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1.  Treatment of filarial lymphoedema and elephantiasis with 5,6-benzo-alpha-pyrone (coumarin). 
BMJ : British Medical Journal  1993;307(6911):1037-1041.
OBJECTIVE--To study efficacy of treatment of filarial lymphoedema and elephantiasis with 5,6-benzo-alpha-pyrone. DESIGN--Randomised, double blind, placebo controlled study with matching for grade and duration of disease, age, and sex. Treatment was given for 367 days, and subjects were followed up for another year. SETTING--A town in Shandong Province, China. SUBJECTS--104 men and women with chronic unilateral filarial lymphoedema or elephantiasis of the leg: 64 were randomised to benzopyrone and 40 to placebo. By the end of the study 19 patients had dropped out of the treatment group and two out of the placebo group. INTERVENTIONS--Two 200 mg tablets of 5,6-benzo-alpha-pyrone or two placebo tablets given daily. MAIN OUTCOME MEASURES--Volumes of the affected and normal legs estimated every three months, and daily listing of any side effects. RESULTS--Benzopyrone reduced oedema for all grades of lymphoedema during the year of treatment (pW0.001) and the follow up year (p = 0.026). During treatment the mean monthly reductions in leg volume were 0.62% (95% confidence intervals 0.4% to 0.85%), 1.1% (0.71% to 1.6%), and 1.6% (0.89% to 2.3%) of the volume of the normal leg for grades 1, 2, and 3-5 (elephantiasis) of lymphoedema respectively. During follow up the mean monthly reductions were 0.18% (0.01% to 0.35%), 0.54% (0.27% to 0.82%), and 0.87% (0.51% to 1.2%). At the end of the trial the total reduction in oedema was 100%, 95%, and 45% for grades 1, 2, and 3-5. Symptoms and complications were considerably reduced, including attacks of secondary acute inflammation, while side effects were minor and disappeared after one month. In the placebo group there were no changes in the severity of lymphoedema. CONCLUSIONS--5,6-benzo-alpha-pyrone reduces the oedema and many symptoms of filarial lymphoedema and elephantiasis. It has few side effects, and its relatively slow action makes it ideal for use without compression garments.
PMCID: PMC1679230  PMID: 8251778
3.  Intersubject Variability of and Genetic Effects on the Brain's Functional Connectivity during Infancy 
The Journal of Neuroscience  2014;34(34):11288-11296.
Infancy is a period featuring a high level of intersubject variability but the brain basis for such variability and the potential genetic/environmental contributions remain largely unexplored. The assessment of the brain's functional connectivity during infancy by the resting state functional magnetic resonance imaging (rsfMRI) technique (Biswal et al., 1995) provides a unique means to probe the brain basis of intersubject variability during infancy. In this study, an unusually large typically developing human infant sample including 58 singletons, 132 dizygotic twins, and 98 monozygotic twins with rsfMRI scans during the first 2 years of life was recruited to delineate the spatial and temporal developmental patterns of both the intersubject variability of and genetic effects on the brain's functional connectivity. Through systematic voxelwise functional connectivity analyses, our results revealed that the intersubject variability at birth features lower variability in primary functional areas but higher values in association areas. Although the relative pattern remains largely consistent, the magnitude of intersubject variability undergoes an interesting U-shaped growth during the first 2 years of life. Overall, the intersubject variability patterns during infancy show both adult-like and infant-specific characteristics (Mueller et al., 2013). On the other hand, age-dependent genetic effects were observed showing significant but bidirectional relationships with intersubject variability. The temporal and spatial patterns of the intersubject variability of and genetic contributions to the brain's functional connectivity documented in this study shed light on the largely uncharted functional development of the brain during infancy.
doi:10.1523/JNEUROSCI.5072-13.2014
PMCID: PMC4138339  PMID: 25143609
early brain development; functional connectivity; genetic effects; infancy; intersubject variability; resting state
4.  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
5.  Spread of Artemisinin Resistance in Plasmodium falciparum Malaria 
The New England journal of medicine  2014;371(5):411-423.
BACKGROUND
Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geographic extent of resistance is essential for planning containment and elimination strategies.
METHODS
Between May 2011 and April 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kilogram of body weight per day or 4 mg per kilogram, for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 hours, and the parasite clearance half-lives were determined.
RESULTS
The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand–Cambodia border. Slowly clearing in fections (parasite clearance half-life >5 hours), strongly associated with single point mutations in the “propeller” region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from southern Vietnam to central Myanmar. The incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was associated with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days.
CONCLUSIONS
Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is associated with mutations in kelch13. Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing. (Funded by the U.K. Department of International Development and others; ClinicalTrials.gov number, NCT01350856.)
doi:10.1056/NEJMoa1314981
PMCID: PMC4143591  PMID: 25075834
6.  Global assessment of the status of coral reef herbivorous fishes: evidence for fishing effects 
On coral reefs, herbivorous fishes consume benthic primary producers and regulate competition between fleshy algae and reef-building corals. Many of these species are also important fishery targets, yet little is known about their global status. Using a large-scale synthesis of peer-reviewed and unpublished data, we examine variability in abundance and biomass of herbivorous reef fishes and explore evidence for fishing impacts globally and within regions. We show that biomass is more than twice as high in locations not accessible to fisheries relative to fisheries-accessible locations. Although there are large biogeographic differences in total biomass, the effects of fishing are consistent in nearly all regions. We also show that exposure to fishing alters the structure of the herbivore community by disproportionately reducing biomass of large-bodied functional groups (scraper/excavators, browsers, grazer/detritivores), while increasing biomass and abundance of territorial algal-farming damselfishes (Pomacentridae). The browser functional group that consumes macroalgae and can help to prevent coral–macroalgal phase shifts appears to be most susceptible to fishing. This fishing down the herbivore guild probably alters the effectiveness of these fishes in regulating algal abundance on reefs. Finally, data from remote and unfished locations provide important baselines for setting management and conservation targets for this important group of fishes.
doi:10.1098/rspb.2013.1835
PMCID: PMC3843826  PMID: 24258715
fishing; reef-fish; phase shift; resilience; herbivory; macroalgae and turf algae
7.  Development of Thalamocortical Connectivity during Infancy and Its Cognitive Correlations 
The Journal of Neuroscience  2014;34(27):9067-9075.
Although commonly viewed as a sensory information relay center, the thalamus has been increasingly recognized as an essential node in various higher-order cognitive circuits, and the underlying thalamocortical interaction mechanism has attracted increasing scientific interest. However, the development of thalamocortical connections and how such development relates to cognitive processes during the earliest stages of life remain largely unknown. Leveraging a large human pediatric sample (N = 143) with longitudinal resting-state fMRI scans and cognitive data collected during the first 2 years of life, we aimed to characterize the age-dependent development of thalamocortical connectivity patterns by examining the functional relationship between the thalamus and nine cortical functional networks and determine the correlation between thalamocortical connectivity and cognitive performance at ages 1 and 2 years. Our results revealed that the thalamus–sensorimotor and thalamus–salience connectivity networks were already present in neonates, whereas the thalamus–medial visual and thalamus–default mode network connectivity emerged later, at 1 year of age. More importantly, brain–behavior analyses based on the Mullen Early Learning Composite Score and visual–spatial working memory performance measured at 1 and 2 years of age highlighted significant correlations with the thalamus–salience network connectivity. These results provide new insights into the understudied early functional brain development process and shed light on the behavioral importance of the emerging thalamocortical connectivity during infancy.
doi:10.1523/JNEUROSCI.0796-14.2014
PMCID: PMC4078084  PMID: 24990927
development; functional connectivity; Mullen scores; resting state; thalamus; working memory
8.  Lessons Learned from Developing a Drug Evidence Base to Support Pharmacovigilance 
Applied Clinical Informatics  2013;4(4):596-617.
Summary
Objective
This work identified challenges associated with extraction and representation of medication-related information from publicly available electronic sources.
Methods
We gained direct observational experience through creating and evaluating the Drug Evidence Base (DEB), a repository of drug indications and adverse effects (ADEs), and supplemented this through literature review. We extracted DEB content from the National Drug File Reference Terminology, from aggregated MEDLINE co-occurrence data, and from the National Library of Medicine’s DailyMed. To understand better the similarities, differences and problems with the content of DEB and the SIDER Side Effect Resource, and Vanderbilt’s MEDI Indication Resource, we carried out statistical evaluations and human expert reviews.
Results
While DEB, SIDER, and MEDI often agreed on medication indications and side effects, cross-system shortcomings limit their current utility. The drug information resources we evaluated frequently employed multiple, disparate vaguely related UMLS concepts to represent a single specific clinical drug indication or adverse effect. Thus, evaluations comparing drug-indication and drug-ADE coverage for such resources will encounter substantial numbers of false negative and false positive matches. Furthermore, our review found that many indication and ADE relationships are too complex – logically and temporally – to represent within existing systems.
Conclusion
To enhance applicability and utility, future drug information systems deriving indications and ADEs from public resources must represent clinical concepts uniformly and as precisely as possible. Future systems must also better represent the inherent complexity of indications and ADEs.
doi:10.4338/ACI-2013-08-RA-0062
PMCID: PMC3885918  PMID: 24454585
Drug therapy; adverse effects; knowledge bases; drug product labeling; unified medical language system
9.  A pharmacodynamic comparison of 5 anti-platelet protocols in patients with ST-elevation myocardial infarction undergoing primary PCI 
Background
Despite advances in anti-platelet treatments, there still exists an early increase in both ischemic as well as bleeding events following primary PCI in patients with ST-elevation myocardial infarction (STEMI). Platelet inhibition data of different anti-platelet treatments in the acute phase of a myocardial infarction might offer some insight into these problems. The aim of this study was to evaluate the pharmacodynamic profile of 5 different anti-platelet treatments in the acute phase of STEMI in patients undergoing primary PCI.
Methods
A total of 223 STEMI patients undergoing primary PCI were prospectively included. Patients received either pre-hospital clopidogrel only, pre-hospital clopidogrel followed by prasugrel switch in the cath lab, prasugrel treatment only, pre-hospital clopidogrel followed by ticagrelor switch in the cath lab or pre-hospital ticagrelor only. Platelet reactivity was measured serially using vasodilator-stimulated phosphoprotein (VASP).
Results
Patients receiving pre-hospital clopidogrel followed by prasugrel switch showed similar platelet inhibition data as patients receiving prasugrel only, with more than 90% being good responders the day after PCI. Average time from prasugrel administration to a VASP value of <50% was 1.5 hours. In patients receiving pre-hospital ticagrelor, 50% were good responders at completion of PCI and average time to a VASP-value of <50% was 2.3 hours. Only 32% of patients receiving clopidogrel only were responders the day after PCI.
Conclusions
Switching from an upstream bolus dose of clopidogrel to prasugrel at the time of PCI, appeared as a safe and feasible option with no tendency for overshoot or attenuation of platelet inhibition. Pre-hospital administration of ticagrelor was associated with a 50% good responder rate at completion of PCI.
doi:10.1186/1471-2261-14-189
PMCID: PMC4274705  PMID: 25516485
Prasugrel; Ticagrelor; Clopidogrel; Upstream; STEMI
10.  Fading Perceptual Resemblance: A Path for Rhesus Macaques (Macaca mulatta) to Conceptual Matching? 
Cognition  2013;129(3):10.1016/j.cognition.2013.08.001.
Cognitive, comparative, and developmental psychologists have long been intrigued by humans’ and animals’ capacity to respond to abstract relations like sameness and difference, because this capacity may underlie crucial aspects of cognition like analogical reasoning. Recently, this capacity has been explored in higher-order, relational matching-to-sample (RMTS) tasks in which humans and animals try to complete analogies of sameness and difference between disparate groups of items. The authors introduced a new paradigm to this area, by yoking the relational-matching cue to a perceptual-matching cue. Then, using established algorithms for shape distortion, the perceptual cue was weakened and eliminated. Humans’ RMTS performance easily transcended the elimination of perceptual support. In contrast, RMTS performance by six macaques faltered as they were weaned from perceptual support. No macaque showed evidence of mature RMTS performance, even given more than 260,000 training trials during which we tried to coax a relational-matching performance from them. It is an important species difference that macaques show so hesitant a response to conceptual relations when humans respond to them so effortlessly. It raises theoretical questions about the emergence of this crucial capacity during humans’ cognitive evolution and during humans’ cognitive development.
doi:10.1016/j.cognition.2013.08.001
PMCID: PMC3809328  PMID: 24076537
same-different; concept learning; relational matching; primate cognition; comparative cognition
11.  Promoting new approaches for cancer care in the Middle East 
Annals of Oncology  2013;24(Suppl 7):vii5-vii10.
Cancer is now the fastest growing killing disease in the Middle East. Accordingly, there is an urgent need to train local health professionals: Oncologists, Palliative Care experts, Oncology Nurses, Psychologists, along with social workers, physiotherapists and spiritual counselors on strategies for early detection, curative therapies and palliation. Professionals in the region, along with the public, need to convince medical administrators, regulators and policymakers about investing in education and training of YOUNG professionals, As well as those with already proven experience in cancer care. Training is the basis for any future cancer care program, which aims at the integration of palliative care practices into standard oncology care across the trajectory of the illness.
doi:10.1093/annonc/mdt267
PMCID: PMC3767160  PMID: 24001764
12.  Chitosan Sponges for Local Synergistic Infection Therapy: A Pilot Study 
Background
Although bacterial antibiotic resistance is increasing, fewer new antibiotics are being developed to compensate. Localized delivery of synergistic antiseptics and antibiotics with a chitosan sponge device may offer an alternative infection treatment.
Questions/purposes
In this pilot study, we asked whether antiseptic and antibiotic combinations provided in vitro synergism against Staphylococcus aureus, whether synergism reduces cell viability, and whether their combination releases drugs at inhibitory levels.
Methods
To investigate the pharmacodynamics among three combinations of the antiseptic chlorhexidine digluconate (CHX) with the antibiotics amikacin, daptomycin, and vancomycin (VAN) (n = 1), we determined the fractional inhibitory concentration (FIC) index against S aureus Cowan I. The determined synergistic combination of CHX and VAN was evaluated for cell compatibility using NIH/3T3 fibroblasts (n = 3) and the drug release profile from a chitosan sponge device (n = 5).
Results
With an FIC index < 0.5, the combination of CHX + VAN exhibited synergism against S aureus. CHX concentrations ≥ 3.91 μg/mL resulted in fibroblast viability decrease, whereas the combination of CHX + VAN did not decrease fibroblast viability until their concentrations reached ≥ 7.81 μg/mL. The CHX and VAN release profile, both individually and in combination, was an initial bolus with no difference between eluate concentrations after Day 5.
Conclusions
CHX + VAN combination may be delivered locally by a chitosan sponge that synergistically inhibits S aureus growth.
Clinical Relevance
The use of synergism between combined antibiotic and antiseptics delivered at high local concentrations with an implanted chitosan sponge may provide a useful alternative infection treatment option.
doi:10.1007/s11999-013-2988-5
PMCID: PMC3773141  PMID: 23604649
13.  Structural Aspects of the Cytochrome b6f Complex; Structure of the Lumen-Side Domain of Cytochrome f 
The following findings concerning the structure of the cytochrome b6f complex and its component polypeptides, cyt b6, subunit IV and cytochrome f subunit are discussed: Comparison of the amino acid sequences of 13 and 16 cytochrome b6 and subunit IV polypeptides, respectively, led to (a) reconsideration of the helix lengths and probable interface regions, (b) identification of two likely surface-seeking helices in cyt b6 and one in SU IV, and (c) documentation of a high degree of sequence invariance compared to the mitochondrial cytochrome. The extent of identity is particularly high (88% for conserved and pseudo- conserved residues) in the segments of cyt b6 predicted to be extrinsic on the n-side of the membrane.The intramembrane attractive forces between trans-membrane helices that normally stabilize the packing of integral membrane proteins are relatively weak.The complex isolated in dimeric form has been visualized, along with isolated monomer, by electron microscopy. The isolated dimer is much more active than the monomer, is the major form of the complex isolated and purified from chloroplasts, and is inferred to be a functional form in the membrane.The isolated cyt b6f complex contains one molecule of chlorophyll a.The structure of the 252 residue lumen-side domain of cytochrome f isolated from turnip chloroplasts has been solved by X-ray diffraction analysis to a resolution of 2.3 Å.
PMCID: PMC4167668  PMID: 8027021
Cytochrome bc1; electron transfer; energy transduction; membrane protein; structure
14.  Comparing methods for estimating R0 from the size distribution of subcritical transmission chains 
Epidemics  2013;5(3):10.1016/j.epidem.2013.05.002.
Many diseases exhibit subcritical transmission (i.e. 0 < R0 < 1) so that infections occur as self-limited ‘stuttering chains’. Given an ensemble of stuttering chains, information about the number of cases in each chain can be used to infer R0, which is of crucial importance for monitoring the risk that a disease will emerge to establish endemic circulation. However, the challenge of imperfect case detection has led authors to adopt a variety of work-around measures when inferring R0, such as discarding data on isolated cases or aggregating intermediate-sized chains together. Each of these methods has the potential to introduce bias, but a quantitative comparison of these approaches has not been reported. By adapting a model based on a negative binomial offspring distribution that permits a variable degree of transmission heterogeneity, we present a unified analysis of existing R0 estimation methods. Simulation studies show that the degree of transmission heterogeneity, when improperly modeled, can significantly impact the bias of R0 estimation methods designed for imperfect observation. These studies also highlight the importance of isolated cases in assessing whether an estimation technique is consistent with observed data. Analysis of data from measles outbreaks shows that likelihood scores are highest for models that allow a flexible degree of transmission heterogeneity. Aggregating intermediate sized chains often has similar performance to analyzing a complete chain size distribution. However, truncating isolated cases is beneficial only when surveillance systems clearly favor full observation of large chains but not small chains. Meanwhile, if data on the type and proportion of cases that are unobserved were known, we demonstrate that maximum likelihood inference of R0 could be adjusted accordingly. This motivates the need for future empirical and theoretical work to quantify observation error and incorporate relevant mechanisms into stuttering chain models used to estimate transmission parameters.
doi:10.1016/j.epidem.2013.05.002
PMCID: PMC3821076  PMID: 24021520
Stuttering chain; Basic reproductive number; Transmission heterogeneity; Imperfect observation; Measles
15.  Arginine-directed glycation and decreased HDL plasma concentration and functionality 
Nutrition & Diabetes  2014;4(9):e134-.
Background/Objectives:
Decreased plasma concentration of high-density lipoprotein cholesterol (HDL-C) is a risk factor linked to increased risk of cardiovascular disease (CVD). Decreased anti-atherogenic properties of HDL are also implicated in increased CVD risk. The cause is unknown but has been linked to impaired glucose tolerance. The aim of this study was to quantify the modification of HDL by methylglyoxal and related dicarbonyls in healthy people and patients with type 2 diabetes characterise structural, functional and physiological consequences of the modification and predict the importance in high CVD risk groups.
Subjects/Methods:
Major fractions of HDL, HDL2 and HDL3 were isolated from healthy human subjects and patients with type 2 diabetes and fractions modified by methylglyoxal and related dicarbonyl metabolites quantified. HDL2 and HDL3 were glycated by methylglyoxal to minimum extent in vitro and molecular, functional and physiological characteristics were determined. A one-compartment model of HDL plasma clearance was produced including formation and clearance of dicarbonyl-modified HDL.
Results:
HDL modified by methylglyoxal and related dicarbonyl metabolites accounted for 2.6% HDL and increased to 4.5% in patients with type 2 diabetes mellitus (T2DM). HDL2 and HDL3 were modified by methylglyoxal to similar extents in vitro. Methylglyoxal modification induced re-structuring of the HDL particles, decreasing stability and plasma half-life in vivo. It occurred at sites of apolipoprotein A-1 in HDL linked to membrane fusion, intramolecular bonding and ligand binding. Kinetic modelling of methylglyoxal modification of HDL predicted a negative correlation of plasma HDL-C with methylglyoxal-modified HDL. This was validated clinically. It also predicted that dicarbonyl modification produces 2–6% decrease in total plasma HDL and 5–13% decrease in functional HDL clinically.
Conclusions:
These results suggest that methylglyoxal modification of HDL accelerates its degradation and impairs its functionality in vivo, likely contributing to increased risk of CVD—particularly in high CVD risk groups.
doi:10.1038/nutd.2014.31
PMCID: PMC4183972  PMID: 25177914
16.  Sorafenib for advanced hepatocellular carcinoma (HCC): impact of rationing in the United Kingdom 
British Journal of Cancer  2013;109(4):888-890.
Background:
The prognosis for hepatocellular carcinoma (HCC) is dependent upon tumour stage, performance status (PS), severity of underlying liver disease, and the availability of appropriate therapies. The unavailability of sorafenib may have a significantly adverse effect on the prognosis of UK patients with advanced HCC. During the study period, access to sorafenib was at the discretion of local health funding bodies, a process that may delay or deny access to the drug and that remains in place for Wales, Scotland, and Northern Ireland. Here, we attempt to address the impact of this system on patients with advanced HCC in the United Kingdom.
Methods:
This is a retrospective study performed in the two largest specialist hepatobiliary oncology units in the United Kingdom. Funding applications were made to local funding bodies for patients with advanced HCC for whom sorafenib was considered appropriate (advanced HCC not suitable for loco-regional therapies, compensated chronic liver disease, PS 0–2).
Results:
A total of 133 applications were made, of which 57 (43%) were approved and 76 (57%) declined. Demographics and prognostic factors were balanced between the two groups. This cohort had a number of adverse prognostic features: patients were predominantly PS 1–2; the majority had multifocal disease with the largest lesion being >5 cm; and macroscopic vascular invasion, metastases, and AFP >1000 ng ml−1, were each present in one-third of cases. The median time from application to funding decision was 17 days (range 3–260 days). For the primary ‘intention-to-treat' analysis, median overall survival was 4.1 months when funding was declined, and 9.5 months when funding was approved (hazard ratio (HR) 0.48; 95% CI 0.3186–0.7267; P=0.0005).
Conclusion:
These data support the use of sorafenib for patients with advanced HCC as an effective intervention. In the United Kingdom, this applies to a relatively small group of patients, estimated to total ∼800 per year who, unfortunately, do not survive long enough to themselves lobby for the availability of this drug. These data provide a comparison of sorafenib with supportive care and demonstrate the potential detrimental impact on patient outcomes of rationing health-care resources on the basis of cost.
doi:10.1038/bjc.2013.410
PMCID: PMC3749577  PMID: 23880824
sorafenib; multikinase inhibitor; advanced hepatocellular cancer; primary care trusts; health-care rationing; supportive care
17.  Stages of Category Learning in Monkeys (Macaca mulatta) and Humans (Homo sapiens) 
Smith and Minda (1998) and Blair and Homa (2001) studied the time course of category learning in humans. They distinguished an early, abstraction-based stage of category learning from a later stage that incorporated a capacity for categorizing exceptional category members. The present authors asked whether similar processing stages characterize the category learning of nonhuman primates. Humans and monkeys participated in category-learning tasks that extended Blair and Homa’s paradigm comparatively. Early in learning, both species improved on typical items more than on exception items, indicating an initial mastery of the categories’ general structure. Later in learning, both species selectively improved their exception-item performance, indicating exception-item resolution or exemplar memorization. An initial stage of abstraction-based category learning may characterize categorization across a substantial range of the order Primates. This default strategy may have an adaptive resonance with the family-resemblance organization of many natural-kind categories.
doi:10.1037/a0016573
PMCID: PMC4130214  PMID: 20141316
category learning; prototypes; stages of learning; abstraction; primate cognition
18.  Carving nature at its joints using a knife called concepts 
The Behavioral and brain sciences  2010;33(0):207-208.
That humans can categorize in different ways does not imply that there are qualitatively distinct underlying natural kinds or that the field of concepts splinters. Rather, it implies that the unitary goal of forming concepts is important enough that it receives redundant expression in cognition. Categorization science focuses on commonalities involved in concept learning. Eliminating “concept” makes this more difficult.
doi:10.1017/S0140525X10000336
PMCID: PMC4128318  PMID: 20584398
19.  A randomised trial of weekend and evening breast screening appointments 
British Journal of Cancer  2013;109(3):597-602.
Background:
There is a need to research interventions that improve access to and convenience of breast cancer screening services.
Methods:
We conducted a randomised trial comparing invitations to out-of-hours appointments with standard office hour appointments. Women who were to be invited for routine breast screening were randomised (3 : 1 : 1 : 1) to one of these screening invitations: standard office hour appointment, office hour appointment with the option to change to an out-of-hours appointment, weekday evening appointment, or weekend appointment.
Results:
A total of 9410 women were invited to an office hour, 3519 to an office hour with the option to change, 3271 to a weekday evening, and 3162 to a weekend appointment. The offer of an initial out-of-hours appointment was associated with a non-significant decrease in attendance rates (73.7% vs 74.1%). The highest attendance was observed in the group offered an initial office hour appointment with the option to change to out-of-hours (76.1% vs 73.3% for standard office hour, P=0.001), with 7% of invitees exercising the option to change.
Conclusion:
The optimum strategy for improving attendance at breast screening is to offer a traditional office hour appointment and including in the letter of invitation an option to change to an evening or weekend appointment if wished.
doi:10.1038/bjc.2013.377
PMCID: PMC3738129  PMID: 23867998
mammography; breast cancer; breast screening; attendance; evening appointment; weekend appointments
20.  TBCRC 018: phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases 
Nearly half of patients with advanced triple negative breast cancer (TNBC) develop brain metastases (BM) and most will also have uncontrolled extracranial disease. This study evaluated the safety and efficacy of iniparib, a small molecule anti-cancer agent that alters reactive oxygen species tumor metabolism and penetrates the blood brain barrier, with the topoisomerase I inhibitor irinotecan in patients with TNBC-BM. Eligible patients had TNBC with new or progressive BM and received irinotecan and iniparib every 3 weeks. Time to progression (TTP) was the primary end point; secondary endpoints were response rate (RR), clinical benefit rate (CBR), overall survival (OS), toxicity, and health-related quality of life. Correlative endpoints included molecular subtyping and gene expression studies on pre-treatment archival tissues, and determination of germline BRCA1/2 status. Thirty-seven patients began treatment; 34 were evaluable for efficacy. Five of 24 patients were known to carry a BRCA germline mutation (4 BRCA1, 1 BRCA2). Median TTP was 2.14 months and median OS was 7.8 months. Intracranial RR was 12 %, while intracranial CBR was 27 %. Treatment was well-tolerated; the most common grade 3/4 adverse events were neutropenia and fatigue. Grade 3/4 diarrhea was rare (3 %). Intrinsic subtyping revealed 19 of 21 tumors (79 %) were basal-like, and intracranial response was associated with high expression of proliferation-related genes. This study suggests a modest benefit of irinotecan plus iniparib in progressive TNBC-BM. More importantly, this trial design is feasible and lays the foundation for additional studies for this treatment-refractory disease.
Electronic supplementary material
The online version of this article (doi:10.1007/s10549-014-3039-y) contains supplementary material, which is available to authorized users.
doi:10.1007/s10549-014-3039-y
PMCID: PMC4112043  PMID: 25001612
Irinotecan; Iniparib; Brain metastases; Breast cancer; Phase II; Triple negative
21.  Chemically diverse polymer microarrays and high throughput surface characterisation: a method for discovery of materials for stem cell culture† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c4bm00054d Click here for additional data file.  
Biomaterials Science  2014;2(11):1604-1611.
Chemically diverse polymer microarrays as a powerful screening tool for the discovery of new materials for a variety of applications.
Materials discovery provides the opportunity to identify novel materials that are tailored to complex biological environments by using combinatorial mixing of monomers to form large libraries of polymers as micro arrays. The materials discovery approach is predicated on the use of the largest chemical diversity possible, yet previous studies into human pluripotent stem cell (hPSC) response to polymer microarrays have been limited to 20 or so different monomer identities in each study. Here we show that it is possible to print and assess cell adhesion of 141 different monomers in a microarray format. This provides access to the largest chemical space to date, allowing us to meet the regenerative medicine challenge to provide scalable synthetic culture ware. This study identifies new materials suitable for hPSC expansion that could not have been predicted from previous knowledge of cell-material interactions.
doi:10.1039/c4bm00054d
PMCID: PMC4183437  PMID: 25328672
22.  Recognition of Famous Names Predicts Episodic Memory Decline in Cognitively Intact Elders 
Neuropsychology  2013;27(3):333-342.
Objective:
Semantic memory impairment is common in both Mild Cognitive Impairment (MCI) and early Alzheimer’s disease (AD), and the ability to recognize familiar people is particularly vulnerable. A time-limited temporal gradient (TG) in which well known people from decades earlier are better recalled than those learned recently is also reported in both AD and MCI. In this study, we hypothesized that the TG pattern on a famous name recognition task (FNRT) administered to cognitively intact elders would predict future episodic memory decline, and would also show a significant correlation with hippocampal volume.
Methods:
78 healthy elders (ages 65-90) with normal cognition and episodic memory at baseline were administered a FNRT. Follow-up episodic memory testing 18 months later produced two groups: Declining (≥ 1 SD reduction in episodic memory) and Stable (< 1 SD).
Results:
The Declining group (N=27) recognized fewer recent famous names than the Stable group (N=51), while recognition for remote names was comparable. Baseline MRI volumes for both the left and right hippocampus was significantly smaller in the Declining group than the Stable group. Smaller baseline hippocampal volume was also significantly correlated with poorer performance for recent, but not remote famous names. Logistic regression analyses indicated that baseline TG performance was a significant predictor of group status (Declining versus Stable) independent of chronological age and APOE ε4 inheritance.
Conclusions:
Famous name recognition may serve as an early pre-clinical cognitive marker of episodic memory decline in older individuals.
doi:10.1037/a0032226
PMCID: PMC3798037  PMID: 23688215
Famous names; episodic memory; hippocampus; semantic memory; temporal gradient
23.  Language-trained chimpanzees (Pan troglodytes) name what they have seen, but look first at what they have not seen 
Psychological science  2013;24(5):660-666.
Metacognition can be defined as knowing what one knows, and the question of whether nonhuman animals are metacognitive has driven an intense debate. We tested three language-trained chimpanzees in an information-seeking task in which the identity of a food item was the critical piece of information needed to obtain the food. In two experiments, the chimpanzees were significantly more likely to visit a container first on trials in which they could not know its contents but were more likely to just name the item without looking into the container on trials in which they had earlier seen the contents of that container. Thus, chimpanzees showed efficient information-seeking behavior that suggested they knew what they had or had not already seen when it was time to name a hidden item.
doi:10.1177/0956797612458936
PMCID: PMC3902479  PMID: 23508741
metacognition; chimpanzees; Pan troglodytes; information-seeking
24.  Who Was Deborah Kallikak? 
The Kallikak Family was, along with The Jukes, one of the most visible eugenic family narratives published in the early 20th Century. Published in 1912 and authored by psychologist Henry Herbert Goddard, director of the psychological laboratory at the Vineland Training School for Feebleminded Children in Vineland, New Jersey, The Kallikak Family told the tale of a supposedly “degenerate” family from rural New Jersey, beginning with Deborah, one of the inmates at The Training School. Like most books in the genre, this pseudoscientific treatise described generations of illiterate, poor, and purportedly immoral, Kallikak family members who were chronically unemployed, supposedly feebleminded, criminals, and, in general, perceived as threats to racial hygiene. Presented as a “natural experiment” in human heredity, this text served to support eugenic activities through much of the first half of the century. This article reviews the story of Deborah Kallikak, including her true identity, and provides evidence that Goddard’s treatise was incorrect. “One bright October day, fourteen years ago, there came to the Training School at Vineland, a little eight year-old girl”(Goddard, 1912, p. 1)
doi:10.1352/1934-9556-50.2.169
PMCID: PMC3987907  PMID: 22642970
25.  Economic benefit of the PHLAME wellness programme on firefighter injury 
Background
Work-related injuries and illness are prevalent and costly. Firefighting is especially hazardous and many firefighters sustain work-related injuries. Workplace health promotion programmes have shown positive return on investment (ROI). Little is known about how similar programmes would impact injury and cost among firefighters.
Aims
To evaluate the impact of a workplace health promotion intervention on workers’ compensation (WC) claims and medical costs among Oregon fire departments participating in the PHLAME (Promoting Healthy Lifestyles: Alternative Models’ Effects) health promotion programme compared with Oregon fire departments not participating in PHLAME.
Methods
Data from firefighters from four large urban fire departments in Oregon were evaluated using a retrospective quasi-experimental study design. Outcomes were (i) total annual firefighter WC claims, (ii) total annual incurred medical costs prior to and after implementation of the PHLAME firefighter worksite health promotion programme (iii) and an ROI analysis.
Results
Data were obtained from 1369 firefighters (mean age of 42 years, 91% white, 93% male). WC claims (P < 0.001) and medical costs (P < 0.01) were significantly lower among PHLAME fire departments compared with Oregon fire departments not participating in the programme. Fire departments participating in the PHLAME TEAM programme demonstrated a positive ROI of 4.61–1.00 (TEAM is used to indicate the 12-session peer-led health promotion programme).
Conclusions
Fire department WC claims and medical costs were reduced after implementation of the PHLAME workplace health promotion programme. This is a low cost, team-based, peer-led, wellness programme that may provide a feasible, cost-effective means to reduce firefighter injury and illness rates.
doi:10.1093/occmed/kqs232
PMCID: PMC3617369  PMID: 23416849
Firefighter; health promotion; occupational health; occupational injury

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