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1.  Are adults with bipolar disorder active? Objectively measured physical activity and sedentary behavior using accelerometry 
Carol A Janney has received research support from Actigraph, Inc for this study. Andrea Fagiolini is/has been a consultant and/or speaker and/or has received grants from: Angelini, Astra Zeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Pfizer, Eli Lilly, Janssen, Lundbeck, Novartis, Otsuka, Roche and Sigma Tau. Holly A. Swartz has received honoraria from Servier, Astra Zeneca, SciMed, Bristol-Myers Squibb, Eli Lilly, and Sanofi. She has received royalties from UpToDate. John M. Jakicic has received an honorarium for scientific presentations from the Nestle Nutrition Institute and JennyCraig. He has served on the scientific advisory board for Alere WellBeing. He has also served as the Principal Investigator on a research grant awarded to the University of Pittsburgh from BodyMedia, Inc.. Robert G. Holleman and Caroline R. Richardson have no financial disclosures.
doi:10.1016/j.jad.2013.09.009
PMCID: PMC3905833  PMID: 24095103
accelerometry; actigraphy; bipolar disorder; adult; physical activity; sedentary behavior; NHANES 2003-2004; mental health services; outpatients
2.  Enzymatic Action on the Capsular Material Produced by Pseudomonas aeruginosa of Cystic Fibrosis Origin 
Journal of Bacteriology  1965;89(2):476-480.
Doggett, Robert G. (Texas Institute for Rehabilitation and Research, Houston), Gunyon M. Harrison, Richard N. Stillwell, and Everett S. Wallis. Enzymatic action on the capsular material produced by Pseudomonas aeruginosa of cystic fibrosis origin. J. Bacteriol. 89:476–480. 1965.—An enzymatic study of the action of α- and β-amylases on the slime envelope produced by Pseudomonas aeruginosa originating from patients with cystic fibrosis (CF) has been reported. It has been shown that these two enzymes in combination prevent the formation of the abnormal ethanol-benzene insoluble mucoid present in the slime layer of the above organism of CF origin. Evidence is also given which suggests that this organism can serve as a tool for studies of chemical abnormalities in the mucous metabolism of CF individuals.
Images
PMCID: PMC305531  PMID: 14255717
3.  SEROLOGY OF THE MIMA-HERELLEA GROUP AND THE GENUS MORAXELLA1 
Journal of Bacteriology  1964;87(4):900-909.
Mitchell, Paul D. (West Virginia University Medical Center, Morgantown), and Robert G. Burrell. Serology of the Mima-Herellea group and the genus Moraxella. J. Bacteriol. 87:900–909. 1964.—The identity of organisms which have been assigned to the Mima-Herellea group of the tribe Mimeae and their taxonomic position are uncertain. In considering the possible relationship of the Mima-Herellea group to the genus Moraxella, the approach used was the isolation and identification of representative antigenic constituents of strains designated Mima polymorpha, M. polymorpha var. oxidans, Herellea vaginicola, Moraxella lwoffi, M. liquefaciens, M. non-liquefaciens, and Bacterium anitratum. Cell-free extracts of sonically disrupted cells were used in these studies, and the precipitinogens derived by this method were considered to be of capsular and somatic origin. Identity among the strains was established by immunodiffusion, with immune sera and antigenic extracts. Heterologous and homologous reactions were performed with adsorbed and unadsorbed sera to verify the cases of identity. In every instance of homologous reaction, at least five distinct antigen-antibody systems were discernible within the Mima-Herellea group. However, as evidenced by heterologous studies, the demonstrable antigenic composition varied among the species and, in some instances, among the strains. M. polymorpha var. oxidans appeared to be serologically distinct from H. vaginicola and M. polymorpha, whereas strains of the latter two organisms were theorized to be closely related serologically. Serological cross-reactions in heterologous studies and reciprocal adsorption tests revealed the existence of a serological relationship between members of the Mima-Herellea group and the genus Moraxella. A tentative scheme of identity is postulated on the basis of these crossreactions and cultural and biochemical reactions among the designated strains of Herellea, Mima, Moraxella, and Bacterium.
PMCID: PMC277109  PMID: 14137629
4.  LIPID COMPOSITION AND SYNTHESIS IN THE PLEUROPNEUMONIA-LIKE ORGANISM MYCOPLASMA GALLISEPTICUM1 
Journal of Bacteriology  1963;86(3):370-379.
Tourtellotte, Mark E. (University of Connecticut, Storrs), Robert G. Jensen, George W. Gander, and Harold J. Morowitz. Lipid composition and synthesis in the pleuropneumonia-like organism Mycoplasma gallisepticum. J. Bacteriol. 86:370–379. 1963.—A simple method of extracting lipids from cells of Mycoplasma gallisepticum by use of silicic acid columns is described. Proteolipids (peptides) extracted with chloroform-methanol (2:1) by other methods were not extracted with the lipid by this method, nor were proteins and nucleic acids. Fractionation of lipids of M. gallisepticum demonstrated the presence of saturated hydrocarbons, free fatty acids, cholesterol, cholesterol esters, di- and triglycerides, phosphatidic acids, cephalins, inositides, phosphatidyl choline, and sphingomyelin. The fatty acid composition of the various fractions was also determined. The positive identification of cholesterol and cholesterol esters in this organism by chromatography, melting point, and infrared spectroscopy confirms reports by others that cholesterol is present in the pleuropneumonia group of microorganisms. The incorporation of P32 orthophosphate into four phospholipid fractions, of oleic acid-1-C14 into neutral and phospholipids, and cholesterol-4-C14 into cholesterol esters clearly demonstrated the ability of M. gallisepticum to synthesize these lipids from simpler compounds. Between 70 and 80% of the lipid of this organism was found in the membrane.
PMCID: PMC278445  PMID: 14071787
5.  COMPARISON OF SOME PROPERTIES OF PSEUDOMONAS AERUGINOSA ISOLATED FROM INFECTIONS IN PERSONS WITH AND WITHOUT CYSTIC FIBROSIS 
Journal of Bacteriology  1964;87(2):427-431.
Doggett, Robert G. (Texas Institute for Rehabilitation and Research, Houston), Gunyon M. Garrison, and Everett S. Wallis. Comparison of some properties of Pseudomonas aeruginosa isolated from infections in persons with and without cystic fibrosis. J. Bacteriol. 87:427–431. 1964.—Pseudomonas aeruginosa, isolated from the respiratory tract of a group of patients diagnosed as having cystic fibrosis (CF) of the pancreas, attained the ability to produce in its capsule a material which was insoluble in certain organic solvents, such as ethanol. The capsule obtained from P. aeruginosa isolated from infected individuals who did not have CF was ethanol-soluble. This alcohol-insoluble mucoid from the CF P. aeruginosa could be demonstrated to persist after sequential subcultures of this organism. The relative viscosity and carbohydrate moiety of this insoluble mucoid fraction of P. aeruginosa from individuals with CF differed from that of the non-CF P. aeruginosa soluble mucoid fraction.
Images
PMCID: PMC277026  PMID: 14151067
6.  Global, regional, and national levels and causes of maternal mortality during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013 
Kassebaum, Nicholas J | Bertozzi-Villa, Amelia | Coggeshall, Megan S | Shackelford, Katya A | Steiner, Caitlyn | Heuton, Kyle R | Gonzalez-Medina, Diego | Barber, Ryan | Huynh, Chantal | Dicker, Daniel | Templin, Tara | Wolock, Timothy M | Ozgoren, Ayse Abbasoglu | Abd-Allah, Foad | Abera, Semaw Ferede | Abubakar, Ibrahim | Achoki, Tom | Adelekan, Ademola | Ademi, Zanfina | Adou, Arsène Kouablan | Adsuar, José C | Agardh, Emilie E | Akena, Dickens | Alasfoor, Deena | Alemu, Zewdie Aderaw | Alfonso-Cristancho, Rafael | Alhabib, Samia | Ali, Raghib | Al Kahbouri, Mazin J | Alla, François | Allen, Peter J | AlMazroa, Mohammad A | Alsharif, Ubai | Alvarez, Elena | Alvis-Guzmán, Nelson | Amankwaa, Adansi A | Amare, Azmeraw T | Amini, Hassan | Ammar, Walid | Antonio, Carl A T | Anwari, Palwasha | Ärnlöv, Johan | Arsenijevic, Valentina S Arsic | Artaman, Ali | Asad, Majed Masoud | Asghar, Rana J | Assadi, Reza | Atkins, Lydia S | Badawi, Alaa | Balakrishnan, Kalpana | Basu, Arindam | Basu, Sanjay | Beardsley, Justin | Bedi, Neeraj | Bekele, Tolesa | Bell, Michelle L | Bernabe, Eduardo | Beyene, Tariku J | Bhutta, Zulfiqar | Abdulhak, Aref Bin | Blore, Jed D | Basara, Berrak Bora | Bose, Dipan | Breitborde, Nicholas | Cárdenas, Rosario | Castañeda-Orjuela, Carlos A | Castro, Ruben Estanislao | Catalá-López, Ferrán | Cavlin, Alanur | Chang, Jung-Chen | Che, Xuan | Christophi, Costas A | Chugh, Sumeet S | Cirillo, Massimo | Colquhoun, Samantha M | Cooper, Leslie Trumbull | Cooper, Cyrus | da Costa Leite, Iuri | Dandona, Lalit | Dandona, Rakhi | Davis, Adrian | Dayama, Anand | Degenhardt, Louisa | De Leo, Diego | del Pozo-Cruz, Borja | Deribe, Kebede | Dessalegn, Muluken | deVeber, Gabrielle A | Dharmaratne, Samath D | Dilmen, Uğur | Ding, Eric L | Dorrington, Rob E | Driscoll, Tim R | Ermakov, Sergei Petrovich | Esteghamati, Alireza | Faraon, Emerito Jose A | Farzadfar, Farshad | Felicio, Manuela Mendonca | Fereshtehnejad, Seyed-Mohammad | de Lima, Graça Maria Ferreira | Forouzanfar, Mohammad H | França, Elisabeth B | Gaffikin, Lynne | Gambashidze, Ketevan | Gankpé, Fortuné Gbètoho | Garcia, Ana C | Geleijnse, Johanna M | Gibney, Katherine B | Giroud, Maurice | Glaser, Elizabeth L | Goginashvili, Ketevan | Gona, Philimon | González-Castell, Dinorah | Goto, Atsushi | Gouda, Hebe N | Gugnani, Harish Chander | Gupta, Rahul | Gupta, Rajeev | Hafezi-Nejad, Nima | Hamadeh, Randah Ribhi | Hammami, Mouhanad | Hankey, Graeme J | Harb, Hilda L | Havmoeller, Rasmus | Hay, Simon I | Heredia Pi, Ileana B | Hoek, Hans W | Hosgood, H Dean | Hoy, Damian G | Husseini, Abdullatif | Idrisov, Bulat T | Innos, Kaire | Inoue, Manami | Jacobsen, Kathryn H | Jahangir, Eiman | Jee, Sun Ha | Jensen, Paul N | Jha, Vivekanand | Jiang, Guohong | Jonas, Jost B | Juel, Knud | Kabagambe, Edmond Kato | Kan, Haidong | Karam, Nadim E | Karch, André | Karema, Corine Kakizi | Kaul, Anil | Kawakami, Norito | Kazanjan, Konstantin | Kazi, Dhruv S | Kemp, Andrew H | Kengne, Andre Pascal | Kereselidze, Maia | Khader, Yousef Saleh | Khalifa, Shams Eldin Ali Hassan | Khan, Ejaz Ahmed | Khang, Young-Ho | Knibbs, Luke | Kokubo, Yoshihiro | Kosen, Soewarta | Defo, Barthelemy Kuate | Kulkarni, Chanda | Kulkarni, Veena S | Kumar, G Anil | Kumar, Kaushalendra | Kumar, Ravi B | Kwan, Gene | Lai, Taavi | Lalloo, Ratilal | Lam, Hilton | Lansingh, Van C | Larsson, Anders | Lee, Jong-Tae | Leigh, James | Leinsalu, Mall | Leung, Ricky | Li, Xiaohong | Li, Yichong | Li, Yongmei | Liang, Juan | Liang, Xiaofeng | Lim, Stephen S | Lin, Hsien-Ho | Lipshultz, Steven E | Liu, Shiwei | Liu, Yang | Lloyd, Belinda K | London, Stephanie J | Lotufo, Paulo A | Ma, Jixiang | Ma, Stefan | Machado, Vasco Manuel Pedro | Mainoo, Nana Kwaku | Majdan, Marek | Mapoma, Christopher Chabila | Marcenes, Wagner | Marzan, Melvin Barrientos | Mason-Jones, Amanda J | Mehndiratta, Man Mohan | Mejia-Rodriguez, Fabiola | Memish, Ziad A | Mendoza, Walter | Miller, Ted R | Mills, Edward J | Mokdad, Ali H | Mola, Glen Liddell | Monasta, Lorenzo | de la Cruz Monis, Jonathan | Hernandez, Julio Cesar Montañez | Moore, Ami R | Moradi-Lakeh, Maziar | Mori, Rintaro | Mueller, Ulrich O | Mukaigawara, Mitsuru | Naheed, Aliya | Naidoo, Kovin S | Nand, Devina | Nangia, Vinay | Nash, Denis | Nejjari, Chakib | Nelson, Robert G | Neupane, Sudan Prasad | Newton, Charles R | Ng, Marie | Nieuwenhuijsen, Mark J | Nisar, Muhammad Imran | Nolte, Sandra | Norheim, Ole F | Nyakarahuka, Luke | Oh, In-Hwan | Ohkubo, Takayoshi | Olusanya, Bolajoko O | Omer, Saad B | Opio, John Nelson | Orisakwe, Orish Ebere | Pandian, Jeyaraj D | Papachristou, Christina | Park, Jae-Hyun | Caicedo, Angel J Paternina | Patten, Scott B | Paul, Vinod K | Pavlin, Boris Igor | Pearce, Neil | Pereira, David M | Pesudovs, Konrad | Petzold, Max | Poenaru, Dan | Polanczyk, Guilherme V | Polinder, Suzanne | Pope, Dan | Pourmalek, Farshad | Qato, Dima | Quistberg, D Alex | Rafay, Anwar | Rahimi, Kazem | Rahimi-Movaghar, Vafa | Rahman, Sajjad ur | Raju, Murugesan | Rana, Saleem M | Refaat, Amany | Ronfani, Luca | Roy, Nobhojit | Sánchez Pimienta, Tania Georgina | Sahraian, Mohammad Ali | Salomon, Joshua A | Sampson, Uchechukwu | Santos, Itamar S | Sawhney, Monika | Sayinzoga, Felix | Schneider, Ione J C | Schumacher, Austin | Schwebel, David C | Seedat, Soraya | Sepanlou, Sadaf G | Servan-Mori, Edson E | Shakh-Nazarova, Marina | Sheikhbahaei, Sara | Shibuya, Kenji | Shin, Hwashin Hyun | Shiue, Ivy | Sigfusdottir, Inga Dora | Silberberg, Donald H | Silva, Andrea P | Singh, Jasvinder A | Skirbekk, Vegard | Sliwa, Karen | Soshnikov, Sergey S | Sposato, Luciano A | Sreeramareddy, Chandrashekhar T | Stroumpoulis, Konstantinos | Sturua, Lela | Sykes, Bryan L | Tabb, Karen M | Talongwa, Roberto Tchio | Tan, Feng | Teixeira, Carolina Maria | Tenkorang, Eric Yeboah | Terkawi, Abdullah Sulieman | Thorne-Lyman, Andrew L | Tirschwell, David L | Towbin, Jeffrey A | Tran, Bach X | Tsilimbaris, Miltiadis | Uchendu, Uche S | Ukwaja, Kingsley N | Undurraga, Eduardo A | Uzun, Selen Begüm | Vallely, Andrew J | van Gool, Coen H | Vasankari, Tommi J | Vavilala, Monica S | Venketasubramanian, N | Villalpando, Salvador | Violante, Francesco S | Vlassov, Vasiliy Victorovich | Vos, Theo | Waller, Stephen | Wang, Haidong | Wang, Linhong | Wang, XiaoRong | Wang, Yanping | Weichenthal, Scott | Weiderpass, Elisabete | Weintraub, Robert G | Westerman, Ronny | Wilkinson, James D | Woldeyohannes, Solomon Meseret | Wong, John Q | Wordofa, Muluemebet Abera | Xu, Gelin | Yang, Yang C | Yano, Yuichiro | Yentur, Gokalp Kadri | Yip, Paul | Yonemoto, Naohiro | Yoon, Seok-Jun | Younis, Mustafa Z | Yu, Chuanhua | Jin, Kim Yun | El SayedZaki, Maysaa | Zhao, Yong | Zheng, Yingfeng | Zhou, Maigeng | Zhu, Jun | Zou, Xiao Nong | Lopez, Alan D | Naghavi, Mohsen | Murray, Christopher J L | Lozano, Rafael
Lancet  2014;384(9947):980-1004.
Summary
Background
The fifth Millennium Development Goal (MDG 5) established the goal of a 75% reduction in the maternal mortality ratio (MMR; number of maternal deaths per 100 000 livebirths) between 1990 and 2015. We aimed to measure levels and track trends in maternal mortality, the key causes contributing to maternal death, and timing of maternal death with respect to delivery.
Methods
We used robust statistical methods including the Cause of Death Ensemble model (CODEm) to analyse a database of data for 7065 site-years and estimate the number of maternal deaths from all causes in 188 countries between 1990 and 2013. We estimated the number of pregnancy-related deaths caused by HIV on the basis of a systematic review of the relative risk of dying during pregnancy for HIV-positive women compared with HIV-negative women. We also estimated the fraction of these deaths aggravated by pregnancy on the basis of a systematic review. To estimate the numbers of maternal deaths due to nine different causes, we identified 61 sources from a systematic review and 943 site-years of vital registration data. We also did a systematic review of reports about the timing of maternal death, identifying 142 sources to use in our analysis. We developed estimates for each country for 1990–2013 using Bayesian meta-regression. We estimated 95% uncertainty intervals (UIs) for all values.
Findings
292 982 (95% UI 261 017–327 792) maternal deaths occurred in 2013, compared with 376 034 (343 483–407 574) in 1990. The global annual rate of change in the MMR was −0·3% (−1·1 to 0·6) from 1990 to 2003, and −2·7% (−3·9 to −1·5) from 2003 to 2013, with evidence of continued acceleration. MMRs reduced consistently in south, east, and southeast Asia between 1990 and 2013, but maternal deaths increased in much of sub-Saharan Africa during the 1990s. 2070 (1290–2866) maternal deaths were related to HIV in 2013, 0·4% (0·2–0·6) of the global total. MMR was highest in the oldest age groups in both 1990 and 2013. In 2013, most deaths occurred intrapartum or postpartum. Causes varied by region and between 1990 and 2013. We recorded substantial variation in the MMR by country in 2013, from 956·8 (685·1–1262·8) in South Sudan to 2·4 (1·6–3·6) in Iceland.
Interpretation
Global rates of change suggest that only 16 countries will achieve the MDG 5 target by 2015. Accelerated reductions since the Millennium Declaration in 2000 coincide with increased development assistance for maternal, newborn, and child health. Setting of targets and associated interventions for after 2015 will need careful consideration of regions that are making slow progress, such as west and central Africa.
Funding
Bill & Melinda Gates Foundation.
doi:10.1016/S0140-6736(14)60696-6
PMCID: PMC4255481  PMID: 24797575
7.  Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013 
Murray, Christopher J L | Ortblad, Katrina F | Guinovart, Caterina | Lim, Stephen S | Wolock, Timothy M | Roberts, D Allen | Dansereau, Emily A | Graetz, Nicholas | Barber, Ryan M | Brown, Jonathan C | Wang, Haidong | Duber, Herbert C | Naghavi, Mohsen | Dicker, Daniel | Dandona, Lalit | Salomon, Joshua A | Heuton, Kyle R | Foreman, Kyle | Phillips, David E | Fleming, Thomas D | Flaxman, Abraham D | Phillips, Bryan K | Johnson, Elizabeth K | Coggeshall, Megan S | Abd-Allah, Foad | Ferede, Semaw | Abraham, Jerry P | Abubakar, Ibrahim | Abu-Raddad, Laith J | Abu-Rmeileh, Niveen Me | Achoki, Tom | Adeyemo, Austine Olufemi | Adou, Arsène Kouablan | Adsuar, José C | Agardh, Emilie Elisabet | Akena, Dickens | Al Kahbouri, Mazin J | Alasfoor, Deena | Albittar, Mohammed I | Alcalá-Cerra, Gabriel | Alegretti, Miguel Angel | Alemu, Zewdie Aderaw | Alfonso-Cristancho, Rafael | Alhabib, Samia | Ali, Raghib | Alla, Francois | Allen, Peter J | Alsharif, Ubai | Alvarez, Elena | Alvis-Guzman, Nelson | Amankwaa, Adansi A | Amare, Azmeraw T | Amini, Hassan | Ammar, Walid | Anderson, Benjamin O | Antonio, Carl Abelardo T | Anwari, Palwasha | Ärnlöv, Johan | Arsenijevic, Valentina S Arsic | Artaman, Ali | Asghar, Rana J | Assadi, Reza | Atkins, Lydia S | Badawi, Alaa | Balakrishnan, Kalpana | Banerjee, Amitava | Basu, Sanjay | Beardsley, Justin | Bekele, Tolesa | Bell, Michelle L | Bernabe, Eduardo | Beyene, Tariku Jibat | Bhala, Neeraj | Bhalla, Ashish | Bhutta, Zulfiqar A | Abdulhak, Aref Bin | Binagwaho, Agnes | Blore, Jed D | Basara, Berrak Bora | Bose, Dipan | Brainin, Michael | Breitborde, Nicholas | Castañeda-Orjuela, Carlos A | Catalá-López, Ferrán | Chadha, Vineet K | Chang, Jung-Chen | Chiang, Peggy Pei-Chia | Chuang, Ting-Wu | Colomar, Mercedes | Cooper, Leslie Trumbull | Cooper, Cyrus | Courville, Karen J | Cowie, Benjamin C | Criqui, Michael H | Dandona, Rakhi | Dayama, Anand | De Leo, Diego | Degenhardt, Louisa | Del Pozo-Cruz, Borja | Deribe, Kebede | Jarlais, Don C Des | Dessalegn, Muluken | Dharmaratne, Samath D | Dilmen, Uğur | Ding, Eric L | Driscoll, Tim R | Durrani, Adnan M | Ellenbogen, Richard G | Ermakov, Sergey Petrovich | Esteghamati, Alireza | Faraon, Emerito Jose A | Farzadfar, Farshad | Fereshtehnejad, Seyed-Mohammad | Fijabi, Daniel Obadare | Forouzanfar, Mohammad H | Paleo, Urbano Fra. | Gaffikin, Lynne | Gamkrelidze, Amiran | Gankpé, Fortuné Gbètoho | Geleijnse, Johanna M | Gessner, Bradford D | Gibney, Katherine B | Ginawi, Ibrahim Abdelmageem Mohamed | Glaser, Elizabeth L | Gona, Philimon | Goto, Atsushi | Gouda, Hebe N | Gugnani, Harish Chander | Gupta, Rajeev | Gupta, Rahul | Hafezi-Nejad, Nima | Hamadeh, Randah Ribhi | Hammami, Mouhanad | Hankey, Graeme J | Harb, Hilda L | Haro, Josep Maria | Havmoeller, Rasmus | Hay, Simon I | Hedayati, Mohammad T | Pi, Ileana B Heredia | Hoek, Hans W | Hornberger, John C | Hosgood, H Dean | Hotez, Peter J | Hoy, Damian G | Huang, John J | Iburg, Kim M | Idrisov, Bulat T | Innos, Kaire | Jacobsen, Kathryn H | Jeemon, Panniyammakal | Jensen, Paul N | Jha, Vivekanand | Jiang, Guohong | Jonas, Jost B | Juel, Knud | Kan, Haidong | Kankindi, Ida | Karam, Nadim E | Karch, André | Karema, Corine Kakizi | Kaul, Anil | Kawakami, Norito | Kazi, Dhruv S | Kemp, Andrew H | Kengne, Andre Pascal | Keren, Andre | Kereselidze, Maia | Khader, Yousef Saleh | Khalifa, Shams Eldin Ali Hassan | Khan, Ejaz Ahmed | Khang, Young-Ho | Khonelidze, Irma | Kinfu, Yohannes | Kinge, Jonas M | Knibbs, Luke | Kokubo, Yoshihiro | Kosen, S | Defo, Barthelemy Kuate | Kulkarni, Veena S | Kulkarni, Chanda | Kumar, Kaushalendra | Kumar, Ravi B | Kumar, G Anil | Kwan, Gene F | Lai, Taavi | Balaji, Arjun Lakshmana | Lam, Hilton | Lan, Qing | Lansingh, Van C | Larson, Heidi J | Larsson, Anders | Lee, Jong-Tae | Leigh, James | Leinsalu, Mall | Leung, Ricky | Li, Yichong | Li, Yongmei | De Lima, Graça Maria Ferreira | Lin, Hsien-Ho | Lipshultz, Steven E | Liu, Shiwei | Liu, Yang | Lloyd, Belinda K | Lotufo, Paulo A | Machado, Vasco Manuel Pedro | Maclachlan, Jennifer H | Magis-Rodriguez, Carlos | Majdan, Marek | Mapoma, Christopher Chabila | Marcenes, Wagner | Marzan, Melvin Barrientos | Masci, Joseph R | Mashal, Mohammad Taufiq | Mason-Jones, Amanda J | Mayosi, Bongani M | Mazorodze, Tasara T | Mckay, Abigail Cecilia | Meaney, Peter A | Mehndiratta, Man Mohan | Mejia-Rodriguez, Fabiola | Melaku, Yohannes Adama | Memish, Ziad A | Mendoza, Walter | Miller, Ted R | Mills, Edward J | Mohammad, Karzan Abdulmuhsin | Mokdad, Ali H | Mola, Glen Liddell | Monasta, Lorenzo | Montico, Marcella | Moore, Ami R | Mori, Rintaro | Moturi, Wilkister Nyaora | Mukaigawara, Mitsuru | Murthy, Kinnari S | Naheed, Aliya | Naidoo, Kovin S | Naldi, Luigi | Nangia, Vinay | Narayan, K M Venkat | Nash, Denis | Nejjari, Chakib | Nelson, Robert G | Neupane, Sudan Prasad | Newton, Charles R | Ng, Marie | Nisar, Muhammad Imran | Nolte, Sandra | Norheim, Ole F | Nowaseb, Vincent | Nyakarahuka, Luke | Oh, In-Hwan | Ohkubo, Takayoshi | Olusanya, Bolajoko O | Omer, Saad B | Opio, John Nelson | Orisakwe, Orish Ebere | Pandian, Jeyaraj D | Papachristou, Christina | Caicedo, Angel J Paternina | Patten, Scott B | Paul, Vinod K | Pavlin, Boris Igor | Pearce, Neil | Pereira, David M | Pervaiz, Aslam | Pesudovs, Konrad | Petzold, Max | Pourmalek, Farshad | Qato, Dima | Quezada, Amado D | Quistberg, D Alex | Rafay, Anwar | Rahimi, Kazem | Rahimi-Movaghar, Vafa | Rahman, Sajjad Ur | Raju, Murugesan | Rana, Saleem M | Razavi, Homie | Reilly, Robert Quentin | Remuzzi, Giuseppe | Richardus, Jan Hendrik | Ronfani, Luca | Roy, Nobhojit | Sabin, Nsanzimana | Saeedi, Mohammad Yahya | Sahraian, Mohammad Ali | Samonte, Genesis May J | Sawhney, Monika | Schneider, Ione J C | Schwebel, David C | Seedat, Soraya | Sepanlou, Sadaf G | Servan-Mori, Edson E | Sheikhbahaei, Sara | Shibuya, Kenji | Shin, Hwashin Hyun | Shiue, Ivy | Shivakoti, Rupak | Sigfusdottir, Inga Dora | Silberberg, Donald H | Silva, Andrea P | Simard, Edgar P | Singh, Jasvinder A | Skirbekk, Vegard | Sliwa, Karen | Soneji, Samir | Soshnikov, Sergey S | Sreeramareddy, Chandrashekhar T | Stathopoulou, Vasiliki Kalliopi | Stroumpoulis, Konstantinos | Swaminathan, Soumya | Sykes, Bryan L | Tabb, Karen M | Talongwa, Roberto Tchio | Tenkorang, Eric Yeboah | Terkawi, Abdullah Sulieman | Thomson, Alan J | Thorne-Lyman, Andrew L | Towbin, Jeffrey A | Traebert, Jefferson | Tran, Bach X | Dimbuene, Zacharie Tsala | Tsilimbaris, Miltiadis | Uchendu, Uche S | Ukwaja, Kingsley N | Uzun, Selen Begüm | Vallely, Andrew J | Vasankari, Tommi J | Venketasubramanian, N | Violante, Francesco S | Vlassov, Vasiliy Victorovich | Vollset, Stein Emil | Waller, Stephen | Wallin, Mitchell T | Wang, Linhong | Wang, XiaoRong | Wang, Yanping | Weichenthal, Scott | Weiderpass, Elisabete | Weintraub, Robert G | Westerman, Ronny | White, Richard A | Wilkinson, James D | Williams, Thomas Neil | Woldeyohannes, Solomon Meseret | Wong, John Q | Xu, Gelin | Yang, Yang C | Yano, Yuichiro | Yentur, Gokalp Kadri | Yip, Paul | Yonemoto, Naohiro | Yoon, Seok-Jun | Younis, Mustafa | Yu, Chuanhua | Jin, Kim Yun | El Sayed Zaki, Maysaa | Zhao, Yong | Zheng, Yingfeng | Zhou, Maigeng | Zhu, Jun | Zou, Xiao Nong | Lopez, Alan D | Vos, Theo
Lancet  2014;384(9947):1005-1070.
Summary
Background
The Millennium Declaration in 2000 brought special global attention to HIV, tuberculosis, and malaria through the formulation of Millennium Development Goal (MDG) 6. The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for between 1990 and 2013, and an opportunity to assess whether accelerated progress has occurred since the Millennium Declaration.
Methods
To estimate incidence and mortality for HIV, we used the UNAIDS Spectrum model appropriately modified based on a systematic review of available studies of mortality with and without antiretroviral therapy (ART). For concentrated epidemics, we calibrated Spectrum models to fit vital registration data corrected for misclassification of HIV deaths. In generalised epidemics, we minimised a loss function to select epidemic curves most consistent with prevalence data and demographic data for all-cause mortality. We analysed counterfactual scenarios for HIV to assess years of life saved through prevention of mother-to-child transmission (PMTCT) and ART. For tuberculosis, we analysed vital registration and verbal autopsy data to estimate mortality using cause of death ensemble modelling. We analysed data for corrected case-notifications, expert opinions on the case-detection rate, prevalence surveys, and estimated cause-specific mortality using Bayesian meta-regression to generate consistent trends in all parameters. We analysed malaria mortality and incidence using an updated cause of death database, a systematic analysis of verbal autopsy validation studies for malaria, and recent studies (2010–13) of incidence, drug resistance, and coverage of insecticide-treated bednets.
Findings
Globally in 2013, there were 1·8 million new HIV infections (95% uncertainty interval 1·7 million to 2·1 million), 29·2 million prevalent HIV cases (28·1 to 31·7), and 1·3 million HIV deaths (1·3 to 1·5). At the peak of the epidemic in 2005, HIV caused 1·7 million deaths (1·6 million to 1·9 million). Concentrated epidemics in Latin America and eastern Europe are substantially smaller than previously estimated. Through interventions including PMTCT and ART, 19·1 million life-years (16·6 million to 21·5 million) have been saved, 70·3% (65·4 to 76·1) in developing countries. From 2000 to 2011, the ratio of development assistance for health for HIV to years of life saved through intervention was US$4498 in developing countries. Including in HIV-positive individuals, all-form tuberculosis incidence was 7·5 million (7·4 million to 7·7 million), prevalence was 11·9 million (11·6 million to 12·2 million), and number of deaths was 1·4 million (1·3 million to 1·5 million) in 2013. In the same year and in only individuals who were HIV-negative, all-form tuberculosis incidence was 7·1 million (6·9 million to 7·3 million), prevalence was 11·2 million (10·8 million to 11·6 million), and number of deaths was 1·3 million (1·2 million to 1·4 million). Annualised rates of change (ARC) for incidence, prevalence, and death became negative after 2000. Tuberculosis in HIV-negative individuals disproportionately occurs in men and boys (versus women and girls); 64·0% of cases (63·6 to 64·3) and 64·7% of deaths (60·8 to 70·3). Globally, malaria cases and deaths grew rapidly from 1990 reaching a peak of 232 million cases (143 million to 387 million) in 2003 and 1·2 million deaths (1·1 million to 1·4 million) in 2004. Since 2004, child deaths from malaria in sub-Saharan Africa have decreased by 31·5% (15·7 to 44·1). Outside of Africa, malaria mortality has been steadily decreasing since 1990.
Interpretation
Our estimates of the number of people living with HIV are 18·7% smaller than UNAIDS’s estimates in 2012. The number of people living with malaria is larger than estimated by WHO. The number of people living with HIV, tuberculosis, or malaria have all decreased since 2000. At the global level, upward trends for malaria and HIV deaths have been reversed and declines in tuberculosis deaths have accelerated. 101 countries (74 of which are developing) still have increasing HIV incidence. Substantial progress since the Millennium Declaration is an encouraging sign of the effect of global action.
Funding
Bill & Melinda Gates Foundation.
doi:10.1016/S0140-6736(14)60844-8
PMCID: PMC4202387  PMID: 25059949
8.  Activity enhances dopaminergic long-duration response in Parkinson disease 
Jung Kang, Un | Auinger, Peggy | Fahn, Stanley | Oakes, David | Shoulson, Ira | Kieburtz, Karl | Rudolph, Alice | Marek, Kenneth | Seibyl, John | Lang, Anthony | Olanow, C. Warren | Tanner, Caroline | Schifitto, Giovanni | Zhao, Hongwei | Reyes, Lydia | Shinaman, Aileen | Comella, Cynthia L. | Goetz, Christopher | Blasucci, Lucia M. | Samanta, Johan | Stacy, Mark | Williamson, Kelli | Harrigan, Mary | Greene, Paul | Ford, Blair | Moskowitz, Carol | Truong, Daniel D. | Pathak, Mayank | Jankovic, Joseph | Ondo, William | Atassi, Farah | Hunter, Christine | Jacques, Carol | Friedman, Joseph H. | Lannon, Margaret | Russell, David S. | Jennings, Danna | Fussell, Barbara | Standaert, David | Schwarzschild, Michael A. | Growdon, John H. | Tennis, Marsha | Gauthier, Serge | Panisset, Michel | Hall, Jean | Gancher, Stephen | Hammerstad, John P. | Stone, Claudia | Alexander-Brown, Barbara | Factor, Stewart A. | Molho, Eric | Brown, Diane | Evans, Sharon | Clark, Jeffrey | Manyam, Bala | Simpson, Patricia | Wulbrecht, Brian | Whetteckey, Jacqueline | Martin, Wayne | Roberts, Ted | King, Pamela | Hauser, Robert | Zesiewicz, Theresa | Gauger, Lisa | Trugman, Joel | Wooten, G. Frederick | Rost-Ruffner, Elke | Perlmutter, Joel | Racette, Brad A. | Suchowersky, Oksana | Ranawaya, Ranjit | Wood, Susan | Pantella, Carol | Kurlan, Roger | Richard, Irene | Pearson, Nancy | Caviness, John N. | Adler, Charles | Lind, Marlene | Simuni, Tanya | Siderowf, Andrew | Colcher, Amy | Lloyd, Mary | Weiner, William | Shulman, Lisa | Koller, William | Lyons, Kelly | Feldman, Robert G. | Saint-Hilaire, Marie H. | Ellias, Samuel | Thomas, Cathi-Ann | Juncos, Jorge | Watts, Ray | Partlow, Anna | Tetrud, James | Togasaki, Daniel M. | Stewart, Tracy | Mark, Margery H. | Sage, Jacob I. | Caputo, Debbie | Gould, Harry | Rao, Jayaraman | McKendrick, Ann | Brin, Mitchell | Danisi, Fabio | Benabou, Reina | Hubble, Jean | Paulson, George W. | Reider, Carson | Birnbaum, Alex | Miyasaki, Janis | Johnston, Lisa | So, Julie | Pahwa, Rajesh | Dubinsky, Richard M. | Wszolek, Zbigniew | Uitti, Ryan | Turk, Margaret | Tuite, Paul | Rottenberg, David | Hansen, Joy | Ramos, Serrano | Waters, Cheryl | Lew, Mark | Welsh, Mickie | Kawai, Connie | O'Brien, Christopher | Kumar, Rajeev | Seeberger, Lauren | Judd, Deborah | Barclay, C. Lynn | Grimes, David A. | Sutherland, Laura | Dawson, Ted | Reich, Stephen | Dunlop, Rebecca | Albin, Roger | Frey, Kirk | Wernette, Kristine | Fahn, Stanley | Oakes, David | Shoulson, Ira | Kieburtz, Karl | Rudolph, Alice | Marek, Kenneth | Seibyl, John | Lang, Anthony | Olanow, C. Warren | Tanner, Caroline | Schifitto, Giovanni | Zhao, Hongwei | Reyes, Lydia | Shinaman, Aileen | Comella, Cynthia L. | Goetz, Christopher | Blasucci, Lucia M. | Samanta, Johan | Stacy, Mark | Williamson, Kelli | Harrigan, Mary | Greene, Paul | Ford, Blair | Moskowitz, Carol | Truong, Daniel D. | Pathak, Mayank | Jankovic, Joseph | Ondo, William | Atassi, Farah | Hunter, Christine | Jacques, Carol | Friedman, Joseph H. | Lannon, Margaret | Russell, David S. | Jennings, Danna | Fussell, Barbara | Standaert, David | Schwarzschild, Michael A. | Growdon, John H. | Tennis, Marsha | Gauthier, Serge | Panisset, Michel | Hall, Jean | Gancher, Stephen | Hammerstad, John P. | Stone, Claudia | Alexander-Brown, Barbara | Factor, Stewart A. | Molho, Eric | Brown, Diane | Evans, Sharon | Clark, Jeffrey | Manyam, Bala | Simpson, Patricia | Wulbrecht, Brian | Whetteckey, Jacqueline | Martin, Wayne | Roberts, Ted | King, Pamela | Hauser, Robert | Zesiewicz, Theresa | Gauger, Lisa | Trugman, Joel | Wooten, G. Frederick | Rost-Ruffner, Elke | Perlmutter, Joel | Racette, Brad A. | Suchowersky, Oksana | Ranawaya, Ranjit | Wood, Susan | Pantella, Carol | Kurlan, Roger | Richard, Irene | Pearson, Nancy | Caviness, John N. | Adler, Charles | Lind, Marlene | Simuni, Tanya | Siderowf, Andrew | Colcher, Amy | Lloyd, Mary | Weiner, William | Shulman, Lisa | Koller, William | Lyons, Kelly | Feldman, Robert G. | Saint-Hilaire, Marie H. | Ellias, Samuel | Thomas, Cathi-Ann | Juncos, Jorge | Watts, Ray | Partlow, Anna | Tetrud, James | Togasaki, Daniel M. | Stewart, Tracy | Mark, Margery H. | Sage, Jacob I. | Caputo, Debbie | Gould, Harry | Rao, Jayaraman | McKendrick, Ann | Brin, Mitchell | Danisi, Fabio | Benabou, Reina | Hubble, Jean | Paulson, George W. | Reider, Carson | Birnbaum, Alex | Miyasaki, Janis | Johnston, Lisa | So, Julie | Pahwa, Rajesh | Dubinsky, Richard M. | Wszolek, Zbigniew | Uitti, Ryan | Turk, Margaret | Tuite, Paul | Rottenberg, David | Hansen, Joy | Ramos, Serrano | Waters, Cheryl | Lew, Mark | Welsh, Mickie | Kawai, Connie | O'Brien, Christopher | Kumar, Rajeev | Seeberger, Lauren | Judd, Deborah | Barclay, C. Lynn | Grimes, David A. | Sutherland, Laura | Dawson, Ted | Reich, Stephen | Dunlop, Rebecca | Albin, Roger | Frey, Kirk | Wernette, Kristine | Mendis, Tilak
Neurology  2012;78(15):1146-1149.
Objective:
We tested the hypothesis that dopamine-dependent motor learning mechanism underlies the long-duration response to levodopa in Parkinson disease (PD) based on our studies in a mouse model. By data-mining the motor task performance in dominant and nondominant hands of the subjects in a double-blind randomized trial of levodopa therapy, the effects of activity and dopamine therapy were examined.
Methods:
We data-mined the Earlier versus Later Levodopa Therapy in Parkinson's Disease (ELLDOPA) study published in 2005 and performed statistical analysis comparing the effects of levodopa and dominance of handedness over 42 weeks.
Results:
The mean change in finger-tapping counts from baseline before the initiation of therapy to predose at 9 weeks and 40 weeks increased more in the dominant compared to nondominant hand in levodopa-treated subjects in a dose-dependent fashion. There was no significant difference in dominant vs nondominant hands in the placebo group. The short-duration response assessed by the difference of postdose performance compared to predose performance at the same visit did not show any significant difference between dominant vs nondominant hands.
Conclusions:
Active use of the dominant hand and dopamine replacement therapy produces synergistic effect on long-lasting motor task performance during “off” medication state. Such effect was confined to dopamine-responsive symptoms and not seen in dopamine-resistant symptoms such as gait and balance. We propose that long-lasting motor learning facilitated by activity and dopamine is a form of disease modification that is often seen in trials of medications that have symptomatic effects.
doi:10.1212/WNL.0b013e31824f8056
PMCID: PMC3466780  PMID: 22459675
9.  Rewarding Teaching Faculty with a Reimbursement Plan 
OBJECTIVE
To develop a system for measuring the teaching effort of medical school faculty and to implement a payment system that is based on it.
DESIGN
An interventional study with outcomes measured before and after the intervention.
SETTING
A department of internal medicine with a university hospital and an affiliated Veterans Administration hospital.
INTERVENTION
We assigned a value in teaching units to each teaching activity in proportion to the time expended by the faculty and the intensity of their effort. We then calculated total teaching units for each faculty member in the Division of General Internal Medicine and for combined faculty effort in each subspecialty division in the Department of Medicine. After determining the dollar value for a teaching unit, we distributed discretionary teaching dollars to each faculty member in the Division of General Internal Medicine and to each subspecialty division according to total teaching units.
MEASUREMENTS AND MAIN RESULTS
The distribution of discretionary teaching dollars was determined. In the year after the intervention, there was a substantial redistribution of discretionary teaching dollars among divisions. Compared with an increase in total discretionary dollars of 11.4%, the change in allocation for individual divisions ranged from an increase of 78.2% to a decrease of −28.5%. Further changes in the second year after the intervention were modest. The distribution of teaching units among divisions was similar to the distribution of questions across subspecialties on the American College of Physicians In-Training Examination (r = .67) and the American Board of Internal Medicine Certifying Examination (r = .88).
CONCLUSIONS
It is possible to measure the value of teaching effort by medical school faculty and to distribute discretionary teaching funds among divisions according to the value of teaching effort. When this intervention was used at our institution, there were substantial changes in the amounts received by some divisions. We believe that the new distribution more closely approximates the desired distribution because it reflects the desired emphasis on knowledge as measured by two of the most experienced professional groups in internal medicine. We also believe that our method is flexible and adaptable to the needs of most clinical teaching
doi:10.1046/j.1525-1497.1999.00350.x
PMCID: PMC1496590  PMID: 10354251
teaching, reimbursement; teaching, recognition
10.  Neural Control of Counter-Regulatory Events during Glucopenia in Man 
Journal of Clinical Investigation  1973;52(8):1841-1844.
The effect of autonomic denervation on the metabolic and hormonal responses during intracellular glucopenia in man was investigated. 2-Deoxy-d-glucose (2 DG), a competitive inhibitor of glucose metabolism, was administered intravenously to nine normal volunteers and to five patients, three with complete cervical cord transection (C-6) and two with idiopathic orthostatic hypotension. Before, during, and after a 20 min infusion of 2 DG (50 mg/kg) plasma concentrations of glucose, lactate, FFA, total catecholamines, immunoreactive insulin (IRI), human growth hormone (HGH), and cortisol were determined for periods up to 150 min. In control subjects, the initial elevation of FFA, glucose. HGH, and cortisol corresponded with the rise in total catecholamines, with maximal levels attained at 60 min, lactate rose at a slower rate, reaching peak levels at 150 min: although no change in IRI was noted. In contrast, 2 DG-induced glucopenic stress in the autonomic denervated subjects was characterized by no detectable catecholamine release or significant rise in glucose, FFA, lactate, or IRI. However, HGH and cortisol responses in four of the five patients were of a similar or greater magnitude than controls.
These studies demonstrate that the integrity of the sympathoadrenomedullary axis is essential for the counter-regulatory response to intracellular glucopenia in man. Cortisol and HGH have no apparent role in these events.
Images
PMCID: PMC302464  PMID: 4719665
12.  Small Renal Masses Progressing to Metastases under Active Surveillance: A Systematic Review and Pooled Analysis 
Cancer  2011;118(4):997-1006.
Purpose
We conducted a systematic review and pooled analysis of small renal masses under active surveillance to identify progression risk and characteristics associated with metastases.
Materials and Methods
A MEDLINE search was performed to identify all clinical series reporting surveillance of localized renal masses. For studies reporting individual level data, clinical and radiographic characteristics of tumors without progression were compared to those progressing to metastases.
Results
18 series (880 patients, 936 masses) met screening criteria from which 18 patients progressing to metastasis were identified (mean 40.2 months). Six studies (259 patients, 284 masses) provided individual level data for pooled analysis. With a mean follow up of 33.5±22.6 months, mean initial tumor diameter was 2.3±1.3 cm and mean linear growth rate was 0.31±0.38 cm/year. 65 masses (23%) exhibited zero net growth under surveillance; of which none progressed to metastasis. Pooled analysis revealed increased age (75.1±9.1 vs. 66.6±12.3 years, p=0.03), initial tumor diameter (4.1±2.1 vs. 2.3±1.3 cm, p<0.0001), initial estimated tumor volume (66.3±100.0 vs. 15.1±60.3 cm3, p<0.0001), linear growth rate (0.8±0.65 vs. 0.3±0.4 cm/yr, p=0.0001), and volumetric growth rate (27.1±24.9 vs. 6.2±27.5 cm3/yr, p<0.0001) in the progression cohort.
Conclusions
A substantial proportion of small renal masses remain radiographically static following an initial period of active surveillance. Progression to metastases occurs in a small percentage of patients and is generally a late event. These results indicate that in patients with competing health risks, radiographic surveillance may be an acceptable initial approach with delayed intervention reserved for those exhibiting significant linear or volumetric growth.
doi:10.1002/cncr.26369
PMCID: PMC4329724  PMID: 21766302
13.  Squamous Cell Carcinoma of the Oral Tongue in Two Patients Previously Exposed to Long-Term Pegylated Liposomal Doxorubicin 
The Oncologist  2012;17(12):1594-1595.
Two cases of squamous cell carcinoma possibly related to exposure to pegylated liposomal doxorubicin are presented.
doi:10.1634/theoncologist.2011-0280
PMCID: PMC3528392  PMID: 22622150
Pegylated Liposomal doxorubicin; Squamous cell carcinoma; Secondary malignancies; Oral tongue carcinoma
14.  Latent class analysis of non-opioid dependent illegal pharmaceutical opioid users in Ohio 
Drug and alcohol dependence  2013;0:10.1016/j.drugalcdep.2013.10.004.
Background
Increases in non-medical use of pharmaceutical opioids in the U.S. have resulted in increases in opioid dependence and unintentional overdose deaths. We characterize heterogeneity in opioid use patterns among a community-based sample of 18–23 year-olds who use non-medical pharmaceutical opioids, yet are not opioid dependent.
Methods
Respondent-driven sampling recruited 390 participants. Latent class analysis stratified by racial/ethnic group identified subgroups of non-medical opioid users based on: six-month frequency of use; number of opioid disorder criteria; oral vs. non-oral administration; number of types of opioids used; use of CNS depressants while under using opioids; and reason for opioid use. Multinomial logistic regression estimated the significance of covariates in predicting class membership.
Results
Within whites and non-white groups, three classes emerged that were, generally, hierarchically ordered with respect to negative characteristics associated with non-medical opioid use. Within each group, the class with the least negative characteristics also had the highest proportion of individuals who use opioids only to self-medicate a health problem. Within each group’s three classes, a larger proportion who had ≥ 2 opioid abuse and dependence disorder criteria always coincided with a larger proportion who use opioids ≥ 3 days per week, a larger proportion who used CNS depressants while under the influence of opioids, and a smaller proportion who used opioids only to self-medicate.
Conclusion
Differences in patterns of opioid use within each racial/ethnic group of young people who are not opioid dependent suggest the need for tailored interventions designed to reduce the risk of transition to opioid dependence.
doi:10.1016/j.drugalcdep.2013.10.004
PMCID: PMC3865109  PMID: 24210772
non-medical pharmaceutical opioid use; latent class analysis
17.  Relaxin Decreases the Severity of Established Hepatic Fibrosis in Mice 
Background
Hepatic fibrosis is characterized by excess collagen deposition, decreased extracellular matrix degradation, and activation of the hepatic stellate cells. The hormone relaxin has shown promise in the treatment of fibrosis in a number of tissues, but the effect of relaxin on established hepatic fibrosis is unknown.
Aims
The aim of this study was to determine the effect of relaxin on an in vivo model after establishing hepatic fibrosis.
Methods
Male mice were made fibrotic by carbon tetrachloride treatment for 4 weeks, followed by treatment with two doses of relaxin (25 or 75 ug/kg/day) or vehicle for 4 weeks, with continued administration of carbon tetrachloride.
Results
Relaxin significantly decreased total hepatic collagen and smooth muscle actin content at both doses, and suppressed collagen I expression at the higher dose. Relaxin increased the expression of the matrix metalloproteinases MMP13 and MMP3, decreased expression of MMP2 and tissue inhibitor of metalloproteinases 2 (TIMP2), and increased the overall level of collagen degrading activity. Relaxin decreased TGFβ-induced Smad2 nuclear localization in mouse hepatic stellate cells.
Conclusions
The results suggest that relaxin reduced collagen deposition and HSC activation in established hepatic fibrosis despite the presence of continued hepatic insult. This reduced fibrosis was associated with increased expression of the fibrillar collagen-degrading enzyme MMP13, decreased expression of TIMP2, and enhanced collagen degrading activity, and impaired TGFβ signaling, consistent with relaxin's effects on activated fibroblastic cells. The results suggest that relaxin may be an effective treatment for the treatment of established hepatic fibrosis.
doi:10.1111/liv.12247
PMCID: PMC3843971  PMID: 23870027
Liver disease; relaxin family peptides; cirrhosis; hepatic stellate cells; collagen
18.  Dynamic Nuclear Polarization of 17O: Direct Polarization 
The journal of physical chemistry. B  2013;117(48):14894-14906.
Dynamic nuclear polarization of 17O was studied using four different polarizing agents – the biradical TOTAPOL, and the monoradicals trityl and SA-BDPA, as well as a mixture of the latter two. Field profiles, DNP mechanisms and enhancements were measured to better understand and optimize directly polarizing this low-gamma quadrupolar nucleus using both mono- and bi-radical polarizing agents. Enhancements were recorded < 88 K and were > 100 using the trityl (OX063) radical and < 10 with the other polarizing agents. The > 10,000 fold savings in acquisition time enabled a series of biologically relevant small molecules to be studied with small sample sizes and the measurement of various quadrupolar parameters. The results are discussed with comparison to room temperature studies and GIPAW quantum chemical calculations. These experimental results illustrate the strength of high field DNP and the importance of radical selection for studying low-gamma nuclei.
doi:10.1021/jp408440z
PMCID: PMC3922122  PMID: 24195759
DNP; NMR; oxygen-17; radicals; cross-effect; solid-effect
19.  Human Antibody Responses to the Polyclonal Dryvax Vaccine for Smallpox Prevention Can Be Distinguished from Responses to the Monoclonal Replacement Vaccine ACAM2000 
Dryvax (Wyeth Laboratories, Inc., Marietta, PA) is representative of the vaccinia virus preparations that were previously used for preventing smallpox. While Dryvax was highly effective, the national supply stocks were depleted, and there were manufacturing concerns regarding sterility and the clonal heterogeneity of the vaccine. ACAM2000 (Acambis, Inc./Sanofi-Pasteur Biologics Co., Cambridge, MA), a single-plaque-purified vaccinia virus derivative of Dryvax, recently replaced the polyclonal smallpox vaccine for use in the United States. A substantial amount of sequence heterogeneity exists within the polyclonal proteome of Dryvax, including proteins that are missing from ACAM2000. Reasoning that a detailed comparison of antibody responses to the polyclonal and monoclonal vaccines may be useful for identifying unique properties of each antibody response, we utilized a protein microarray comprised of approximately 94% of the vaccinia poxvirus proteome (245 proteins) to measure protein-specific antibody responses of 71 individuals receiving a single vaccination with ACAM2000 or Dryvax. We observed robust antibody responses to 21 poxvirus proteins in vaccinated individuals, including 11 proteins that distinguished Dryvax responses from ACAM2000. Analysis of protein sequences from Dryvax clones revealed amino acid level differences in these 11 antigenic proteins and suggested that sequence variation and clonal heterogeneity may contribute to the observed differences between Dryvax and ACAM2000 antibody responses.
doi:10.1128/CVI.00035-14
PMCID: PMC4054243  PMID: 24759651
20.  Reverse micelles as a platform for dynamic nuclear polarization in solution NMR of proteins 
Despite tremendous advances in recent years, solution NMR remains fundamentally restricted due to its inherent insensitivity. Dynamic nuclear polarization (DNP) potentially offers significant improvements in this respect. The basic DNP strategy is to irradiate the EPR transitions of a stable radical and transfer this non-equilibrium polarization to the hydrogen spins of water, which will in turn transfer polarization to the hydrogens of the macromolecule. Unfortunately, these EPR transitions lie in the microwave range of the electromagnetic spectrum where bulk water absorbs strongly often resulting in catastrophic heating. Furthermore, the residence times of water on the surface of the protein in bulk solution are generally too short for efficient transfer of polarization. Here we take advantage of the properties of solutions of encapsulated proteins dissolved in low viscosity solvents to implement DNP in liquids. Such samples are largely transparent to the microwave frequencies required and thereby avoid significant heating. Nitroxide radicals are introduced into the reverse micelle system in three ways: attached to the protein; embedded in the reverse micelle shell; and free in the aqueous core. Significant enhancements of the water resonance ranging up to ~−93 at 0.35 T were observed. We also find that the hydration properties of encapsulated proteins allow for efficient polarization transfer from water to the protein. These and other observations suggest that merging reverse micelle encapsulation technology with DNP offers a route to a significant increase in the sensitivity of solution NMR spectroscopy of proteins and other bio-molecules.
doi:10.1021/ja4107176
PMCID: PMC3955360  PMID: 24456213
21.  Physician Willingness to Respond to Disasters: What Can We Learn? 
doi:10.4300/JGME-D-13-00210.1
PMCID: PMC3771191  PMID: 24404324
22.  Inhibition of Established Micrometastases by Targeted Drug Delivery via Cell Surface Associated GRP78 
Purpose
The major cause of morbidity in breast cancer is development of metastatic disease, for which few effective therapies exist. Since tumor cell dissemination is often an early event in breast cancer progression and can occur prior to diagnosis, new therapies need to focus on targeting established metastatic disease in secondary organs. We report an effective therapy based on targeting cell surface-localized glucose regulated protein 78 (GRP78). GRP78 is expressed normally in the endoplasmic reticulum, but many tumors and disseminated tumor cells are subjected to environmental stresses and exhibit elevated levels of GRP78, some of which is localized at the plasma membrane.
Experimental Design and Results
Here we show that matched primary tumors and metastases from patients who died from advanced breast cancer also express high levels of GRP78. We utilized a peptidomimetic targeting strategy that employs a known GRP78-binding peptide fused to a pro-apoptotic moiety (designated BMTP78) and show that it can selectively kill breast cancer cells that express surface-localized GRP78. Further, in preclinical metastasis models, we demonstrate that administration of BMTP78 can inhibit primary tumor growth as well as prolong overall survival by reducing the extent of outgrowth of established lung and bone micrometastases.
Conclusions
The data presented here provide strong evidence that it is possible to induce cell death in established micrometastases by peptide mediated targeting of cell surface localized GRP in advanced breast cancers. The significance to patients with advanced breast cancer of a therapy that can reduce established metastatic disease should not be underestimated.
doi:10.1158/1078-0432.CCR-12-2991
PMCID: PMC4331071  PMID: 23470966
Breast cancer; metastasis; GRP78; targeted therapy; cell stress
23.  Why summary comorbidity measures such as the Charlson Comorbidity Index and Elixhauser score work 
Medical care  2013;10.1097/MLR.0b013e318297429c.
Background
Comorbidity adjustment is an important component of health services research and clinical prognosis. When adjusting for comorbidities in statistical models, researchers can include comorbidities individually or through the use of summary measures such as the Charlson Comorbidity Index or Elixhauser score. We examined the conditions under which individual versus summary measures are most appropriate.
Methods
We provide an analytic proof of the utility of comorbidity summary measures when used in place of individual comorbidities. We compared the use of the Charlson and Elixhauser scores versus individual comorbidities in prognostic models using a SEER-Medicare data example. We examined the ability of summary comorbidity measures to adjust for confounding using simulations.
Results
We devised a mathematical proof that found that the comorbidity summary measures are appropriate prognostic or adjustment mechanisms in survival analyses. Once one knows the comorbidity score, no other information about the comorbidity variables used to create the score is generally needed. Our data example and simulations largely confirmed this finding.
Conclusions
Summary comorbidity measures, such as the Charlson Comorbidity Index and Elixhauser scores, are commonly used for clinical prognosis and comorbidity adjustment. We have provided a theoretical justification that validates the use of such scores under many conditions. Our simulations generally confirm the utility of the summary comorbidity measures as substitutes for use of the individual comorbidity variables in health services research. One caveat is that a summary measure may only be as good as the variables used to create it.
doi:10.1097/MLR.0b013e318297429c
PMCID: PMC3818341  PMID: 23703645
24.  MultiComponent Exercise and theRApeutic lifeStyle (CERgAS) intervention to improve physical performance and maintain independent living among urban poor older people - a cluster randomised controlled trial 
BMC Geriatrics  2015;15:8.
Background
The ability of older people to function independently is crucial as physical disability and functional limitation have profound impacts on health. Interventions that either delay the onset of frailty or attenuate its severity potentially have cascading benefits for older people, their families and society. This study aims to develop and evaluate the effectiveness of a multiComponent Exercise and theRApeutic lifeStyle (CERgAS) intervention program targeted at improving physical performance and maintaining independent living as compared to general health education among older people in an urban poor setting in Malaysia.
Methods
This cluster randomised controlled trial will be a 6-week community-based intervention programme for older people aged 60 years and above from urban poor settings. A minimum of 164 eligible participants will be recruited from 8 clusters (low-cost public subsidised flats) and randomised to the intervention and control arm. This study will be underpinned by the Health Belief Model with an emphasis towards self-efficacy. The intervention will comprise multicomponent group exercise sessions, nutrition education, oral care education and on-going support and counselling. These will be complemented with a kit containing practical tips on exercise, nutrition and oral care after each session. Data will be collected over four time points; at baseline, immediately post-intervention, 3-months and 6-months follow-up.
Discussion
Findings from this trial will potentially provide valuable evidence to improve physical function and maintain independence among older people from low-resource settings. This will inform health policies and identify locally acceptable strategies to promote healthy aging, prevent and delay functional decline among older Malaysian adults.
Trial registration
ISRCTN22749696.
doi:10.1186/s12877-015-0002-7
PMCID: PMC4334409
Elderly; Exercise; Physical function; Frailty; Randomised controlled trial; Lifestyle
25.  High Field Dynamic Nuclear Polarization NMR with Surfactant Sheltered Biradicals 
The Journal of Physical Chemistry. B  2014;118(7):1825-1830.
We illustrate the ability to place a water-insoluble biradical, bTbk, into a glycerol/water matrix with the assistance of a surfactant, sodium octyl sulfate (SOS). This surfactant approach enables a previously water insoluble biradical, bTbk, with favorable electron–electron dipolar coupling to be used for dynamic nuclear polarization (DNP) nuclear magnetic resonance (NMR) experiments in frozen, glassy, aqueous media. Nuclear Overhauser enhancement (NOE) and paramagnetic relaxation enhancement (PRE) experiments are conducted to determine the distribution of urea and several biradicals within the SOS macromolecular assembly. We also demonstrate that SOS assemblies are an effective approach by which mixed biradicals are created through an assembly process.
doi:10.1021/jp410387e
PMCID: PMC3983347  PMID: 24506193

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