diagnosis of LPL deficiency. She experienced an event of acute pancreatitis at the age of 65 y., Results: Next-generation sequencing analysis revealed a homozygous nonsense mutation in the LPL gene, c.1277G > A (p.Trp409Ter). Her serum TG, LPL and hepatic lipase (HL) concentrations were 15.0 mmol/l, 23 ng/ml and 66 ng/ml, respectively. Fifteen minutes after intravenous heparin injection (30 U/kg), her serum TG, LPL and HL concentrations turned to 14.1 mmol/l, 20 ng/ml and 660 ng/ml, respectively. Eight weeks of pemafibrate treatment (0.2 mg/day) caused a modest reductions in serum TG (15.02 → 13.58 mmol/l) and considerable increases in preheparin HL (66 → 76 ng/ml) and PHP-HL (660 → 1118 ng/ml) concentrations and PHP-HL activities (253 → 369U/l) despite almost no effect on LPL concentrations and activities., Conclusions: These findings suggest that HL may contribute to the reduction of plasma TG in LPL deficiency., (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Published
- 2020
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