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1.  Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture 
Berndt, Sonja I. | Gustafsson, Stefan | Mägi, Reedik | Ganna, Andrea | Wheeler, Eleanor | Feitosa, Mary F. | Justice, Anne E. | Monda, Keri L. | Croteau-Chonka, Damien C. | Day, Felix R. | Esko, Tõnu | Fall, Tove | Ferreira, Teresa | Gentilini, Davide | Jackson, Anne U. | Luan, Jian’an | Randall, Joshua C. | Vedantam, Sailaja | Willer, Cristen J. | Winkler, Thomas W. | Wood, Andrew R. | Workalemahu, Tsegaselassie | Hu, Yi-Juan | Lee, Sang Hong | Liang, Liming | Lin, Dan-Yu | Min, Josine L. | Neale, Benjamin M. | Thorleifsson, Gudmar | Yang, Jian | Albrecht, Eva | Amin, Najaf | Bragg-Gresham, Jennifer L. | Cadby, Gemma | den Heijer, Martin | Eklund, Niina | Fischer, Krista | Goel, Anuj | Hottenga, Jouke-Jan | Huffman, Jennifer E. | Jarick, Ivonne | Johansson, Åsa | Johnson, Toby | Kanoni, Stavroula | Kleber, Marcus E. | König, Inke R. | Kristiansson, Kati | Kutalik, Zoltán | Lamina, Claudia | Lecoeur, Cecile | Li, Guo | Mangino, Massimo | McArdle, Wendy L. | Medina-Gomez, Carolina | Müller-Nurasyid, Martina | Ngwa, Julius S. | Nolte, Ilja M. | Paternoster, Lavinia | Pechlivanis, Sonali | Perola, Markus | Peters, Marjolein J. | Preuss, Michael | Rose, Lynda M. | Shi, Jianxin | Shungin, Dmitry | Smith, Albert Vernon | Strawbridge, Rona J. | Surakka, Ida | Teumer, Alexander | Trip, Mieke D. | Tyrer, Jonathan | Van Vliet-Ostaptchouk, Jana V. | Vandenput, Liesbeth | Waite, Lindsay L. | Zhao, Jing Hua | Absher, Devin | Asselbergs, Folkert W. | Atalay, Mustafa | Attwood, Antony P. | Balmforth, Anthony J. | Basart, Hanneke | Beilby, John | Bonnycastle, Lori L. | Brambilla, Paolo | Bruinenberg, Marcel | Campbell, Harry | Chasman, Daniel I. | Chines, Peter S. | Collins, Francis S. | Connell, John M. | Cookson, William | de Faire, Ulf | de Vegt, Femmie | Dei, Mariano | Dimitriou, Maria | Edkins, Sarah | Estrada, Karol | Evans, David M. | Farrall, Martin | Ferrario, Marco M. | Ferrières, Jean | Franke, Lude | Frau, Francesca | Gejman, Pablo V. | Grallert, Harald | Grönberg, Henrik | Gudnason, Vilmundur | Hall, Alistair S. | Hall, Per | Hartikainen, Anna-Liisa | Hayward, Caroline | Heard-Costa, Nancy L. | Heath, Andrew C. | Hebebrand, Johannes | Homuth, Georg | Hu, Frank B. | Hunt, Sarah E. | Hyppönen, Elina | Iribarren, Carlos | Jacobs, Kevin B. | Jansson, John-Olov | Jula, Antti | Kähönen, Mika | Kathiresan, Sekar | Kee, Frank | Khaw, Kay-Tee | Kivimaki, Mika | Koenig, Wolfgang | Kraja, Aldi T. | Kumari, Meena | Kuulasmaa, Kari | Kuusisto, Johanna | Laitinen, Jaana H. | Lakka, Timo A. | Langenberg, Claudia | Launer, Lenore J. | Lind, Lars | Lindström, Jaana | Liu, Jianjun | Liuzzi, Antonio | Lokki, Marja-Liisa | Lorentzon, Mattias | Madden, Pamela A. | Magnusson, Patrik K. | Manunta, Paolo | Marek, Diana | März, Winfried | Mateo Leach, Irene | McKnight, Barbara | Medland, Sarah E. | Mihailov, Evelin | Milani, Lili | Montgomery, Grant W. | Mooser, Vincent | Mühleisen, Thomas W. | Munroe, Patricia B. | Musk, Arthur W. | Narisu, Narisu | Navis, Gerjan | Nicholson, George | Nohr, Ellen A. | Ong, Ken K. | Oostra, Ben A. | Palmer, Colin N.A. | Palotie, Aarno | Peden, John F. | Pedersen, Nancy | Peters, Annette | Polasek, Ozren | Pouta, Anneli | Pramstaller, Peter P. | Prokopenko, Inga | Pütter, Carolin | Radhakrishnan, Aparna | Raitakari, Olli | Rendon, Augusto | Rivadeneira, Fernando | Rudan, Igor | Saaristo, Timo E. | Sambrook, Jennifer G. | Sanders, Alan R. | Sanna, Serena | Saramies, Jouko | Schipf, Sabine | Schreiber, Stefan | Schunkert, Heribert | Shin, So-Youn | Signorini, Stefano | Sinisalo, Juha | Skrobek, Boris | Soranzo, Nicole | Stančáková, Alena | Stark, Klaus | Stephens, Jonathan C. | Stirrups, Kathleen | Stolk, Ronald P. | Stumvoll, Michael | Swift, Amy J. | Theodoraki, Eirini V. | Thorand, Barbara | Tregouet, David-Alexandre | Tremoli, Elena | Van der Klauw, Melanie M. | van Meurs, Joyce B.J. | Vermeulen, Sita H. | Viikari, Jorma | Virtamo, Jarmo | Vitart, Veronique | Waeber, Gérard | Wang, Zhaoming | Widén, Elisabeth | Wild, Sarah H. | Willemsen, Gonneke | Winkelmann, Bernhard R. | Witteman, Jacqueline C.M. | Wolffenbuttel, Bruce H.R. | Wong, Andrew | Wright, Alan F. | Zillikens, M. Carola | Amouyel, Philippe | Boehm, Bernhard O. | Boerwinkle, Eric | Boomsma, Dorret I. | Caulfield, Mark J. | Chanock, Stephen J. | Cupples, L. Adrienne | Cusi, Daniele | Dedoussis, George V. | Erdmann, Jeanette | Eriksson, Johan G. | Franks, Paul W. | Froguel, Philippe | Gieger, Christian | Gyllensten, Ulf | Hamsten, Anders | Harris, Tamara B. | Hengstenberg, Christian | Hicks, Andrew A. | Hingorani, Aroon | Hinney, Anke | Hofman, Albert | Hovingh, Kees G. | Hveem, Kristian | Illig, Thomas | Jarvelin, Marjo-Riitta | Jöckel, Karl-Heinz | Keinanen-Kiukaanniemi, Sirkka M. | Kiemeney, Lambertus A. | Kuh, Diana | Laakso, Markku | Lehtimäki, Terho | Levinson, Douglas F. | Martin, Nicholas G. | Metspalu, Andres | Morris, Andrew D. | Nieminen, Markku S. | Njølstad, Inger | Ohlsson, Claes | Oldehinkel, Albertine J. | Ouwehand, Willem H. | Palmer, Lyle J. | Penninx, Brenda | Power, Chris | Province, Michael A. | Psaty, Bruce M. | Qi, Lu | Rauramaa, Rainer | Ridker, Paul M. | Ripatti, Samuli | Salomaa, Veikko | Samani, Nilesh J. | Snieder, Harold | Sørensen, Thorkild I.A. | Spector, Timothy D. | Stefansson, Kari | Tönjes, Anke | Tuomilehto, Jaakko | Uitterlinden, André G. | Uusitupa, Matti | van der Harst, Pim | Vollenweider, Peter | Wallaschofski, Henri | Wareham, Nicholas J. | Watkins, Hugh | Wichmann, H.-Erich | Wilson, James F. | Abecasis, Goncalo R. | Assimes, Themistocles L. | Barroso, Inês | Boehnke, Michael | Borecki, Ingrid B. | Deloukas, Panos | Fox, Caroline S. | Frayling, Timothy | Groop, Leif C. | Haritunian, Talin | Heid, Iris M. | Hunter, David | Kaplan, Robert C. | Karpe, Fredrik | Moffatt, Miriam | Mohlke, Karen L. | O’Connell, Jeffrey R. | Pawitan, Yudi | Schadt, Eric E. | Schlessinger, David | Steinthorsdottir, Valgerdur | Strachan, David P. | Thorsteinsdottir, Unnur | van Duijn, Cornelia M. | Visscher, Peter M. | Di Blasio, Anna Maria | Hirschhorn, Joel N. | Lindgren, Cecilia M. | Morris, Andrew P. | Meyre, David | Scherag, André | McCarthy, Mark I. | Speliotes, Elizabeth K. | North, Kari E. | Loos, Ruth J.F. | Ingelsson, Erik
Nature genetics  2013;45(5):501-512.
Approaches exploiting extremes of the trait distribution may reveal novel loci for common traits, but it is unknown whether such loci are generalizable to the general population. In a genome-wide search for loci associated with upper vs. lower 5th percentiles of body mass index, height and waist-hip ratio, as well as clinical classes of obesity including up to 263,407 European individuals, we identified four new loci (IGFBP4, H6PD, RSRC1, PPP2R2A) influencing height detected in the tails and seven new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3, ZZZ3) for clinical classes of obesity. Further, we show that there is large overlap in terms of genetic structure and distribution of variants between traits based on extremes and the general population and little etiologic heterogeneity between obesity subgroups.
doi:10.1038/ng.2606
PMCID: PMC3973018  PMID: 23563607
2.  Ensuring Quality Cancer Care: A Follow-Up Review of the Institute of Medicine’s Ten Recommendations for Improving the Quality of Cancer Care in America 
Cancer  2011;118(10):2571-2582.
Responding to growing concerns regarding the safety, quality, and efficacy of cancer care in the United States, the Institute of Medicine (IOM) of the National Academy of Sciences commissioned a comprehensive review of cancer care delivery in the US healthcare system in the late 1990s. The National Cancer Policy Board (NCPB), a twenty-member board with broad representation, performed this review. In its review, the NCPB focused on the state of cancer care delivery at that time, its shortcomings, and ways to measure and improve the quality of cancer care. The NCPB described an ideal cancer care system, where patients would have equitable access to coordinated, guideline-based care and novel therapies throughout the course of their disease. In 1999, the IOM published the results of this review in its influential report, Ensuring Quality Cancer Care. This report outlined ten recommendations, which, when implemented, would: 1) improve the quality of cancer care; 2) increase our understanding of quality cancer care; and, 3) reduce or eliminate access barriers to quality cancer care.
Despite the fervor generated by this report, there are lingering doubts regarding the safety and quality of cancer care in the United States today. Increased awareness of medical errors and barriers to quality care, coupled with escalating healthcare costs, has prompted national efforts to reform the healthcare system. These efforts by healthcare providers and policymakers should bridge the gap between the ideal state described in Ensuring Quality Cancer Care and the current state of cancer care in the United States.
doi:10.1002/cncr.26536
PMCID: PMC3272132  PMID: 22045610
Oncology Service; Hospital; Quality of Health Care; Benchmarking; Guideline Adherence; Medically Uninsured; Palliative Care; Comparative Effectiveness Research
4.  Filtering and polychromatic vision in mantis shrimps: themes in visible and ultraviolet vision 
Stomatopod crustaceans have the most complex and diverse assortment of retinal photoreceptors of any animals, with 16 functional classes. The receptor classes are subdivided into sets responsible for ultraviolet vision, spatial vision, colour vision and polarization vision. Many of these receptor classes are spectrally tuned by filtering pigments located in photoreceptors or overlying optical elements. At visible wavelengths, carotenoproteins or similar substances are packed into vesicles used either as serial, intrarhabdomal filters or lateral filters. A single retina may contain a diversity of these filtering pigments paired with specific photoreceptors, and the pigments used vary between and within species both taxonomically and ecologically. Ultraviolet-filtering pigments in the crystalline cones serve to tune ultraviolet vision in these animals as well, and some ultraviolet receptors themselves act as birefringent filters to enable circular polarization vision. Stomatopods have reached an evolutionary extreme in their use of filter mechanisms to tune photoreception to habitat and behaviour, allowing them to extend the spectral range of their vision both deeper into the ultraviolet and further into the red.
doi:10.1098/rstb.2013.0032
PMCID: PMC3886321  PMID: 24395960
Stomatopod; colour vision; ultraviolet vision; polarization vision; spectral filtering; visual ecology
5.  Newborn Screening for Spinal Muscular Atrophy by Calibrated Short-Amplicon Melt Profiling 
Clinical chemistry  2012;58(6):1033-1039.
BACKGROUND
The management options for the autosomal recessive neurodegenerative disorder spinal muscular atrophy (SMA) are evolving; however, their efficacy may require presymptom diagnosis and continuous treatment. To identify presymptomatic SMA patients, we created a DNA-based newborn-screening assay to identify the homozygous deletions of the SMN1 (survival of motor neuron 1, telomeric) gene observed in 95%–98% of affected patients.
METHODS
We developed primers that amplify a 52-bp PCR product from homologous regions in the SMN1 and SMN2 (survival of motor neuron 2, centromeric) genes that flank a divergent site at site c.840. Post-PCR high-resolution melt profiling assessed the amplification product, and we used a unique means of melt calibration to normalize profiles. Samples that we had previously characterized for the numbers of SMN1 and SMN2 copies established genotypes associated with particular profiles. The system was evaluated with approximately 1000 purified DNA samples, 100 self-created dried blood spots, and >1200 dried blood spots from newborn-screening tests.
RESULTS
Homozygous deletion of SMN1 exon 7 produced a distinctive melt profile that identified SMA patients. Samples with different numbers of SMN1 and SMN2 copies were resolved by their profiles. All samples with homozygous deletions were unambiguously recognized, and no normal sample was misidentified as a positive.
CONCLUSIONS
This assay has characteristics suitable for population-based screening. A reliable screening test will facilitate the identification of an SMA-affected cohort to receive early intervention to maximize the benefit from treatment. A prospective screening trial will allow the efficacy of treatment options to be assessed, which may justify the inclusion of SMA as a target for population screening.
doi:10.1373/clinchem.2012.183038
PMCID: PMC4334578  PMID: 22490618
6.  Natural History of Denervation in SMA: Relation to Age, SMN2 Copy Number, and Function 
Annals of neurology  2005;57(5):704-712.
Denervation was assessed in 89 spinal muscular atrophy (SMA) 1, 2, and 3 subjects via motor unit number estimation (MUNE) and maximum compound motor action potential amplitude (CMAP) studies, and results correlated with SMN2 copy, age, and function. MUNE and maximum CMAP values were distinct among SMA subtypes (p < 0.05). Changes in MUNE and maximum CMAP values over time were dependent on age, SMA type, and SMN2 copy number. SMN2 copy number less than 3 correlated with lower MUNE and maximum CMAP values (p < 0.0001) and worse functional outcomes. As SMN2 copy number increases, so does functional status (p < 0.0001). Change in MUNE longitudinally over the time intervals examined in this study was not statistically significant for any SMA cohort. However, a decline in maximum CMAP over time was apparent in SMA2 subjects (p = 0.049). Age-dependent decline in MUNE and maximum CMAP was apparent in both SMA 1 (p < 0.0001) and SMA 2 (p < 0.0001) subjects, with age as an independent factor regardless of type. Maximum CMAP at the time of the initial assessment was most predictive of functional outcome (p < 0.0001). Prospective longitudinal studies in four prenatally diagnosed infants demonstrated significant progressive denervation in association with symptomatic onset or functional decline. These data highlight the potential value of such measures in increasing our understanding of pathophysiological factors involved in denervation in SMA.
doi:10.1002/ana.20473
PMCID: PMC4334582  PMID: 15852397
7.  A meta-analysis of genome-wide association studies for adiponectin levels in East Asians identifies a novel locus near WDR11-FGFR2 
Human Molecular Genetics  2013;23(4):1108-1119.
Blood levels of adiponectin, an adipocyte-secreted protein correlated with metabolic and cardiovascular risks, are highly heritable. Genome-wide association (GWA) studies for adiponectin levels have identified 14 loci harboring variants associated with blood levels of adiponectin. To identify novel adiponectin-associated loci, particularly those of importance in East Asians, we conducted a meta-analysis of GWA studies for adiponectin in 7827 individuals, followed by two stages of replications in 4298 and 5954 additional individuals. We identified a novel adiponectin-associated locus on chromosome 10 near WDR11-FGFR2 (P = 3.0 × 10−14) and provided suggestive evidence for a locus on chromosome 12 near OR8S1-LALBA (P = 1.2 × 10−7). Of the adiponectin-associated loci previously described, we confirmed the association at CDH13 (P = 6.8 × 10−165), ADIPOQ (P = 1.8 × 10−22), PEPD (P = 3.6 × 10−12), CMIP (P = 2.1 × 10−10), ZNF664 (P = 2.3 × 10−7) and GPR109A (P = 7.4 × 10−6). Conditional analysis at ADIPOQ revealed a second signal with suggestive evidence of association only after conditioning on the lead SNP (Pinitial = 0.020; Pconditional = 7.0 × 10−7). We further confirmed the independence of two pairs of closely located loci (<2 Mb) on chromosome 16 at CMIP and CDH13, and on chromosome 12 at GPR109A and ZNF664. In addition, the newly identified signal near WDR11-FGFR2 exhibited evidence of association with triglycerides (P = 3.3 × 10−4), high density lipoprotein cholesterol (HDL-C, P = 4.9 × 10−4) and body mass index (BMI)-adjusted waist–hip ratio (P = 9.8 × 10−3). These findings improve our knowledge of the genetic basis of adiponectin variation, demonstrate the shared allelic architecture for adiponectin with lipids and central obesity and motivate further studies of underlying mechanisms.
doi:10.1093/hmg/ddt488
PMCID: PMC3900106  PMID: 24105470
8.  Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization 
Arking, Dan E. | Pulit, Sara L. | Crotti, Lia | van der Harst, Pim | Munroe, Patricia B. | Koopmann, Tamara T. | Sotoodehnia, Nona | Rossin, Elizabeth J. | Morley, Michael | Wang, Xinchen | Johnson, Andrew D. | Lundby, Alicia | Gudbjartsson, Daníel F. | Noseworthy, Peter A. | Eijgelsheim, Mark | Bradford, Yuki | Tarasov, Kirill V. | Dörr, Marcus | Müller-Nurasyid, Martina | Lahtinen, Annukka M. | Nolte, Ilja M. | Smith, Albert Vernon | Bis, Joshua C. | Isaacs, Aaron | Newhouse, Stephen J. | Evans, Daniel S. | Post, Wendy S. | Waggott, Daryl | Lyytikäinen, Leo-Pekka | Hicks, Andrew A. | Eisele, Lewin | Ellinghaus, David | Hayward, Caroline | Navarro, Pau | Ulivi, Sheila | Tanaka, Toshiko | Tester, David J. | Chatel, Stéphanie | Gustafsson, Stefan | Kumari, Meena | Morris, Richard W. | Naluai, Åsa T. | Padmanabhan, Sandosh | Kluttig, Alexander | Strohmer, Bernhard | Panayiotou, Andrie G. | Torres, Maria | Knoflach, Michael | Hubacek, Jaroslav A. | Slowikowski, Kamil | Raychaudhuri, Soumya | Kumar, Runjun D. | Harris, Tamara B. | Launer, Lenore J. | Shuldiner, Alan R. | Alonso, Alvaro | Bader, Joel S. | Ehret, Georg | Huang, Hailiang | Kao, W.H. Linda | Strait, James B. | Macfarlane, Peter W. | Brown, Morris | Caulfield, Mark J. | Samani, Nilesh J. | Kronenberg, Florian | Willeit, Johann | Smith, J. Gustav | Greiser, Karin H. | zu Schwabedissen, Henriette Meyer | Werdan, Karl | Carella, Massimo | Zelante, Leopoldo | Heckbert, Susan R. | Psaty, Bruce M. | Rotter, Jerome I. | Kolcic, Ivana | Polašek, Ozren | Wright, Alan F. | Griffin, Maura | Daly, Mark J. | Arnar, David O. | Hólm, Hilma | Thorsteinsdottir, Unnur | Denny, Joshua C. | Roden, Dan M. | Zuvich, Rebecca L. | Emilsson, Valur | Plump, Andrew S. | Larson, Martin G. | O'Donnell, Christopher J. | Yin, Xiaoyan | Bobbo, Marco | D'Adamo, Adamo P. | Iorio, Annamaria | Sinagra, Gianfranco | Carracedo, Angel | Cummings, Steven R. | Nalls, Michael A. | Jula, Antti | Kontula, Kimmo K. | Marjamaa, Annukka | Oikarinen, Lasse | Perola, Markus | Porthan, Kimmo | Erbel, Raimund | Hoffmann, Per | Jöckel, Karl-Heinz | Kälsch, Hagen | Nöthen, Markus M. | consortium, HRGEN | den Hoed, Marcel | Loos, Ruth J.F. | Thelle, Dag S. | Gieger, Christian | Meitinger, Thomas | Perz, Siegfried | Peters, Annette | Prucha, Hanna | Sinner, Moritz F. | Waldenberger, Melanie | de Boer, Rudolf A. | Franke, Lude | van der Vleuten, Pieter A. | Beckmann, Britt Maria | Martens, Eimo | Bardai, Abdennasser | Hofman, Nynke | Wilde, Arthur A.M. | Behr, Elijah R. | Dalageorgou, Chrysoula | Giudicessi, John R. | Medeiros-Domingo, Argelia | Barc, Julien | Kyndt, Florence | Probst, Vincent | Ghidoni, Alice | Insolia, Roberto | Hamilton, Robert M. | Scherer, Stephen W. | Brandimarto, Jeffrey | Margulies, Kenneth | Moravec, Christine E. | Fabiola Del, Greco M. | Fuchsberger, Christian | O'Connell, Jeffrey R. | Lee, Wai K. | Watt, Graham C.M. | Campbell, Harry | Wild, Sarah H. | El Mokhtari, Nour E. | Frey, Norbert | Asselbergs, Folkert W. | Leach, Irene Mateo | Navis, Gerjan | van den Berg, Maarten P. | van Veldhuisen, Dirk J. | Kellis, Manolis | Krijthe, Bouwe P. | Franco, Oscar H. | Hofman, Albert | Kors, Jan A. | Uitterlinden, André G. | Witteman, Jacqueline C.M. | Kedenko, Lyudmyla | Lamina, Claudia | Oostra, Ben A. | Abecasis, Gonçalo R. | Lakatta, Edward G. | Mulas, Antonella | Orrú, Marco | Schlessinger, David | Uda, Manuela | Markus, Marcello R.P. | Völker, Uwe | Snieder, Harold | Spector, Timothy D. | Ärnlöv, Johan | Lind, Lars | Sundström, Johan | Syvänen, Ann-Christine | Kivimaki, Mika | Kähönen, Mika | Mononen, Nina | Raitakari, Olli T. | Viikari, Jorma S. | Adamkova, Vera | Kiechl, Stefan | Brion, Maria | Nicolaides, Andrew N. | Paulweber, Bernhard | Haerting, Johannes | Dominiczak, Anna F. | Nyberg, Fredrik | Whincup, Peter H. | Hingorani, Aroon | Schott, Jean-Jacques | Bezzina, Connie R. | Ingelsson, Erik | Ferrucci, Luigi | Gasparini, Paolo | Wilson, James F. | Rudan, Igor | Franke, Andre | Mühleisen, Thomas W. | Pramstaller, Peter P. | Lehtimäki, Terho J. | Paterson, Andrew D. | Parsa, Afshin | Liu, Yongmei | van Duijn, Cornelia | Siscovick, David S. | Gudnason, Vilmundur | Jamshidi, Yalda | Salomaa, Veikko | Felix, Stephan B. | Sanna, Serena | Ritchie, Marylyn D. | Stricker, Bruno H. | Stefansson, Kari | Boyer, Laurie A. | Cappola, Thomas P. | Olsen, Jesper V. | Lage, Kasper | Schwartz, Peter J. | Kääb, Stefan | Chakravarti, Aravinda | Ackerman, Michael J. | Pfeufer, Arne | de Bakker, Paul I.W. | Newton-Cheh, Christopher
Nature genetics  2014;46(8):826-836.
The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal Mendelian Long QT Syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals we identified 35 common variant QT interval loci, that collectively explain ∼8-10% of QT variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT loci in 298 unrelated LQTS probands identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode for proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies novel candidate genes for ventricular arrhythmias, LQTS,and SCD.
doi:10.1038/ng.3014
PMCID: PMC4124521  PMID: 24952745
genome-wide association study; QT interval; Long QT Syndrome; sudden cardiac death; myocardial repolarization; arrhythmias
9.  Predicting Hematoma Expansion After Primary Intracerebral Hemorrhage 
JAMA neurology  2014;71(2):158-164.
IMPORTANCE
Many clinical trials focus on restricting hematoma expansion following acute intracerebral hemorrhage (ICH), but selecting those patients at highest risk of hematoma expansion is challenging.
OBJECTIVE
To develop a prediction score for hematoma expansion in patients with primary ICH.
DESIGN, SETTING, AND PARTICIPANTS
Prospective cohort study at 2 urban academic medical centers among patients having primary ICH with available baseline and follow-up computed tomography for volumetric analysis (817 patients in the development cohort and 195 patients in the independent validation cohort).
MAIN OUTCOMES AND MEASURES
Hematoma expansion was assessed using semiautomated software and was defined as more than 6 mL or 33% growth. Covariates were tested for association with hematoma expansion using univariate and multivariable logistic regression. A 9-point prediction score was derived based on the regression estimates and was subsequently tested in the independent validation cohort.
RESULTS
Hematoma expansion occurred in 156 patients (19.1%). In multivariable analysis, predictors of expansion were as follows: warfarin sodium use, the computed tomography angiography spot sign, and shorter time to computed tomography (≤ 6 vs >6 hours) (P <.001 for all), as well as baseline ICH volume (<30 [reference], 30–60 [P =.03], and >60 [P =.005] mL). The incidence of hematoma expansion steadily increased with higher scores. In the independent validation cohort (n = 195), our prediction score performed well and showed strong association with hematoma expansion (odds ratio, 4.59; P <.001 for a high vs low score). The C statistics for the score were 0.72 for the development cohort and 0.77 for the independent validation cohort.
CONCLUSIONS AND RELEVANCE
A 9-point prediction score for hematoma expansion was developed and independently validated. The results open a path for individualized treatment and trial design in ICH aimed at patients at highest risk of hematoma expansion with maximum potential for therapeutic benefit.
doi:10.1001/jamaneurol.2013.5433
PMCID: PMC4131760  PMID: 24366060
10.  Vesicular Stomatitis Virus–Based Vaccines against Lassa and Ebola Viruses 
Emerging Infectious Diseases  2015;21(2):305-307.
We demonstrated that previous vaccination with a vesicular stomatitis virus (VSV)–based Lassa virus vaccine does not alter protective efficacy of subsequent vaccination with a VSV-based Ebola virus vaccine. These findings demonstrate the utility of VSV-based vaccines against divergent viral pathogens, even when preexisting immunity to the vaccine vector is present.
doi:10.3201/eid2102.141649
PMCID: PMC4313664  PMID: 25625358
vesicular stomatitis virus; VSV; viruses; pre-existing immunity; viral hemorrhagic fever; vaccines; virus-based vaccines; Lassa virus; Ebola virus; sequential vaccination; nonhuman primates; West Africa
11.  Avian Egg Odour Encodes Information on Embryo Sex, Fertility and Development 
PLoS ONE  2015;10(1):e0116345.
Avian chemical communication is a rapidly emerging field, but has been hampered by a critical lack of information on volatile chemicals that communicate ecologically relevant information (semiochemicals). A possible, but as yet unexplored, function of olfaction and chemical communication in birds is in parent-embryo and embryo-embryo communication. Communication between parents and developing embryos may act to mediate parental behaviour, while communication between embryos can control the synchronicity of hatching. Embryonic vocalisations and vibrations have been implicated as a means of communication during the later stages of development but in the early stages, before embryos are capable of independent movement and vocalisation, this is not possible. Here we show that volatiles emitted from developing eggs of Japanese quail (Coturnix japonica) convey information on egg fertility, along with the sex and developmental status of the embryo. Specifically, egg volatiles changed over the course of incubation, differed between fertile and infertile eggs, and were predictive of embryo sex as early as day 1 of incubation. Egg odours therefore have the potential to facilitate parent-embryo and embryo-embryo interactions by allowing the assessment of key measures of embryonic development long before this is possible through other modalities. It also opens up the intriguing possibility that parents may be able to glean further relevant information from egg volatiles, such as the health, viability and heritage of embryos. By determining information conveyed by egg-derived volatiles, we hope to stimulate further investigation into the ecological role of egg odours.
doi:10.1371/journal.pone.0116345
PMCID: PMC4309571  PMID: 25629413
12.  Long-term insulin glargine therapy in type 2 diabetes mellitus: a focus on cardiovascular outcomes 
Cardiovascular disease is the leading cause of mortality in type 2 diabetes mellitus. Hyperinsulinemia is associated with increased cardiovascular risk, but the effects of exogenous insulin on cardiovascular disease progression have been less well studied. Insulin has been shown to have both cardioprotective and atherosclerosis-promoting effects in laboratory animal studies. Long-term clinical trials using insulin to attain improved diabetes control in younger type 1 and type 2 diabetes patients have shown improved cardiovascular outcomes. Shorter trials of intensive diabetes control with high insulin use in higher risk patients with type 2 diabetes have shown either no cardiovascular benefit or increased all cause and cardiovascular mortality. Glargine insulin is a basal insulin analog widely used to treat patients with type 1 and type 2 diabetes. This review focuses on the effects of glargine on cardiovascular outcomes. Glargine lowers triglycerides, leads to a modest weight gain, causes less hypoglycemia when compared with intermediate-acting insulin, and has a neutral effect on blood pressure. The Outcome Reduction With Initial Glargine Intervention (ORIGIN trial), a 6.2 year dedicated cardiovascular outcomes trial of glargine demonstrated no increased cardiovascular risk.
doi:10.2147/VHRM.S50286
PMCID: PMC4315664  PMID: 25657589
glargine; insulin; type 2 diabetes; cardiovascular disease; cardiovascular outcomes
13.  Increased sample volume and use of quantitative reverse-transcription PCR can improve prediction of liver-to-blood inoculum size in controlled human malaria infection studies 
Malaria Journal  2015;14:33.
Background
Controlled human malaria infection (CHMI) studies increasingly rely on nucleic acid test (NAT) methods to detect and quantify parasites in the blood of infected participants. The lower limits of detection and quantification vary amongst the assays used throughout the world, which may affect the ability of mathematical models to accurately estimate the liver-to-blood inoculum (LBI) values that are used to judge the efficacy of pre-erythrocytic vaccine and drug candidates.
Methods
Samples were collected around the time of onset of pre-patent parasitaemia from subjects who enrolled in two different CHMI clinical trials. Blood samples were tested for Plasmodium falciparum 18S rRNA and/or rDNA targets by different NAT methods and results were compared. Methods included an ultrasensitive, large volume modification of an established quantitative reverse transcription PCR (qRT-PCR) assay that achieves detection of as little as one parasite/mL of whole blood.
Results
Large volume qRT-PCR at the University of Washington was the most sensitive test and generated quantifiable data more often than any other NAT methodology. Standard quantitative PCR (qPCR) performed at the University of Oxford and standard volume qRT-PCR performed at the University of Washington were less sensitive than the large volume qRT-PCR, especially at 6.5 days after CHMI. In these trials, the proportion of participants for whom LBI could be accurately quantified using parasite density value greater than or equal to the lower limit of quantification was increased. A greater improvement would be expected in trials in which numerous subjects receive a lower LBI or low dose challenge.
Conclusions
Standard qPCR and qRT-PCR methods with analytical sensitivities of ~20 parasites/mL probably suffice for most CHMI purposes, but the newly developed large volume qRT-PCR may be able to answer specific questions when more analytical sensitivity is required.
doi:10.1186/s12936-015-0541-6
PMCID: PMC4318195  PMID: 25627033
Plasmodium falciparum; 18S rRNA; PCR; RT-PCR; Standards; Controls; Calibrators; Pre-erythrocytic
14.  Correlation of circular RNA abundance with proliferation – exemplified with colorectal and ovarian cancer, idiopathic lung fibrosis, and normal human tissues 
Scientific Reports  2015;5:8057.
Circular RNAs are a recently (re-)discovered abundant RNA species with presumed function as miRNA sponges, thus part of the competing endogenous RNA network. We analysed the expression of circular and linear RNAs and proliferation in matched normal colon mucosa and tumour tissues. We predicted >1,800 circular RNAs and proved the existence of five randomly chosen examples using RT-qPCR. Interestingly, the ratio of circular to linear RNA isoforms was always lower in tumour compared to normal colon samples and even lower in colorectal cancer cell lines. Furthermore, this ratio correlated negatively with the proliferation index. The correlation of global circular RNA abundance (the circRNA index) and proliferation was validated in a non-cancerous proliferative disease, idiopathic pulmonary fibrosis, ovarian cancer cells compared to cultured normal ovarian epithelial cells, and 13 normal human tissues. We are the first to report a global reduction of circular RNA abundance in colorectal cancer cell lines and cancer compared to normal tissues and discovered a negative correlation of global circular RNA abundance and proliferation. This negative correlation seems to be a general principle in human tissues as validated with three different settings. Finally, we present a simple model how circular RNAs could accumulate in non-proliferating cells.
doi:10.1038/srep08057
PMCID: PMC4306919  PMID: 25624062
15.  Provision of specific dental procedures by general dentists in the National Dental Practice-Based Research Network: questionnaire findings 
BMC Oral Health  2015;15:11.
Background
Objectives were to: (1) determine whether and how often general dentists (GDs) provide specific dental procedures; and (2) test the hypothesis that provision is associated with key dentist, practice, and patient characteristics.
Methods
GDs (n = 2,367) in the United States National Dental Practice-Based Research Network completed an Enrollment Questionnaire that included: (1) dentist; (2) practice; and (3) patient characteristics, and how commonly they provide each of 10 dental procedures. We determined how commonly procedures were provided and tested the hypothesis that provision was substantively related to the three sets of characteristics.
Results
Two procedure categories were classified as “uncommon” (orthodontics, periodontal surgery), three were “common” (molar endodontics; implants; non-surgical periodontics), and five were “very common” (restorative; esthetic procedures; extractions; removable prosthetics; non-molar endodontics). Dentist, practice, and patient characteristics were substantively related to procedure provision; several characteristics seemed to have pervasive effects, such as dentist gender, training after dental school, full-time/part-time status, private practice vs. institutional practice, presence of a specialist in the same practice, and insurance status of patients.
Conclusions
As a group, GDs provide a comprehensive range of procedures. However, provision by individual dentists is substantively related to certain dentist, practice, and patient characteristics. A large number and broad range of factors seem to influence which procedures GDs provide. This may have implications for how GDs respond to the ever-changing landscape of dental care utilization, patient population demography, scope of practice, delivery models and GDs’ evolving role in primary care.
Electronic supplementary material
The online version of this article (doi:10.1186/1472-6831-15-11) contains supplementary material, which is available to authorized users.
doi:10.1186/1472-6831-15-11
PMCID: PMC4324862  PMID: 25608862
Dentist practice patterns; Practice-based research; Dentistry; Health services research
16.  Changing Rates for Liver and Lung Cancer in Qidong, China 
Residents of Qidong, China are undergoing a rapid fluctuation in cancer incidence rates at many organ sites, reflecting a dynamic interplay of socio-behavioral, economic and environmental factors. This Perspective On Statistical Trends examines the China age-standardized incidence rates (CASR), as tracked by the Qidong Cancer Registry for the past 40 years, for the two leading cancer killers in Qidong, liver and lung. Both cancer types are strongly influenced by environmental factors. The CASR for liver cancer has dropped nearly 50% in the last 4 decades, in part from access to deep-well drinking water in the 1970s with consequent diminished exposure to tumor promoting microcystins produced by blue-green algae. There have also been substantive reductions in exposures to dietary aflatoxins, as economic reform in the mid-1980s fostered a wholesale change in dietary staple from maize to rice. In men, lung cancer CASR has trebled over this period, likely driven by a high prevalence of smokers (~65%) and an ever increasing smoking frequency in this population. Qidong women, by contrast, rarely smoke and have exhibited a flat CASR until the last decade where lung cancer rates have now doubled. This upturn may reflect an increasing burden of indoor and outdoor air pollution.
doi:10.1021/tx400313j
PMCID: PMC3946948  PMID: 24215631
17.  A fast recoiling silk-like elastomer facilitates nanosecond nematocyst discharge 
BMC Biology  2015;13:3.
Background
The discharge of the Cnidarian stinging organelle, the nematocyst, is one of the fastest processes in biology and involves volume changes of the highly pressurised (150 bar) capsule of up to 50%. Hitherto, the molecular basis for the unusual biomechanical properties of nematocysts has been elusive, as their structure was mainly defined as a stress-resistant collagenous matrix.
Results
Here, we characterise Cnidoin, a novel elastic protein identified as a structural component of Hydra nematocysts. Cnidoin is expressed in nematocytes of all types and immunostainings revealed incorporation into capsule walls and tubules concomitant with minicollagens. Similar to spider silk proteins, to which it is related at sequence level, Cnidoin possesses high elasticity and fast coiling propensity as predicted by molecular dynamics simulations and quantified by force spectroscopy. Recombinant Cnidoin showed a high tendency for spontaneous aggregation to bundles of fibrillar structures.
Conclusions
Cnidoin represents the molecular factor involved in kinetic energy storage and release during the ultra-fast nematocyst discharge. Furthermore, it implies an early evolutionary origin of protein elastomers in basal metazoans.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-014-0113-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12915-014-0113-1
PMCID: PMC4321713  PMID: 25592740
Hydra; Nematocyst; Elastomer; Molecular dynamics; Single molecule force spectroscopy
18.  Effect of head impacts on diffusivity measures in a cohort of collegiate contact sport athletes 
Neurology  2014;82(1):63-69.
Objective:
To determine whether exposure to repetitive head impacts over a single season affects white matter diffusion measures in collegiate contact sport athletes.
Methods:
A prospective cohort study at a Division I NCAA athletic program of 80 nonconcussed varsity football and ice hockey players who wore instrumented helmets that recorded the acceleration-time history of the head following impact, and 79 non–contact sport athletes. Assessment occurred preseason and shortly after the season with diffusion tensor imaging and neurocognitive measures.
Results:
There was a significant (p = 0.011) athlete-group difference for mean diffusivity (MD) in the corpus callosum. Postseason fractional anisotropy (FA) differed (p = 0.001) in the amygdala (0.238 vs 0.233). Measures of head impact exposure correlated with white matter diffusivity measures in several brain regions, including the corpus callosum, amygdala, cerebellar white matter, hippocampus, and thalamus. The magnitude of change in corpus callosum MD postseason was associated with poorer performance on a measure of verbal learning and memory.
Conclusion:
This study suggests a relationship between head impact exposure, white matter diffusion measures, and cognition over the course of a single season, even in the absence of diagnosed concussion, in a cohort of college athletes. Further work is needed to assess whether such effects are short term or persistent.
doi:10.1212/01.wnl.0000438220.16190.42
PMCID: PMC3873621  PMID: 24336143
19.  Head Impact Exposure in Male and Female Collegiate Ice Hockey Players 
Journal of biomechanics  2013;47(1):109-114.
The purpose of this study was to quantify head impact exposure (frequency, location and magnitude of head impacts) for individual male and female collegiate ice hockey players and to investigate differences in exposure by sex, player position, session type, and team. Ninety-nine (41 male, 58 female) players were enrolled and 37,411 impacts were recorded over three seasons. Frequency of impacts varied significantly by sex (males: 287 per season, females: 170, p<0.001) and helmet impact location (p<0.001), but not by player position (p=0.088). Head impact frequency also varied by session type; both male and female players sustained more impacts in games than in practices (p<0.001), however the magnitude of impacts did not differ between session types. There was no difference in 95th percentile peak linear acceleration between sexes (males: 41.6g, females: 40.8g), but 95th percentile peak rotational acceleration and HITsp (a composite severity measure) were greater for males than females (4424, 3409 rad/s2, and 25.6, 22.3, respectively). Impacts to the back of the helmet resulted in the greatest 95th percentile peak linear accelerations for males (45.2g) and females (50.4g), while impacts to the side and back of the head were associated with the greatest 95th percentile peak rotational accelerations (males: 4719, 4256 rad/sec2, females: 3567, 3784 rad/sec2 respectively). It has been proposed that reducing an individual’s head impact exposure is a practical approach for reducing the risk of brain injuries. Strategies to decrease an individual athlete’s exposure need to be sport and gender specific, with considerations for team and session type.
doi:10.1016/j.jbiomech.2013.10.004
PMCID: PMC3902856  PMID: 24210478
impact biomechanics; hockey; gender; concussion
20.  Enhanced Antiretroviral Therapy in Rhesus Macaques Improves RT-SHIV Viral Decay Kinetics 
Using an established nonhuman primate model, rhesus macaques were infected intravenously with a chimeric simian immunodeficiency virus (SIV) consisting of SIVmac239 with the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase from clone HXBc2 (RT-SHIV). The impacts of two enhanced (four- and five-drug) highly active antiretroviral therapies (HAART) on early viral decay and rebound were determined. The four-drug combination consisted of an integrase inhibitor, L-870-812 (L-812), together with a three-drug regimen comprising emtricitabine [(−)-FTC], tenofovir (TFV), and efavirenz (EFV). The five-drug combination consisted of one analog for each of the four DNA precursors {using TFV, (−)-FTC, (−)-β-d-(2R,4R)-1,3-dioxolane-2,6-diaminopurine (amdoxovir [DAPD]), and zidovudine (AZT)}, together with EFV. A cohort treated with a three-drug combination of (−)-FTC, TFV, and EFV served as treated controls. Daily administration of a three-, four-, or five-drug combination of antiretroviral agents was initiated at week 6 or 8 after inoculation and continued up to week 50, followed by a rebound period. Plasma samples were collected routinely, and drug levels were monitored using liquid chromatography-tandem mass spectrometry (LC–MS-MS). Viral loads were monitored with a standard TaqMan quantitative reverse transcriptase PCR (qRT-PCR) assay. Comprehensive analyses of replication dynamics were performed. RT-SHIV infection in rhesus macaques produced typical viral infection kinetics, with untreated controls establishing persistent viral loads of >104 copies of RNA/ml. RT-SHIV loads at the start of treatment (V0) were similar in all treated cohorts (P > 0.5). All antiretroviral drug levels were measureable in plasma. The four-drug and five-drug combination regimens (enhanced HAART) improved suppression of the viral load (within 1 week; P < 0.01) and had overall greater potency (P < 0.02) than the three-drug regimen (HAART). Moreover, rebound viremia occurred rapidly following cessation of any treatment. The enhanced HAART (four- or five-drug combination) showed significant improvement in viral suppression compared to the three-drug combination, but no combination was sufficient to eliminate viral reservoirs.
doi:10.1128/AAC.02522-14
PMCID: PMC4068512  PMID: 24777106
21.  Effect of Dietary Restriction and Exercise on Lower Extremity Tissue Compartments in Obese, Older Women: A Pilot Study 
Background.
Accumulating evidence suggests that both dietary restriction and exercise (DR + E) should be incorporated in weight loss interventions to treat obese, older adults. However, more information is needed on the effects to lower extremity tissue composition—an important consideration for preserving mobility in older adults.
Methods.
Twenty-seven sedentary women (body mass index: 36.3±5.4kg/m2; age: 63.6±5.6 yrs) were randomly assigned to 6 months of DR + E or a health education control group. Thigh and calf muscle, subcutaneous adipose tissue (SAT), and intermuscular adipose tissue (IMAT) size were determined using magnetic resonance imaging. Physical function was measured using a long-distance corridor walk and knee extension strength.
Results.
Compared with control, DR + E significantly reduced body mass (-6.6±3.7kg vs control: -0.05±3.5kg; p < .01). Thigh and calf muscle volumes responded similarly between groups. Within the DR + E group, adipose tissue was reduced more in the thigh than in the calf (p < .04). Knee extension strength was unaltered by DR + E, but a trend toward increased walking speed was observed in the DR + E group (p = .09). Post hoc analyses showed that reductions in SAT and IMAT within the calf, but not the thigh, were associated with faster walking speed achieved with DR + E (SAT: r = -0.62; p = .01; IMAT: r = -0.62; p = .01).
Conclusions.
DR + E preserved lower extremity muscle size and function and reduced regional lower extremity adipose tissue. Although the magnitude of reduction in adipose tissue was greater in the thigh than the calf region, post hoc analyses demonstrated that reductions in calf SAT and IMAT were associated with positive adaptations in physical function.
doi:10.1093/gerona/gls337
PMCID: PMC4158399  PMID: 23682155
Body composition; Weight loss; Obesity; Aging; Disability.
22.  Nighttime lights time series of tsunami damage, recovery, and economic metrics in Sumatra, Indonesia 
Remote sensing letters (Print)  2014;5(3):286-294.
On 26 December 2004, a magnitude 9.2 earthquake off the west coast of the northern Sumatra, Indonesia resulted in 160,000 Indonesians killed. We examine the Defense Meteorological Satellite Program-Operational Linescan System (DMSP-OLS) nighttime light imagery brightness values for 307 communities in the Study of the Tsunami Aftermath and Recovery (STAR), a household survey in Sumatra from 2004 to 2008. We examined night light time series between the annual brightness and extent of damage, economic metrics collected from STAR households and aggregated to the community level. There were significant changes in brightness values from 2004 to 2008 with a significant drop in brightness values in 2005 due to the tsunami and pre-tsunami nighttime light values returning in 2006 for all damage zones. There were significant relationships between the nighttime imagery brightness and per capita expenditures, and spending on energy and on food. Results suggest that Defense Meteorological Satellite Program nighttime light imagery can be used to capture the impacts and recovery from the tsunami and other natural disasters and estimate time series economic metrics at the community level in developing countries.
doi:10.1080/2150704X.2014.900205
PMCID: PMC4235966  PMID: 25419471
23.  TRANSCRIPTIONAL IMPACT OF DIETARY METHIONINE RESTRICTION ON SYSTEMIC INFLAMMATION: RELEVANCE TO BIOMARKERS OF METABOLIC DISEASE DURING AGING 
BioFactors (Oxford, England)  2013;40(1):13-26.
Calorie restriction (CR) without malnutrition increases lifespan and produces significant improvements in biomarkers of metabolic health. The improvements are attributable in part to effects of CR on energy balance, which limit fat accumulation by restricting energy intake. Normal age-associated increases in adiposity and insulin resistance are associated with development of a systemic pro-inflammatory state, while chronic CR limits fat deposition and expression of inflammatory markers. Dietary methionine restriction (MR) has emerged as an effective CR mimetic because it produces a comparable extension in lifespan. MR also reduces adiposity through a compensatory increase in energy expenditure that effectively limits fat accumulation, but essentially nothing is known about the effects of MR on systemic inflammation. Here we review the relationships between these two interventions and discuss their transcriptional impact. In addition, using tissues from rats after long term consumption of CR or MR diets, transcriptional profiling was used to examine retrospectively the systems biology of 59 networks of molecules annotated to inflammation. Transcriptional effects of both diets occurred primarily in white adipose tissue and liver, and the responses to MR were far more robust than those to CR. The primary transcriptional targets of MR in both liver and white adipose tissue were phagocytes and macrophages, where expression of genes associated with immune cell infiltration and quantity was reduced. These findings support the conclusion that anti-inflammatory responses produced by CR and MR are not strictly dependent upon reduced adiposity, but are significantly influenced by the metabolic mechanisms through which energy balance is altered.
doi:10.1002/biof.1111
PMCID: PMC3796060  PMID: 23813805
obesity; animal models; insulin sensitivity; amino acid sensing
24.  Amygdala response to negative images in postpartum vs nulliparous women and intranasal oxytocin 
The neuroendocrine state of new mothers may alter their neural processing of stressors in the environment through modulatory actions of oxytocin on the limbic system. We predicted that amygdala sensitivity to negatively arousing stimuli would be suppressed in postpartum compared to nulliparous women and that this suppression would be modulated by administration of oxytocin nasal spray. We measured brain activation (fMRI) and subjective arousal in response to negatively arousing pictures in 29 postpartum and 30 nulliparous women who received either oxytocin nasal spray or placebo before scanning. Pre- and post-exposure urinary cortisol levels were also measured. Postpartum women (placebo) demonstrated lower right amygdala activation in response to negative images, lower cortisol and lower negative photo arousal ratings to nulliparous women. Nulliparous women receiving oxytocin had lower right amygdala activation compared to placebo. Cortisol levels in the placebo group, and ratings of arousal across all women, were positively associated with right amygdala activation. Together, these findings demonstrate reductions in both amygdala activation and subjective negative arousal in untreated postpartum vs nulliparous women, supporting the hypothesis of an attenuated neural response to arousing stimuli in postpartum women. A causal role of oxytocin and the timing of potential effects require future investigation.
doi:10.1093/scan/nss100
PMCID: PMC3871727  PMID: 22956670
postpartum; oxytocin; arousal; amygdale; cortisol
25.  Sleep Duration and Cardiovascular Responses to Stress in Undergraduate Men 
Psychophysiology  2013;51(1):10.1111/psyp.12144.
Short sleep has been related to incident cardiovascular disease, but physiological mechanisms accounting for this relationship are largely unknown. This study examines sleep duration and cardiovascular stress responses in 79 healthy, young men. Sleep duration was assessed by wrist actigraphy for seven nights. Participants then completed a series of laboratory stress tasks while heart rate and blood pressure were monitored. Shorter total sleep time was related to a greater reduction in high-frequency heart rate variability during stress tasks, and to prolonged elevations in heart rate and diastolic pressure following tasks. Associations were independent of age, race, body mass index, caffeine intake, and smoking status. In sum, healthy young men with shorter actigraphy-assessed sleep exhibit less cardiac vagal activity, and poorer heart rate and diastolic blood pressure recovery, upon encountering stressful stimuli, than those with longer sleep.
doi:10.1111/psyp.12144
PMCID: PMC3883723  PMID: 24016263
sleep; actigraphy; reactivity; recovery; heart rate; blood pressure; vagal; stress; heart rate variability

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