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1.  FUNCTIONAL NEUROANATOMY OF THE COGNITIVE PROCESS OF MAPPING DURING DISCOURSE COMPREHENSION 
Psychological science  2000;11(3):255-260.
We used functional magnetic resonance imaging (fMRI) to identify brain regions involved in the process of mapping coherent discourse onto a developing mental representation. We manipulated discourse coherence by presenting sentences with definite articles (which lead to more coherent discourse) or indefinite articles (which lead to less coherent discourse). Comprehending connected discourse, compared with reading unrelated sentences, produced more neural activity in the right than left hemisphere of the frontal lobe. Thus, the right hemisphere of the frontal lobe is involved in some of the processes underlying mapping. In contrast, left-hemisphere structures were associated with lower-level processes in reading (such as word recognition and syntactic processing). Our results demonstrate the utility of using fMRI to investigate the neural substrates of higher-level cognitive processes such as discourse comprehension.
PMCID: PMC4301434  PMID: 11273413
2.  The First Myriapod Genome Sequence Reveals Conservative Arthropod Gene Content and Genome Organisation in the Centipede Strigamia maritima 
Chipman, Ariel D. | Ferrier, David E. K. | Brena, Carlo | Qu, Jiaxin | Hughes, Daniel S. T. | Schröder, Reinhard | Torres-Oliva, Montserrat | Znassi, Nadia | Jiang, Huaiyang | Almeida, Francisca C. | Alonso, Claudio R. | Apostolou, Zivkos | Aqrawi, Peshtewani | Arthur, Wallace | Barna, Jennifer C. J. | Blankenburg, Kerstin P. | Brites, Daniela | Capella-Gutiérrez, Salvador | Coyle, Marcus | Dearden, Peter K. | Du Pasquier, Louis | Duncan, Elizabeth J. | Ebert, Dieter | Eibner, Cornelius | Erikson, Galina | Evans, Peter D. | Extavour, Cassandra G. | Francisco, Liezl | Gabaldón, Toni | Gillis, William J. | Goodwin-Horn, Elizabeth A. | Green, Jack E. | Griffiths-Jones, Sam | Grimmelikhuijzen, Cornelis J. P. | Gubbala, Sai | Guigó, Roderic | Han, Yi | Hauser, Frank | Havlak, Paul | Hayden, Luke | Helbing, Sophie | Holder, Michael | Hui, Jerome H. L. | Hunn, Julia P. | Hunnekuhl, Vera S. | Jackson, LaRonda | Javaid, Mehwish | Jhangiani, Shalini N. | Jiggins, Francis M. | Jones, Tamsin E. | Kaiser, Tobias S. | Kalra, Divya | Kenny, Nathan J. | Korchina, Viktoriya | Kovar, Christie L. | Kraus, F. Bernhard | Lapraz, François | Lee, Sandra L. | Lv, Jie | Mandapat, Christigale | Manning, Gerard | Mariotti, Marco | Mata, Robert | Mathew, Tittu | Neumann, Tobias | Newsham, Irene | Ngo, Dinh N. | Ninova, Maria | Okwuonu, Geoffrey | Ongeri, Fiona | Palmer, William J. | Patil, Shobha | Patraquim, Pedro | Pham, Christopher | Pu, Ling-Ling | Putman, Nicholas H. | Rabouille, Catherine | Ramos, Olivia Mendivil | Rhodes, Adelaide C. | Robertson, Helen E. | Robertson, Hugh M. | Ronshaugen, Matthew | Rozas, Julio | Saada, Nehad | Sánchez-Gracia, Alejandro | Scherer, Steven E. | Schurko, Andrew M. | Siggens, Kenneth W. | Simmons, DeNard | Stief, Anna | Stolle, Eckart | Telford, Maximilian J. | Tessmar-Raible, Kristin | Thornton, Rebecca | van der Zee, Maurijn | von Haeseler, Arndt | Williams, James M. | Willis, Judith H. | Wu, Yuanqing | Zou, Xiaoyan | Lawson, Daniel | Muzny, Donna M. | Worley, Kim C. | Gibbs, Richard A. | Akam, Michael | Richards, Stephen
PLoS Biology  2014;12(11):e1002005.
Myriapods (e.g., centipedes and millipedes) display a simple homonomous body plan relative to other arthropods. All members of the class are terrestrial, but they attained terrestriality independently of insects. Myriapoda is the only arthropod class not represented by a sequenced genome. We present an analysis of the genome of the centipede Strigamia maritima. It retains a compact genome that has undergone less gene loss and shuffling than previously sequenced arthropods, and many orthologues of genes conserved from the bilaterian ancestor that have been lost in insects. Our analysis locates many genes in conserved macro-synteny contexts, and many small-scale examples of gene clustering. We describe several examples where S. maritima shows different solutions from insects to similar problems. The insect olfactory receptor gene family is absent from S. maritima, and olfaction in air is likely effected by expansion of other receptor gene families. For some genes S. maritima has evolved paralogues to generate coding sequence diversity, where insects use alternate splicing. This is most striking for the Dscam gene, which in Drosophila generates more than 100,000 alternate splice forms, but in S. maritima is encoded by over 100 paralogues. We see an intriguing linkage between the absence of any known photosensory proteins in a blind organism and the additional absence of canonical circadian clock genes. The phylogenetic position of myriapods allows us to identify where in arthropod phylogeny several particular molecular mechanisms and traits emerged. For example, we conclude that juvenile hormone signalling evolved with the emergence of the exoskeleton in the arthropods and that RR-1 containing cuticle proteins evolved in the lineage leading to Mandibulata. We also identify when various gene expansions and losses occurred. The genome of S. maritima offers us a unique glimpse into the ancestral arthropod genome, while also displaying many adaptations to its specific life history.
Author Summary
Arthropods are the most abundant animals on earth. Among them, insects clearly dominate on land, whereas crustaceans hold the title for the most diverse invertebrates in the oceans. Much is known about the biology of these groups, not least because of genomic studies of the fruit fly Drosophila, the water flea Daphnia, and other species used in research. Here we report the first genome sequence from a species belonging to a lineage that has previously received very little attention—the myriapods. Myriapods were among the first arthropods to invade the land over 400 million years ago, and survive today as the herbivorous millipedes and venomous centipedes, one of which—Strigamia maritima—we have sequenced here. We find that the genome of this centipede retains more characteristics of the presumed arthropod ancestor than other sequenced insect genomes. The genome provides access to many aspects of myriapod biology that have not been studied before, suggesting, for example, that they have diversified receptors for smell that are quite different from those used by insects. In addition, it shows specific consequences of the largely subterranean life of this particular species, which seems to have lost the genes for all known light-sensing molecules, even though it still avoids light.
doi:10.1371/journal.pbio.1002005
PMCID: PMC4244043  PMID: 25423365
3.  Endonuclease G preferentially cleaves 5-hydroxymethylcytosine-modified DNA creating a substrate for recombination 
Nucleic Acids Research  2014;42(21):13280-13293.
5-hydroxymethylcytosine (5hmC) has been suggested to be involved in various nucleic acid transactions and cellular processes, including transcriptional regulation, demethylation of 5-methylcytosine and stem cell pluripotency. We have identified an activity that preferentially catalyzes the cleavage of double-stranded 5hmC-modified DNA. Using biochemical methods we purified this activity from mouse liver extracts and demonstrate that the enzyme responsible for the cleavage of 5hmC-modified DNA is Endonuclease G (EndoG). We show that recombinant EndoG preferentially recognizes and cleaves a core sequence when one specific cytosine within that core sequence is hydroxymethylated. Additionally, we provide in vivo evidence that EndoG catalyzes the formation of double-stranded DNA breaks and that this cleavage is dependent upon the core sequence, EndoG and 5hmC. Finally, we demonstrate that the 5hmC modification can promote conservative recombination in an EndoG-dependent manner.
doi:10.1093/nar/gku1032
PMCID: PMC4245937  PMID: 25355512
4.  Comprehensive molecular characterization of gastric adenocarcinoma 
Bass, Adam J. | Thorsson, Vesteinn | Shmulevich, Ilya | Reynolds, Sheila M. | Miller, Michael | Bernard, Brady | Hinoue, Toshinori | Laird, Peter W. | Curtis, Christina | Shen, Hui | Weisenberger, Daniel J. | Schultz, Nikolaus | Shen, Ronglai | Weinhold, Nils | Kelsen, David P. | Bowlby, Reanne | Chu, Andy | Kasaian, Katayoon | Mungall, Andrew J. | Robertson, A. Gordon | Sipahimalani, Payal | Cherniack, Andrew | Getz, Gad | Liu, Yingchun | Noble, Michael S. | Pedamallu, Chandra | Sougnez, Carrie | Taylor-Weiner, Amaro | Akbani, Rehan | Lee, Ju-Seog | Liu, Wenbin | Mills, Gordon B. | Yang, Da | Zhang, Wei | Pantazi, Angeliki | Parfenov, Michael | Gulley, Margaret | Piazuelo, M. Blanca | Schneider, Barbara G. | Kim, Jihun | Boussioutas, Alex | Sheth, Margi | Demchok, John A. | Rabkin, Charles S. | Willis, Joseph E. | Ng, Sam | Garman, Katherine | Beer, David G. | Pennathur, Arjun | Raphael, Benjamin J. | Wu, Hsin-Ta | Odze, Robert | Kim, Hark K. | Bowen, Jay | Leraas, Kristen M. | Lichtenberg, Tara M. | Weaver, Stephanie | McLellan, Michael | Wiznerowicz, Maciej | Sakai, Ryo | Getz, Gad | Sougnez, Carrie | Lawrence, Michael S. | Cibulskis, Kristian | Lichtenstein, Lee | Fisher, Sheila | Gabriel, Stacey B. | Lander, Eric S. | Ding, Li | Niu, Beifang | Ally, Adrian | Balasundaram, Miruna | Birol, Inanc | Bowlby, Reanne | Brooks, Denise | Butterfield, Yaron S. N. | Carlsen, Rebecca | Chu, Andy | Chu, Justin | Chuah, Eric | Chun, Hye-Jung E. | Clarke, Amanda | Dhalla, Noreen | Guin, Ranabir | Holt, Robert A. | Jones, Steven J.M. | Kasaian, Katayoon | Lee, Darlene | Li, Haiyan A. | Lim, Emilia | Ma, Yussanne | Marra, Marco A. | Mayo, Michael | Moore, Richard A. | Mungall, Andrew J. | Mungall, Karen L. | Nip, Ka Ming | Robertson, A. Gordon | Schein, Jacqueline E. | Sipahimalani, Payal | Tam, Angela | Thiessen, Nina | Beroukhim, Rameen | Carter, Scott L. | Cherniack, Andrew D. | Cho, Juok | Cibulskis, Kristian | DiCara, Daniel | Frazer, Scott | Fisher, Sheila | Gabriel, Stacey B. | Gehlenborg, Nils | Heiman, David I. | Jung, Joonil | Kim, Jaegil | Lander, Eric S. | Lawrence, Michael S. | Lichtenstein, Lee | Lin, Pei | Meyerson, Matthew | Ojesina, Akinyemi I. | Pedamallu, Chandra Sekhar | Saksena, Gordon | Schumacher, Steven E. | Sougnez, Carrie | Stojanov, Petar | Tabak, Barbara | Taylor-Weiner, Amaro | Voet, Doug | Rosenberg, Mara | Zack, Travis I. | Zhang, Hailei | Zou, Lihua | Protopopov, Alexei | Santoso, Netty | Parfenov, Michael | Lee, Semin | Zhang, Jianhua | Mahadeshwar, Harshad S. | Tang, Jiabin | Ren, Xiaojia | Seth, Sahil | Yang, Lixing | Xu, Andrew W. | Song, Xingzhi | Pantazi, Angeliki | Xi, Ruibin | Bristow, Christopher A. | Hadjipanayis, Angela | Seidman, Jonathan | Chin, Lynda | Park, Peter J. | Kucherlapati, Raju | Akbani, Rehan | Ling, Shiyun | Liu, Wenbin | Rao, Arvind | Weinstein, John N. | Kim, Sang-Bae | Lee, Ju-Seog | Lu, Yiling | Mills, Gordon | Laird, Peter W. | Hinoue, Toshinori | Weisenberger, Daniel J. | Bootwalla, Moiz S. | Lai, Phillip H. | Shen, Hui | Triche, Timothy | Van Den Berg, David J. | Baylin, Stephen B. | Herman, James G. | Getz, Gad | Chin, Lynda | Liu, Yingchun | Murray, Bradley A. | Noble, Michael S. | Askoy, B. Arman | Ciriello, Giovanni | Dresdner, Gideon | Gao, Jianjiong | Gross, Benjamin | Jacobsen, Anders | Lee, William | Ramirez, Ricardo | Sander, Chris | Schultz, Nikolaus | Senbabaoglu, Yasin | Sinha, Rileen | Sumer, S. Onur | Sun, Yichao | Weinhold, Nils | Thorsson, Vésteinn | Bernard, Brady | Iype, Lisa | Kramer, Roger W. | Kreisberg, Richard | Miller, Michael | Reynolds, Sheila M. | Rovira, Hector | Tasman, Natalie | Shmulevich, Ilya | Ng, Santa Cruz Sam | Haussler, David | Stuart, Josh M. | Akbani, Rehan | Ling, Shiyun | Liu, Wenbin | Rao, Arvind | Weinstein, John N. | Verhaak, Roeland G.W. | Mills, Gordon B. | Leiserson, Mark D. M. | Raphael, Benjamin J. | Wu, Hsin-Ta | Taylor, Barry S. | Black, Aaron D. | Bowen, Jay | Carney, Julie Ann | Gastier-Foster, Julie M. | Helsel, Carmen | Leraas, Kristen M. | Lichtenberg, Tara M. | McAllister, Cynthia | Ramirez, Nilsa C. | Tabler, Teresa R. | Wise, Lisa | Zmuda, Erik | Penny, Robert | Crain, Daniel | Gardner, Johanna | Lau, Kevin | Curely, Erin | Mallery, David | Morris, Scott | Paulauskis, Joseph | Shelton, Troy | Shelton, Candace | Sherman, Mark | Benz, Christopher | Lee, Jae-Hyuk | Fedosenko, Konstantin | Manikhas, Georgy | Potapova, Olga | Voronina, Olga | Belyaev, Smitry | Dolzhansky, Oleg | Rathmell, W. Kimryn | Brzezinski, Jakub | Ibbs, Matthew | Korski, Konstanty | Kycler, Witold | ŁaŸniak, Radoslaw | Leporowska, Ewa | Mackiewicz, Andrzej | Murawa, Dawid | Murawa, Pawel | Spychała, Arkadiusz | Suchorska, Wiktoria M. | Tatka, Honorata | Teresiak, Marek | Wiznerowicz, Maciej | Abdel-Misih, Raafat | Bennett, Joseph | Brown, Jennifer | Iacocca, Mary | Rabeno, Brenda | Kwon, Sun-Young | Penny, Robert | Gardner, Johanna | Kemkes, Ariane | Mallery, David | Morris, Scott | Shelton, Troy | Shelton, Candace | Curley, Erin | Alexopoulou, Iakovina | Engel, Jay | Bartlett, John | Albert, Monique | Park, Do-Youn | Dhir, Rajiv | Luketich, James | Landreneau, Rodney | Janjigian, Yelena Y. | Kelsen, David P. | Cho, Eunjung | Ladanyi, Marc | Tang, Laura | McCall, Shannon J. | Park, Young S. | Cheong, Jae-Ho | Ajani, Jaffer | Camargo, M. Constanza | Alonso, Shelley | Ayala, Brenda | Jensen, Mark A. | Pihl, Todd | Raman, Rohini | Walton, Jessica | Wan, Yunhu | Demchok, John A. | Eley, Greg | Mills Shaw, Kenna R. | Sheth, Margi | Tarnuzzer, Roy | Wang, Zhining | Yang, Liming | Zenklusen, Jean Claude | Davidsen, Tanja | Hutter, Carolyn M. | Sofia, Heidi J. | Burton, Robert | Chudamani, Sudha | Liu, Jia
Nature  2014;513(7517):202-209.
Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein–Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also knownasPD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies.
doi:10.1038/nature13480
PMCID: PMC4170219  PMID: 25079317
5.  Identification of developmentally-specific kinotypes and mechanisms of Varroa mite resistance through whole-organism, kinome analysis of honeybee 
Frontiers in Genetics  2014;5:139.
Recent investigations associate Varroa destructor (Mesostigmata: Varroidae) parasitism and its associated pathogens and agricultural pesticides with negative effects on colony health, resulting in sporadic global declines in domestic honeybee (Apis mellifera) populations. These events have motivated efforts to develop research tools that can offer insight into the causes of declining bee health as well as identify biomarkers to guide breeding programs. Here we report the development of a bee-specific peptide array for characterizing global cellular kinase activity in whole bee extracts. The arrays reveal distinct, developmentally-specific signaling profiles between bees with differential susceptibility to infestation by Varroa mites. Gene ontology analysis of the differentially phosphorylated peptides indicates that the differential susceptibility to Varroa mite infestation does not reflect compromised immunity; rather, there is evidence for mite-mediated immune suppression within the susceptible phenotype that may reduce the ability of these bees to counter secondary viral infections. This hypothesis is supported by the demonstration of more diverse viral infections in mite-infested, susceptible adult bees. The bee-specific peptide arrays are an effective tool for understanding the molecular basis of this complex phenotype as well as for the discovery and utilization of phosphorylation biomarkers for breeding programs.
doi:10.3389/fgene.2014.00139
PMCID: PMC4033134  PMID: 24904639
peptide arrays; kinome; kinotype; Varroa destructor; honeybee; Apis mellifera
6.  Vascular and connective tissue anomalies associated with X-linked periventricular heterotopia due to mutations in Filamin A 
Mutations conferring loss of function at the FLNA (encoding filamin A) locus lead to X-linked periventricular nodular heterotopia (XL-PH), with seizures constituting the most common clinical manifestation of this disorder in female heterozygotes. Vascular dilatation (mainly the aorta), joint hypermobility and variable skin findings are also associated anomalies, with some reports suggesting that this might represents a separate syndrome allelic to XL-PH, termed as Ehlers-Danlos syndrome-periventricular heterotopia variant (EDS-PH). Here, we report a cohort of 11 males and females with both hypomorphic and null mutations in FLNA that manifest a wide spectrum of connective tissue and vascular anomalies. The spectrum of cutaneous defects was broader than previously described and is inconsistent with a specific type of EDS. We also extend the range of vascular anomalies associated with XL-PH to included peripheral arterial dilatation and atresia. Based on these observations, we suggest that there is little molecular or clinical justification for considering EDS-PH as a separate entity from XL-PH, but instead propose that there is a spectrum of vascular and connective tissues anomalies associated with this condition for which all individuals with loss-of-function mutations in FLNA should be evaluated. In addition, since some patients with XL-PH can present primarily with a joint hypermobility syndrome, we propose that screening for cardiovascular manifestations should be offered to those patients when there are associated seizures or an X-linked pattern of inheritance.
doi:10.1038/ejhg.2012.209
PMCID: PMC3641385  PMID: 23032111
filamin A; periventricular heterotopia; Ehlers-Danlos syndrome; screening
7.  Phenotypic and genotypic analyses to guide selection of reverse transcriptase inhibitors in second-line HIV therapy following extended virological failure in Uganda 
Goodall, R. L. | Dunn, D. T. | Pattery, T. | van Cauwenberge, A. | Nkurunziza, P. | Awio, P. | Ndembi, N. | Munderi, P. | Kityo, C. | Gilks, C. F. | Kaleebu, P. | Pillay, D. | Kaleebu, P. | Pillay, D. | Awio, P. | Chirara, M. | Dunn, D. | Gibb, D. M. | Gilks, C. | Goodall, R. | Kapaata, A. | Katuramur, M. | Lyagoba, F. | Magala, R. | Magambo, B. | Mataruka, K. | McCormick, A. | Mugarura, L. | Musunga, T. | Nabankkema, M. | Nkalubo, J. | Nkurunziza, P. | Parry, C. | Robertson, V. | Spyer, M. | Yirrell, D. | Grosskurth, H. | Munderi, P. | Kabuye, G. | Nsibambi, D. | Kasirye, R. | Zalwango, E. | Nakazibwe, M. | Kikaire, B. | Nassuna, G. | Massa, R. | Fadhiru, K. | Namyalo, M. | Zalwango, A. | Generous, L. | Khauka, P. | Rutikarayo, N. | Nakahima, W. | Mugisha, A. | Todd, J. | Levin, J. | Muyingo, S. | Ruberantwari, A. | Kaleebu, P. | Yirrell, D. | Ndembi, N. | Lyagoba, F. | Hughes, P. | Aber, M. | Medina Lara, A. | Foster, S. | Amurwon, J. | Nyanzi Wakholi, B. | Mugyenyi, P. | Kityo, C. | Ssali, F. | Tumukunde, D. | Otim, T. | Kabanda, J. | Musana, H. | Akao, J. | Kyomugisha, H. | Byamukama, A. | Sabiiti, J. | Komugyena, J. | Wavamunno, P. | Mukiibi, S. | Drasiku, A. | Byaruhanga, R. | Labeja, O. | Katundu, P. | Tugume, S. | Awio, P. | Namazzi, A. | Bakeinyaga, G. T. | Katabira, H. | Abaine, D. | Tukamushaba, J. | Anywar, W. | Ojiambo, W. | Angweng, E. | Murungi, S. | Haguma, W. | Atwiine, S. | Kigozi, J. | Latif, A. | Hakim, J. | Robertson, V. | Reid, A. | Chidziva, E. | Bulaya-Tembo, R. | Musoro, G. | Taziwa, F. | Chimbetete, C. | Chakonza, L. | Mawora, A. | Muvirimi, C. | Tinago, G. | Svovanapasis, P. | Simango, M. | Chirema, O. | Machingura, J. | Mutsai, S. | Phiri, M. | Bafana, T. | Chirara, M. | Muchabaiwa, L. | Muzambi, M. | Katabira, E. | Ronald, A. | Kambungu, A. | Lutwama, F. | Nanfuka, A. | Walusimbi, J. | Nabankema, E. | Nalumenya, R. | Namuli, T. | Kulume, R. | Namata, I. | Nyachwo, L. | Florence, A. | Kusiima, A. | Lubwama, E. | Nairuba, R. | Oketta, F. | Buluma, E. | Waita, R. | Ojiambo, H. | Sadik, F. | Wanyama, J. | Nabongo, P.
Objectives
We investigated phenotypic and genotypic resistance after 2 years of first-line therapy with two HIV treatment regimens in the absence of virological monitoring.
Methods
NORA [Nevirapine OR Abacavir study, a sub-study of the Development of AntiRetroviral Therapy in Africa (DART) trial] randomized 600 symptomatic HIV-infected Ugandan adults (CD4 cell count <200 cells/mm3) to receive zidovudine/lamivudine plus abacavir (cABC arm) or nevirapine (cNVP arm). All virological tests were performed retrospectively, including resistance tests on week 96 plasma samples with HIV RNA levels ≥1000 copies/mL. Phenotypic resistance was expressed as fold-change in IC50 (FC) relative to wild-type virus.
Results
HIV-1 RNA viral load ≥1000 copies/mL at week 96 was seen in 58/204 (28.4%) cABC participants and 21/159 (13.2%) cNVP participants. Resistance results were available in 35 cABC and 17 cNVP participants; 31 (89%) cABC and 16 (94%) cNVP isolates had a week 96 FC below the biological cut-off for tenofovir (2.2). In the cNVP arm, 16/17 participants had resistance mutations synonymous with high-level resistance to nevirapine and efavirenz; FC values for etravirine were above the biological cut-off in 9 (53%) isolates. In multivariate regression models, K65R, Y115F and the presence of thymidine analogue-associated mutations were associated with increased susceptibility to etravirine in the cABC arm.
Conclusions
Our data support the use of tenofovir following failure of a first-line zidovudine-containing regimen and shed further light on non-nucleoside reverse transcriptase inhibitor hypersusceptibility.
doi:10.1093/jac/dku052
PMCID: PMC4054985  PMID: 24633208
resistance; Africa; hypersusceptibility
8.  High Rate of HIV Resuppression After Viral Failure on First-line Antiretroviral Therapy in the Absence of Switch to Second-line Therapy 
Gupta, Ravindra K. | Goodall, Ruth L. | Ranopa, Michael | Kityo, Cissy | Munderi, Paula | Lyagoba, Fred | Mugarura, Lincoln | Gilks, Charles F. | Kaleebu, Pontiano | Pillay, Deenan | Grosskurth, H. | Munderi, P. | Kabuye, G. | Nsibambi, D. | Kasirye, R. | Zalwango, E. | Nakazibwe, M. | Kikaire, B. | Nassuna, G. | Massa, R. | Fadhiru, K. | Namyalo, M. | Zalwango, A. | Generous, L. | Khauka, P. | Rutikarayo, N. | Nakahima, W. | Mugisha, A. | Todd, J. | Levin, J. | Muyingo, S. | Ruberantwari, A. | Kaleebu, P. | Yirrell, D. | Ndembi, N. | Lyagoba, F. | Hughes, P. | Aber, M. | Medina Lara, A. | Foster, S. | Amurwon, J. | Mugyenyi, P. | Kityo, C. | Ssali, F. | Tumukunde, D. | Otim, T. | Kabanda, J. | Musana, H. | Akao, J. | Kyomugisha, H. | Byamukama, A. | Sabiiti, J. | Komugyena, J. | Wavamunno, P. | Mukiibi, S. | Drasiku, A. | Byaruhanga, R. | Labeja, O. | Katundu, P. | Tugume, S. | Awio, P. | Namazzi, A. | Bakeinyaga, T. G. | Katabira, H. | Abaine, D. | Tukamushaba, J. | Anywar, W. | Ojiambo, W. | Angweng, E. | Murungi, S. | Haguma, W. | Atwiine, S. | Kigozi, J. | Latif, A. | Hakim, J. | Robertson, V. | Reid, A. | Chidziva, E. | Bulaya-Tembo, R. | Musoro, G. | Taziwa, F. | Chimbetete, C. | Chakonza, L. | Mawora, A. | Muvirimi, C. | Tinago, G. | Svovanapasis, P. | Simango, M. | Chirema, O. | Machingura, J. | Mutsai, S. | Phiri, M. | Bafana, T. | Chirara, M. | Muchabaiwa, L. | Muzambi, M. | Katabira, E. | Ronald, A. | Kambungu, A. | Lutwama, F. | Nanfuka, A. | Walusimbi, J. | Nabankema, E. | Nalumenya, R. | Namuli, T. | Kulume, R. | Namata, I. | Nyachwo, L. | Florence, A. | Kusiima, A. | Lubwama, E. | Nairuba, R. | Oketta, F. | Buluma, E. | Waita, R. | Ojiambo, H. | Sadik, F. | Wanyama, J. | Nabongo, P. | Ochai, R. | Muhweezi, D. | Gilks, C. | Boocock, K. | Puddephatt, C. | Winogron, D. | Bohannon, J. | Darbyshire, J. | Gibb, M. D. | Burke, A. | Bray, D. | Babiker, A. | Walker, S. A. | Wilkes, H. | Rauchenberger, M. | Sheehan, S. | Peto, L. | Taylor, K. | Spyer, M. | Ferrier, A. | Naidoo, B. | Dunn, D. | Goodall, R. | Nanfuka, R. | Mufuka-Kapuya, C. | Kaleebu, P. | Pillay, D. | Awio, P. | Chirara, M. | Dunn, D. | Gilks, C. | Goodall, R. | Kapaata, A. | Katuramur, M. | Lyagoba, F. | Magala, R. | Magambo, B. | Mataruka, K. | McCormick, A. | Mugarura, L. | Musunga, T. | Nabankkema, M. | Nkalubo, J. | Nkurunziza, P. | Parry, C. | Robertson, V. | Spyer, M. | Yirrell, D. | Medina Lara, A. | Foster, S. | Amurwon, J. | Nyanzi Wakholi, B. | Kigozi, J. | Muchabaiwa, L. | Muzambi, M. | Weller, I. | Babiker, A. | Bahendeka, S. | Bassett, M. | Chogo Wapakhabulo, A. | Darbyshire, J. | Gazzard, B. | Gilks, C. | Hakim, J. | Latif, A. | Mapuchere, C. | Mugurungi, O. | Mugyenyi, P. | Burke, C. | Jones, S. | Newland, C. | Rahim, S. | Rooney, J. | Smith, M. | Snowden, W. | Steens, J.-M. | Breckenridge, A. | McLaren, A. | Hill, C. | Matenga, J. | Pozniak, A. | Serwadda, D. | Peto, T. | Palfreeman, A. | Borok, M.
In a randomized comparison of nevirapine or abacavir with zidovudine plus lamivudine, routine viral load monitoring was not performed, yet 27% of individuals with viral failure at week 48 experienced resuppression by week 96 without switching. This supports World Health Organization recommendations that suspected viral failure should trigger adherence counseling and repeat measurement before a treatment switch is considered.
doi:10.1093/cid/cit933
PMCID: PMC3952602  PMID: 24352348
HIV; failure; viral resuppression; resistance; Africa
9.  Application of a High Throughput Method of Biomarker Discovery to Improvement of the EarlyCDT®-Lung Test 
PLoS ONE  2012;7(12):e51002.
Background
The National Lung Screening Trial showed that CT screening for lung cancer led to a 20% reduction in mortality. However, CT screening has a number of disadvantages including low specificity. A validated autoantibody assay is available commercially (EarlyCDT®-Lung) to aid in the early detection of lung cancer and risk stratification in patients with pulmonary nodules detected by CT.
Recent advances in high throughput (HTP) cloning and expression methods have been developed into a discovery pipeline to identify biomarkers that detect autoantibodies. The aim of this study was to demonstrate the successful clinical application of this strategy to add to the EarlyCDT-Lung panel in order to improve its sensitivity and specificity (and hence positive predictive value, (PPV)).
Methods and Findings
Serum from two matched independent cohorts of lung cancer patients were used (n = 100 and n = 165). Sixty nine proteins were initially screened on an abridged HTP version of the autoantibody ELISA using protein prepared on small scale by a HTP expression and purification screen. Promising leads were produced in shake flask culture and tested on the full assay. These results were analyzed in combination with those from the EarlyCDT-Lung panel in order to provide a set of re-optimized cut-offs. Five proteins that still displayed cancer/normal differentiation were tested for reproducibility and validation on a second batch of protein and a separate patient cohort. Addition of these proteins resulted in an improvement in the sensitivity and specificity of the test from 38% and 86% to 49% and 93% respectively (PPV improvement from 1 in 16 to 1 in 7).
Conclusion
This is a practical example of the value of investing resources to develop a HTP technology. Such technology may lead to improvement in the clinical utility of the EarlyCDT­-Lung test, and so further aid the early detection of lung cancer.
doi:10.1371/journal.pone.0051002
PMCID: PMC3521770  PMID: 23272083
10.  catena-Poly[sodium-μ2-(N,N,N′,N′-tetra­methyl­ethane-1,2-diamine)-κ2 N:N′-sodium-bis­[μ2-bis­(trimethyl­sil­yl)aza­nido-κ2 N:N]] 
The title compound, [Na2(C6H18NSi2)2(C6H16N2)]n, was found to consist of dimeric [Na(NSiMe3)2] units with crystallographically imposed centrosymmetry based upon four-membered NaNNaN rings. The dimers are bridged by N,N,N′,N′-tetra­methyl­ethylenediamine ligands, which act in an unusual extended non-chelating coordination mode. This gives a one-dimensional coordination polymer that extends parallel to the a-axis direction.
doi:10.1107/S1600536812045126
PMCID: PMC3588730  PMID: 23468695
11.  JNK Inhibition Protects Dopamine Neurons and Provides Behavioral Improvement in a Rat 6-hydroxydopamine Model of Parkinson’s Disease 
ACS chemical neuroscience  2011;2(4):207-212.
Parkinson’s disease (PD) results from the loss of dopamine neurons located in the substantia nigra pars compacta (SNpc) that project to the striatum. A therapeutic has yet to be identified that halts this neurodegenerative process, and as such, development of a brain penetrant small molecule neuroprotective agent would represent a significant advancement in the treatment of the disease. To fill this void we developed an aminopyrimidine JNK inhibitor (SR-3306) that reduced the loss of dopaminergic cell bodies in the SNpc and their terminals in the striatum produced by unilateral injection of 6-hydroxydopamine (6-OHDA) into the nigrostriatal pathway. Administration of SR-3306 [10 mg/kg/day (s.c.) for 14 days] increased the number of tyrosine hydroxylase immunoreactive (TH+) neurons in the SNpc by six-fold and reduced the loss of the TH+ terminals in the striatum relative to the corresponding side of 6-OHDA-lesioned rats that received only vehicle (p<0.05). In addition, SR-3306 [10 mg/kg/day (s.c.) for 14 days] decreased d-amphetamine-induced circling by 87% compared to 6-OHDA-lesioned animals given vehicle. Steady-state brain levels of SR-3306 at day 14 were 347 nM, which was approximately two-fold higher than the cell-based IC50 for this compound. Finally, immunohistochemical staining for phospho-c-jun (p-c-jun) revealed that SR-3306 [10 mg/kg/day (s.c.) for 14 days] produced a 2.3-fold reduction of the number of immunoreactive neurons in the SNpc relative to vehicle treated rats. Collectively, these data suggest that orally bioavailable JNK inhibitors may be useful neuroprotective agents for the treatment of Parkinson’s disease.
doi:10.1021/cn1001107
PMCID: PMC3110072  PMID: 21666838
12.  JNK Inhibition Protects Dopamine Neurons and Provides Behavioral Improvement in a Rat 6-Hydroxydopamine Model of Parkinson’s Disease 
ACS Chemical Neuroscience  2011;2(4):207-212.
Parkinson’s disease (PD) results from the loss of dopamine neurons located in the substantia nigra pars compacta (SNpc) that project to the striatum. A therapeutic has yet to be identified that halts this neurodegenerative process, and as such, development of a brain penetrant small molecule neuroprotective agent would represent a significant advancement in the treatment of the disease. To fill this void, we developed an aminopyrimidine JNK inhibitor (SR-3306) that reduced the loss of dopaminergic cell bodies in the SNpc and their terminals in the striatum produced by unilateral injection of 6-hydroxydopamine (6-OHDA) into the nigrostriatal pathway. Administration of SR-3306 [10 mg/kg/day (s.c.) for 14 days] increased the number of tyrosine hydroxylase immunoreactive (TH+) neurons in the SNpc by 6-fold and reduced the loss of the TH+ terminals in the striatum relative to the corresponding side of 6-OHDA-lesioned rats that received only vehicle (p < 0.05). In addition, SR-3306 [10 mg/kg/day (s.c.) for 14 days] decreased d-amphetamine-induced circling by 87% compared to 6-OHDA-lesioned animals given vehicle. Steady-state brain levels of SR-3306 at day 14 were 347 nM, which was approximately 2-fold higher than the cell-based IC50 for this compound. Finally, immunohistochemical staining for phospho-c-jun (p-c-jun) revealed that SR-3306 [10 mg/kg/day (s.c.) for 14 days] produced a 2.3-fold reduction of the number of immunoreactive neurons in the SNpc relative to vehicle treated rats. Collectively, these data suggest that orally bioavailable JNK inhibitors may be useful neuroprotective agents for the treatment of Parkinson’s disease.
doi:10.1021/cn1001107
PMCID: PMC3110072  PMID: 21666838
JNK; 6-OHDA; neuroprotection; Parkinson’s disease
13.  EarlyCDT®-Lung test: improved clinical utility through additional autoantibody assays 
Tumour Biology  2012;33(5):1319-1326.
Tumor-associated autoantibodies (AAbs) have been described in patients with lung cancer, and the EarlyCDT®-Lung test that measures such AAbs is available as an aid for the early detection of lung cancer in high-risk populations. Improvements in specificity would improve its cost-effectiveness, as well as reduce anxiety associated with false positive tests. Samples from 235 patients with newly diagnosed lung cancer and matched controls were measured for the presence of AAbs to a panel of six (p53, NY-ESO-1, CAGE, GBU4-5, Annexin I, and SOX2) or seven (p53, NY-ESO-1, CAGE, GBU4-5, SOX2, HuD, and MAGE A4) antigens. Data were assessed in relation to cancer type and stage. The sensitivity and specificity of these two panels were also compared in two prospective consecutive series of 776 and 836 individuals at an increased risk of developing lung cancer. The six-AAb panel gave a sensitivity of 39 % with a specificity of 89 %, while the seven-AAb panel gave a sensitivity of 41 % with a specificity of 91 % which, once adjusted for occult cancers in the population, resulted in a specificity of 93 %. Analysis of these AAb assays in the at-risk population confirmed that the seven-AAb panel resulted in a significant increase in the specificity of the test from 82 to 90 %, with no significant change in sensitivity. The change from a six- to a seven-AAb assay can improve the specificity of the test and would result in a PPV of 1 in 8 and an overall accuracy of 92 %.
doi:10.1007/s13277-012-0379-2
PMCID: PMC3460172  PMID: 22492236
Autoantibodies; Lung cancer; Lung cancer diagnosis
14.  Avian Use of Perennial Biomass Feedstocks as Post-Breeding and Migratory Stopover Habitat 
PLoS ONE  2011;6(3):e16941.
Increased production of biomass crops in North America will require new agricultural land, intensify the cultivation of land already under production and introduce new types of biomass crops. Assessing the potential biodiversity impacts of novel agricultural systems is fundamental to the maintenance of biodiversity in agricultural landscapes, yet the consequences of expanded biomass production remain unclear. We evaluate the ability of two candidate second generation biomass feedstocks (switchgrass, Panicum virgatum, and mixed-grass prairie) not currently managed as crops to act as post-breeding and fall migratory stopover habitat for birds. In total, we detected 41 bird species, including grassland specialists and species of state and national conservation concern (e.g. Henslow's Sparrow, Ammodramus henslowii). Avian species richness was generally comparable in switchgrass and prairie and increased with patch size in both patch types. Grassland specialists were less abundant and less likely to occur in patches within highly forested landscapes and were more common and likely to occur in larger patches, indicating that this group is also area-sensitive outside of the breeding season. Variation in the biomass and richness of arthropod food within patches was generally unrelated to richness and abundance metrics. Total bird abundance and that of grassland specialists was higher in patches with greater vegetation structural heterogeneity. Collectively, we find that perennial biomass feedstocks have potential to provide post-breeding and migratory stopover habitat for birds, but that the placement and management of crops will be critical factors in determining their suitability for species of conservation concern. Industrialization of cellulosic bioenergy production that results in reduced crop structural heterogeneity is likely to dramatically reduce the suitability of perennial biomass crops for birds.
doi:10.1371/journal.pone.0016941
PMCID: PMC3048387  PMID: 21390274
15.  Clinical investigation of an outbreak of alveolitis and asthma in a car engine manufacturing plant 
Thorax  2007;62(11):981-990.
Background
Exposure to metal working fluid (MWF) has been associated with outbreaks of extrinsic allergic alveolitis (EAA) in the USA, with bacterial contamination of MWF being a possible cause, but is uncommon in the UK. Twelve workers developed EAA in a car engine manufacturing plant in the UK, presenting clinically between December 2003 and May 2004. This paper reports the subsequent epidemiological investigation of the whole workforce. The study had three aims: (1) to measure the extent of the outbreak by identifying other workers who may have developed EAA or other work‐related respiratory diseases; (2) to provide case detection so that those affected could be treated; and (3) to provide epidemiological data to identify the cause of the outbreak.
Methods
The outbreak was investigated in a three‐phase cross‐sectional survey of the workforce. In phase I a respiratory screening questionnaire was completed by 808/836 workers (96.7%) in May 2004. In phase II 481 employees with at least one respiratory symptom on screening and 50 asymptomatic controls were invited for investigation at the factory in June 2004. This included a questionnaire, spirometry and clinical opinion. 454/481 (94.4%) responded and 48/50 (96%) controls. Workers were identified who needed further investigation and serial measurements of peak expiratory flow (PEF). In phase III 162 employees were seen at the Birmingham Occupational Lung Disease clinic. 198 employees returned PEF records, including 141 of the 162 who attended for clinical investigation. Case definitions for diagnoses were agreed.
Results
87 workers (10.4% of the workforce) met case definitions for occupational lung disease, comprising EAA (n = 19), occupational asthma (n = 74) and humidifier fever (n = 7). 12 workers had more than one diagnosis. The peak onset of work‐related breathlessness was Spring 2003. The proportion of workers affected was higher for those using MWF from a large sump (27.3%) than for those working all over the manufacturing area (7.9%) (OR = 4.39, p<0.001). Two workers had positive specific provocation tests to the used but not the unused MWF solution.
Conclusions
Extensive investigation of the outbreak of EAA detected a large number of affected workers, not only with EAA but also occupational asthma. This is the largest reported outbreak in Europe. Mist from used MWF is the likely cause. In workplaces using MWF there is a need to carry out risk assessments, to monitor and maintain fluid quality, to control mist and to carry out respiratory health surveillance.
doi:10.1136/thx.2006.072199
PMCID: PMC2117138  PMID: 17504818
16.  Clinical validation of an autoantibody test for lung cancer 
Annals of Oncology  2010;22(2):383-389.
Background: Autoantibodies may be present in a variety of underlying cancers several years before tumours can be detected and testing for their presence may allow earlier diagnosis. We report the clinical validation of an autoantibody panel in newly diagnosed patients with lung cancer (LC).
Patients and methods: Three cohorts of patients with newly diagnosed LC were identified: group 1 (n = 145), group 2 (n = 241) and group 3 (n = 269). Patients were individually matched by gender, age and smoking history to a control individual with no history of malignant disease. Serum samples were obtained after diagnosis but before any anticancer treatment. Autoantibody levels were measured against a panel of six tumour-related antigens (p53, NY-ESO-1, CAGE, GBU4-5, Annexin 1 and SOX2). Assay sensitivity was tested in relation to demographic variables and cancer type/stage.
Results: The autoantibody panel demonstrated a sensitivity/specificity of 36%/91%, 39%/89% and 37%/90% in groups 1, 2 and 3, respectively, with good reproducibility. There was no significant difference between different LC stages, indicating that the antigens included covered the different types of LC well.
Conclusion: This assay confirms the value of an autoantibody panel as a diagnostic tool and offers a potential system for monitoring patients at high risk of LC.
doi:10.1093/annonc/mdq361
PMCID: PMC3030465  PMID: 20675559
autoantibodies; clinical validation; lung cancer; newly diagnosed patients
17.  An Nkx2-5/Bmp2/Smad1 negative feedback loop controls second heart field progenitor specification and proliferation 
Cell  2007;128(5):947-959.
Summary
During heart development the second heart field (SHF) provides progenitor cells for most cardiomyocytes and expresses the homeodomain factor Nkx2-5. We now show that feedback repression of Bmp2/Smad1 signaling by Nkx2-5 critically regulates SHF proliferation and outflow tract (OFT) morphology. In the cardiac fields of Nkx2-5 mutants, genes controlling cardiac specification (including Bmp2) and maintenance of the progenitor state were up-regulated, leading initially to progenitor over-specification, but subsequently to failed SHF proliferation and OFT truncation. In Smad1 mutants, SHF proliferation and deployment to the OFT were increased, while Smad1 deletion in Nkx2-5 mutants rescued SHF proliferation and OFT development. In Nkx2-5 hypomorphic mice, which recapitulate human congenital heart disease (CHD), OFT anomalies were also rescued by Smad1 deletion. Our findings demonstrate that Nkx2-5 orchestrates the transition between periods of cardiac induction, progenitor proliferation and OFT morphogenesis via a Smad1-dependent negative feedback loop, which may be a frequent molecular target in CHD.
doi:10.1016/j.cell.2007.01.042
PMCID: PMC2092439  PMID: 17350578
18.  cisRED: a database system for genome-scale computational discovery of regulatory elements 
Nucleic Acids Research  2005;34(Database issue):D68-D73.
We describe cisRED, a database for conserved regulatory elements that are identified and ranked by a genome-scale computational system (). The database and high-throughput predictive pipeline are designed to address diverse target genomes in the context of rapidly evolving data resources and tools. Motifs are predicted in promoter regions using multiple discovery methods applied to sequence sets that include corresponding sequence regions from vertebrates. We estimate motif significance by applying discovery and post-processing methods to randomized sequence sets that are adaptively derived from target sequence sets, retain motifs with p-values below a threshold and identify groups of similar motifs and co-occurring motif patterns. The database offers information on atomic motifs, motif groups and patterns. It is web-accessible, and can be queried directly, downloaded or installed locally.
doi:10.1093/nar/gkj075
PMCID: PMC1347438  PMID: 16381958
19.  Isolation and characterization of a novel DNA methyltransferase complex linking DNMT3B with components of the mitotic chromosome condensation machinery 
Nucleic Acids Research  2004;32(9):2716-2729.
Proper patterns of genome-wide DNA methylation, mediated by DNA methyltransferases DNMT1, -3A and -3B, are essential for embryonic development and genomic stability in mammalian cells. The de novo DNA methyltransferase DNMT3B is of particular interest because it is frequently overexpressed in tumor cells and is mutated in immunodeficiency, centromere instability and facial anomalies (ICF) syndrome. In order to gain a better understanding of DNMT3B, in terms of the targeting of its methylation activity and its role in genome stability, we biochemically purified endogenous DNMT3B from HeLa cells. DNMT3B co-purifies and interacts, both in vivo and in vitro, with several components of the condensin complex (hCAP-C, hCAP-E and hCAP-G) and KIF4A. Condensin mediates genome-wide chromosome condensation at the onset of mitosis and is critical for proper segregation of sister chromatids. KIF4A is proposed to be a motor protein carrying DNA as cargo. DNMT3B also interacts with histone deacetylase 1 (HDAC1), the co-repressor SIN3A and the ATP-dependent chromatin remodeling enzyme hSNF2H. Further more, DNMT3B co-localizes with condensin and KIF4A on condensed chromosomes throughout mitosis. These studies therefore reveal the first direct link between the machineries regulating DNA methylation and mitotic chromosome condensation in mammalian cells.
doi:10.1093/nar/gkh589
PMCID: PMC419596  PMID: 15148359
20.  Modification of de novo DNA methyltransferase 3a (Dnmt3a) by SUMO-1 modulates its interaction with histone deacetylases (HDACs) and its capacity to repress transcription 
Nucleic Acids Research  2004;32(2):598-610.
The de novo DNA methyltransferase Dnmt3a is one of three mammalian DNA methyltransferases that has been shown to play crucial roles in embryonic development, genomic imprinting and transcriptional silencing. Despite its importance, very little is known about how the enzymatic activity and transcriptional repression functions of Dnmt3a are regulated. Here we show that Dnmt3a interacts with multiple components of the sumoylation machinery, namely the E2 sumo conjugating enzyme Ubc9 and the E3 sumo ligases PIAS1 and PIASxα, all of which are involved in conjugating the small ubiquitin-like modifier polypeptide, SUMO-1, to its target proteins. Dnmt3a is modified by SUMO-1 in vivo and in vitro and the region of Dnmt3a responsible for interaction maps to the N-terminal regulatory domain. Functionally, sumoylation of Dnmt3a disrupts its ability to interact with histone deacetylases (HDAC1/2), but not with another interaction partner, Dnmt3b. Conditions that enhance the sumoylation of Dnmt3a in vivo abolish its capacity to repress transcription. These studies reveal a new level of regulation governing Dnmt3a whereby a post-translational modification can dramatically regulate its interaction with specific protein partners and alter its ability to repress transcription.
doi:10.1093/nar/gkh195
PMCID: PMC373322  PMID: 14752048
21.  Paul Bernard Gregory McKee 
BMJ : British Medical Journal  2002;324(7332):302.
PMCID: PMC1122226  PMID: 12008726
22.  Effects of Information Framing on the Intentions of Family Physicians to Prescribe Long-Term Hormone Replacement Therapy 
OBJECTIVE
To determine whether the way in which information on benefits and harms of long-term hormone replacement therapy (HRT) is presented influences family physicians' intentions to prescribe this treatment.
DESIGN
Family physicians were randomized to receive information on treatment outcomes expressed in relative terms, or as the number needing to be treated (NNT) with HRT to prevent or cause an event. A control group received no information.
SETTING
Primary care.
PARTICIPANTS
Family physicians practicing in the Hunter Valley, New South Wales, Australia.
INTERVENTION
Estimates of the impact of long-term HRT on risk of coronary events, hip fractures, and breast cancer were summarized as relative (proportional) decreases or increases in risk, or as NNT.
MEASUREMENTS AND MAIN RESULTS
Intention to prescribe HRT for seven hypothetical patients was measured on Likert scales. Of 389 family physicians working in the Hunter Valley, 243 completed the baseline survey and 215 participated in the randomized trial. Baseline intention to prescribe varied across patients—it was highest in the presence of risk factors for hip fracture, but coexisting risk factors for breast cancer had a strong negative influence. Overall, a larger proportion of subjects receiving information expressed as NNT had reduced intentions, and a smaller proportion had increased intentions to prescribe HRT than those receiving the information expressed in relative terms, or the control group. However, the differences were small and only reached statistical significance for three hypothetical patients. Framing effects were minimal when the hypothetical patient had coexisting risk factors for breast cancer.
CONCLUSIONS
Information framing had some effect on family physicians' intentions to prescribe HRT, but the effects were smaller than those previously reported, and they were modified by the presence of serious potential adverse treatment effects.
doi:10.1046/j.1525-1497.1999.09028.x
PMCID: PMC1496748  PMID: 10571703
information framing; medical decision making; relative risk; absolute risk; randomized controlled trial
23.  Pulmonary arteriovenous malformations. 
Thorax  1995;50(7):707-708.
PMCID: PMC474639  PMID: 7570401
24.  Sympathetic and baroreceptor reflex function in neurally mediated syncope evoked by tilt. 
Journal of Clinical Investigation  1997;99(11):2736-2744.
The pathophysiology of neurally mediated syncope is poorly understood. It has been widely assumed that excessive sympathetic activation in a setting of left ventricular hypovolemia stimulates ventricular afferents that trigger hypotension and bradycardia. We tested this hypothesis by determining if excessive sympathetic activation precedes development of neurally mediated syncope, and if this correlates with alterations in baroreflex function. We studied the changes in intraarterial blood pressure (BP), heart rate (HR), central venous pressure (CVP), muscle sympathetic nerve activity (MSNA), and plasma catecholamines evoked by upright tilt in recurrent neurally mediated syncope patients (SYN, 5+/-1 episodes/mo, n = 14), age- and sex-matched controls (CON, n = 23), and in healthy subjects who consistently experienced syncope during tilt (FS+, n = 20). Baroreflex responses were evaluated from changes in HR, BP, and MSNA that were obtained after infusions of phenylephrine and sodium nitroprusside. Compared to CON, patients with SYN had blunted increases in MSNA at low tilt levels, followed by a progressive decrease and ultimately complete disappearance of MSNA with syncope. SYN patients also had attenuation of norepinephrine increases and lower baroreflex slope sensitivity, both during tilt and after pharmacologic testing. FS+ subjects had the largest decrease in CVP with tilt and had significant increases in MSNA and heart rate baroreflex slopes. These data challenge the view that excessive generalized sympathetic activation is the precursor of the hemodynamic abnormality underlying recurrent neurally mediated syncope.
PMCID: PMC508120  PMID: 9169504
25.  After the epidemic: follow up study of HIV seroprevalence and changing patterns of drug use. 
BMJ : British Medical Journal  1990;300(6719):219-223.
OBJECTIVE--To follow up known intravenous drug users to determine current health state and drug use, compare characteristics with those of recent drug users, and examine HIV exposure and serostate. DESIGN--Subjects were identified from conventional general practice records and recruited from 1980 to the end of 1985; they were followed up during 1987 and 1988 and compared with drug users identified in the same way but recruited after 1985. SETTING--General practice and community in north west Edinburgh. Follow up conducted throughout the United Kingdom. SUBJECTS--Subjects known to have injected illegal drugs before 1986 (n = 203) and since that time. MAIN OUTCOME MEASURES--Mortality from and prevalence of HIV seropositivity and various parameters indicative of abstinence. RESULTS--Of the 203 subjects in the follow up group, 189 (93%) were traced; 16 (8%) had died and the remaining 173 (85%) were interviewed. In all, 146 (72% of the follow up cohort) had been tested for HIV antibodies, 94 (64%) having positive and 52 (36%) negative results; 57 (28%) had not been tested. Of the 65 subjects in the recently recruited group, 51 (79%) had been tested for HIV, 15 (29%) having positive results. A further 21 (43%) were currently negative for HIV antibody but still at risk. Thirty three (19%) of those followed up were confirmed abstinent, although more (about half) showed evidence of diminished drug injecting. Age correlated strongly with abstinence (p less than 0.001). One third of the group currently used cannabis, buprenorphine, dihydrocodeine, or diazepam. When the two groups were analysed together there was a strong association between the date of starting injecting and HIV seropositivity (chi 3 = 23.81, df = 2, p less than 0.001), with a peak around 1980-3. CONCLUSIONS--Although only a fifth of the followed up group were convincingly abstinent, a much larger group showed evidence of prolonged periods of remission. Overall, much use of oral drugs was confirmed and worrying trends towards taking buprenorphine and benzodiazepines were evident. The peak incidence of starting drug use and the comparatively low seroprevalence of HIV in the newer drug users probably explain the anomalous high seroprevalence in Edinburgh drug users during 1980-5. The epidemic of HIV during the first half of the 1980s in the group suggests that the virus was probably being transmitted because of a pattern of behaviour. Changing patterns of HIV transmission suggest a need to concentrate on heterosexual transmission as the main problem in the future.
PMCID: PMC1662036  PMID: 2106928

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