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1.  Effect of Right Ventricular Function and Venous Congestion on Cardio-Renal Interactions during the Treatment of Decompensated Heart Failure 
The American journal of cardiology  2010;105(4):511-516.
Recent reports have demonstrated the adverse effects of venous congestion on renal function and challenged the assumption that worsening renal function (RF) is driven by diminished cardiac output (CO). We hypothesized that diuresis in patients with right ventricular (RV) dysfunction, despite diminished CO, would lead to a reduction in venous congestion and resultant improvement in renal function. We reviewed consecutive admissions with a discharge diagnosis of heart failure (HF). RV function was assessed by multiple echocardiographic methods and those with ≥2 measures of RV dysfunction were considered to have significant RV dysfunction. Worsening RF was defined as an increase in creatinine of ≥0.3 mg/dL and improved RF as improvement in glomerular filtration rate ≥25%. A total of 141 admissions met eligibility criteria, 34% developed worsening RF. Venous congestion was more common in those with RV dysfunction (OR=3.3, p=0.009). All measures of RV dysfunction excluding RV dilation correlated with CO (p<0.05). Significant RV dysfunction predicted a lower incidence of worsening RF (OR=0.21, p<0.001) and higher incidence of improved RF (OR=6.4, p<0.001). CO emerged as a significant predictor of change in glomerular filtration rate during hospitalization in those without significant RV dysfunction (r=0.38, p<0.001). In conclusion, RV dysfunction is a strong predictor of improved renal outcomes in patients with acute decompensated HF, an effect likely mediated by relief of venous congestion.
PMCID: PMC2995805  PMID: 20152246
Cardio-renal syndrome; worsening renal function; RV dysfunction; improved renal function
2.  Leptin Acts via Lateral Hypothalamic Area Neurotensin Neurons to Inhibit Orexin Neurons by Multiple GABA-Independent Mechanisms 
The Journal of Neuroscience  2014;34(34):11405-11415.
The adipocyte-derived hormone leptin modulates neural systems appropriately for the status of body energy stores. Leptin inhibits lateral hypothalamic area (LHA) orexin (OX; also known as hypocretin)-producing neurons, which control feeding, activity, and energy expenditure, among other parameters. Our previous results suggest that GABAergic LHA leptin receptor (LepRb)-containing and neurotensin (Nts)-containing (LepRbNts) neurons lie in close apposition with OX neurons and control Ox mRNA expression. Here, we show that, similar to leptin, activation of LHA Nts neurons by the excitatory hM3Dq DREADD (designer receptor exclusively activated by designer drugs) hyperpolarizes membrane potential and suppresses action potential firing in OX neurons in mouse hypothalamic slices. Furthermore, ablation of LepRb from Nts neurons abrogated the leptin-mediated inhibition, demonstrating that LepRbNts neurons mediate the inhibition of OX neurons by leptin. Leptin did not significantly enhance GABAA-mediated inhibitory synaptic transmission, and GABA receptor antagonists did not block leptin-mediated inhibition of OX neuron activity. Rather, leptin diminished the frequency of spontaneous EPSCs onto OX neurons. Furthermore, leptin indirectly activated an ATP-sensitive potassium (KATP) channel in OX neurons, which was required for the hyperpolarization of OX neurons by leptin. Although Nts did not alter OX activity, galanin, which is coexpressed in LepRbNts neurons, inhibited OX neurons, whereas the galanin receptor antagonist M40 (galanin-(1–12)-Pro3-(Ala-Leu)2-Ala amide) prevented the leptin-induced hyperpolarization of OX cells. These findings demonstrate that leptin indirectly inhibits OX neurons by acting on LHA LepRbNts neurons to mediate two distinct GABA-independent mechanisms of inhibition: the presynaptic inhibition of excitatory neurotransmission and the opening of KATP channels.
PMCID: PMC4138347  PMID: 25143620
EPSC; GABA; leptin; LHA; neurotensin; orexin
3.  Influence of Bioluminescence Imaging Dynamics by D-Luciferin Uptake and Efflux Mechanisms 
Molecular imaging  2012;11(6):499-506.
Bioluminescence imaging (BLI) detects light generated by luciferase-mediated oxidation of substrate and is used widely for evaluating transgene expression in cell-based assays and in vivo in relevant preclinical models. The most commonly used luciferase for in vivo applications is firefly luciferase (fLuc), for which D-luciferin serves as the substrate. We demonstrated previously that the expression of the ABCG2 efflux transporter can significantly reduce BLI signal output and that HhAntag-691 can inhibit the efflux of D-luciferin, thereby enhancing BLI signal. Here we show that an HhAntag-691-sensitive uptake mechanism facilitates the intracellular concentration of D-luciferin and that the BLI dynamics of different cell lines are coregulated by this uptake mechanism in conjunction with ABCG2-mediated efflux. After administration of D-luciferin, the HhAntag-691-sensitive uptake mechanism generates a rapid increase in BLI signal that decreases over time, whereas ABCG2-mediated efflux stably reduces signal output. We implicate SLC22A4 (OCTN1), a member of the organic cation/zwitterion uptake transporter family, as one potential mediator of the HhAntag-691-sensitive D-luciferin uptake. These findings provide insight into mechanisms that contribute to the cellular uptake kinetics and in vivo biodistribution of D-luciferin.
PMCID: PMC4332814  PMID: 23084250
4.  64Cu-Labeled Inhibitors of Prostate-Specific Membrane Antigen for PET Imaging of Prostate Cancer 
Journal of Medicinal Chemistry  2014;57(6):2657-2669.
Prostate-specific membrane antigen (PSMA) is a well-recognized target for identification and therapy of a variety of cancers. Here we report five 64Cu-labeled inhibitors of PSMA, [64Cu]3–7, which are based on the lysine–glutamate urea scaffold and utilize a variety of macrocyclic chelators, namely NOTA(3), PCTA(4), Oxo-DO3A(5), CB-TE2A(6), and DOTA(7), in an effort to determine which provides the most suitable pharmacokinetics for in vivo PET imaging. [64Cu]3–7 were prepared in high radiochemical yield (60–90%) and purity (>95%). Positron emission tomography (PET) imaging studies of [64Cu]3–7 revealed specific accumulation in PSMA-expressing xenografts (PSMA+ PC3 PIP) relative to isogenic control tumor (PSMA– PC3 flu) and background tissue. The favorable kinetics and high image contrast provided by CB-TE2A chelated [64Cu]6 suggest it as the most promising among the candidates tested. That could be due to the higher stability of [64Cu]CB-TE2A as compared with [64Cu]NOTA, [64Cu]PCTA, [64Cu]Oxo-DO3A, and [64Cu]DOTA chelates in vivo.
PMCID: PMC3983358  PMID: 24533799
5.  Birthdating of myenteric neuron subtypes in the small intestine of the mouse 
The Journal of comparative neurology  2014;522(3):10.1002/cne.23423.
There are many different types of enteric neurons. Previous studies have identified the time at which some enteric neuron subtypes are born (exit the cell cycle) in the mouse, but the birthdates of some major enteric neuron subtypes are still incompletely characterized or unknown. We combined 5-ethynynl-2’-deoxyuridine (EdU) labeling with antibody markers that identify myenteric neuron subtypes to determine when neuron subtypes are born in the mouse small intestine. We found that different neurochemical classes of enteric neuron differed in their birthdates; serotonin neurons were born first with peak cell cycle exit at E11.5, followed by neurofilament-M neurons, calcitonin gene-related peptide neurons (peak cell cycle exit for both at E12.5-E13.5), tyrosine hydroxylase neurons (E15.5), nitric oxide synthase 1 (NOS1) neurons (E15.5) and calretinin neurons (P0). The vast majority of myenteric neurons had exited the cell cycle by P10. We did not observe any EdU+/NOS1+ myenteric neurons in the small intestine of adult mice following EdU injection at E10.5 or E11.5, which was unexpected as previous studies have shown that NOS1 neurons are present in E11.5 mice. Studies using the proliferation marker, Ki67, revealed that very few NOS1 neurons in the E11.5 and E12.5 gut were proliferating. However, Cre-lox-based genetic fate-mapping revealed a small sub-population of myenteric neurons that appears to express NOS1 only transiently. Together, our results confirm a relationship between enteric neuron subtype and birthdate, and suggest that some enteric neurons exhibit neurochemical phenotypes during development that are different from their mature phenotype.
PMCID: PMC3877185  PMID: 23861145
6.  The Evolution of Imaging in Cancer: Current State and Future Challenges 
Seminars in oncology  2011;38(1):3-15.
Molecular imaging allows for the remote, noninvasive sensing and measurement of cellular and molecular processes in living subjects. Drawing upon a variety of modalities, molecular imaging provides a window into the biology of cancer from the subcellular level to the patient undergoing a new, experimental therapy. As signal transduction cascades and protein interaction networks become clarified, an increasing number of relevant targets for cancer therapy—and imaging—become available. Although conventional imaging is already critical to the management of patients with cancer, molecular imaging will provide even more relevant information, such as early detection of changes with therapy, identification of patient-specific cellular and metabolic abnormalities, and the disposition of therapeutic, gene-tagged cells throughout the body—all of which will have a considerable impact on morbidity and mortality. This overview discusses molecular imaging in oncology, providing examples from a variety of modalities, with an emphasis on emerging techniques for translational imaging.
PMCID: PMC4313866  PMID: 21362512
7.  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.
PMCID: PMC4124521  PMID: 24952745
genome-wide association study; QT interval; Long QT Syndrome; sudden cardiac death; myocardial repolarization; arrhythmias
8.  Proteomic analysis shows that stress response proteins are significantly up-regulated in resistant diploid wheat (Triticum monococcum) in response to attack by the grain aphid (Sitobion avenae) 
Molecular Breeding  2015;35:57.
The grain aphid Sitobion avenae (F.) is a major pest of wheat, acting as a virus vector as well as causing direct plant damage. Commonly grown wheat varieties in the UK have only limited resistance to this pest. The present study was carried out to investigate the potential of a diploid wheat line (ACC20 PGR1755), reported as exhibiting resistance to S. avenae, to serve as a source of resistance genes. The diploid wheat line was confirmed as partially resistant, substantially reducing the fecundity, longevity and growth rate of the aphid. Proteomic analysis showed that approximately 200 protein spots were reproducibly detected in leaf extracts from both the resistant line and a comparable susceptible line (ACC5 PGR1735) using two-dimensional gel electrophoresis and image comparison software. Twenty-four spots were significantly up-regulated (>2-fold) in the resistant line after 24 h of aphid feeding (13 and 11 involved in local and systemic responses, respectively). Approximately 50 % of all differentially expressed protein spots were identified by a combination of database searching with MS and MS/MS data, revealing that the majority of proteins up-regulated by aphid infestation were involved in metabolic processes (including photosynthesis) and transcriptional regulation. However, in the resistant line only, several stress response proteins (including NBS–LRR-like proteins) and oxidative stress response proteins were identified as up-regulated in response to aphid feeding, as well as proteins involved in DNA synthesis/replication/repair. This study indicates that the resistant diploid line ACC20 PGR1755 may provide a valuable resource in breeding wheat for resistance to aphids.
Electronic supplementary material
The online version of this article (doi:10.1007/s11032-015-0220-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4308650  PMID: 25642140
Aphid resistance; Biotic stress; Diploid wheat; Oxidative stress; Stress response; Wheat proteomics
9.  Heterobivalent Agents Targeting PSMA and Integrin-αvβ3 
Bioconjugate Chemistry  2014;25(2):393-405.
Differential expression of surface proteins on normal vs malignant cells provides the rationale for the development of receptor-, antigen-, and transporter-based, cancer-selective imaging and therapeutic agents. However, tumors are heterogeneous, and do not always express what can be considered reliable, tumor-selective markers. That suggests development of more flexible targeting platforms that incorporate multiple moieties enabling concurrent targeting to a variety of putative markers. We report the synthesis, biochemical, in vitro, and preliminary in vivo evaluation of a new heterobivalent (HtBv) imaging agent targeting both the prostate-specific membrane antigen (PSMA) and integrin-αvβ3 surface markers, each of which can be overexpressed in certain tumor epithelium and/or neovasculature. The HtBv agent was functionalized with either 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or the commercially available IRDye800CW. DOTA-conjugated HtBv probe 9 bound to PSMA or αvβ3 with affinities similar to those of monovalent (Mnv) compounds designed to bind to their targets independently. In situ energy minimization experiments support a model describing the conformations adapted by 9 that enable it to bind both targets. IRDye800-conjugated HtBv probe 10 demonstrated target-specific binding to either PSMA or integrin-αvβ3 overexpressing xenografts. HtBv agents 9 and 10 may enable dual-targeted imaging of malignant cells and tissues in an effort to address heterogeneity that confounds many cancer-targeted imaging agents.
PMCID: PMC4112557  PMID: 24410012
10.  Relationship Among Circulating Inflammatory Proteins, Platelet Gene Expression, and Cardiovascular Risk 
Cardiovascular disease is a complex disorder influenced by interactions of genetic variants with environmental factors. However, there is no information from large community-based studies examining the relationship of circulating cell–specific RNA to inflammatory proteins. In light of the associations among inflammatory biomarkers, obesity, platelet function, and cardiovascular disease, we sought to examine the relationships of C-reactive protein (CRP) and interleukin-6 (IL-6) to the expression of key inflammatory transcripts in platelets.
Approach and Results
We quantified circulating levels of CRP and IL-6 in 1625 participants of the Framingham Heart Study (FHS) Offspring cohort examination 8 (mean age, 66.6±6.6 years; 46% men). We measured the expression of 15 relevant genes by high-throughput quantitative reverse transcriptase polymerase chain reaction from platelet-derived RNA and used multivariable regression to relate serum concentrations of CRP and IL-6 with gene expression. Levels of CRP and IL-6 were associated with 10 of the 15 platelet-derived inflammatory transcripts, ALOX5, CRP, IFIT1, IL6, PTGER2, S100A9, SELENBP1, TLR2, TLR4, and TNFRSF1B (P<0.001). Associations between platelet mRNA expression with CRP and IL-6 persisted after multivariable adjustment for potentially confounding factors. Six genes positively associated with CRP or IL-6 in the FHS sample were also upregulated in megakaryocytes in response to CRP or IL-6 exposure.
Our data highlight the strong connection between the circulating inflammatory biomarkers CRP and IL-6 and platelet gene expression, adjusting for cardiovascular disease risk factors. Our results also suggest that body weight may directly influence these associations.
PMCID: PMC4289138  PMID: 23968978
cardiovascular disease; inflammation; mRNA platelets
11.  Climate-driven spatial mismatches between British orchards and their pollinators: increased risks of pollination deficits 
Global Change Biology  2014;20(9):2815-2828.
Understanding how climate change can affect crop-pollinator systems helps predict potential geographical mismatches between a crop and its pollinators, and therefore identify areas vulnerable to loss of pollination services. We examined the distribution of orchard species (apples, pears, plums and other top fruits) and their pollinators in Great Britain, for present and future climatic conditions projected for 2050 under the SRES A1B Emissions Scenario. We used a relative index of pollinator availability as a proxy for pollination service. At present, there is a large spatial overlap between orchards and their pollinators, but predictions for 2050 revealed that the most suitable areas for orchards corresponded to low pollinator availability. However, we found that pollinator availability may persist in areas currently used for fruit production, which are predicted to provide suboptimal environmental suitability for orchard species in the future. Our results may be used to identify mitigation options to safeguard orchard production against the risk of pollination failure in Great Britain over the next 50 years; for instance, choosing fruit tree varieties that are adapted to future climatic conditions, or boosting wild pollinators through improving landscape resources. Our approach can be readily applied to other regions and crop systems, and expanded to include different climatic scenarios.
PMCID: PMC4285753  PMID: 24638986
climate change; Maxent; perennial fruit; pollination services; range shifts; species distribution models
12.  Satisfaction with Information Used to Choose Prostate Cancer Treatment 
The Journal of urology  2013;191(5):1265-1271.
After being diagnosed with prostate cancer men must assimilate information regarding the cancer. Satisfaction with information reflects the evaluation of information sources used before treatment to select a therapy. We describe the use and helpfulness of several information sources available to prostate cancer survivors. We also identified factors associated with satisfaction with information.
Materials and Methods
A total of 1,204 men with newly diagnosed prostate cancer were enrolled in the prospective, multicenter Prostate Cancer Outcomes and Satisfaction with Therapy Quality Assessment study. The validated satisfaction with information domain of the Service Satisfaction Scale-Cancer was administered to subjects 2 months after treatment. The relationship between several factors, such as demographics, socioeconomic factors, cancer severity and types of information sources, and satisfaction with information were evaluated using multiple regression.
Sources of information endorsed by subjects varied by race, education and study site. The most helpful sources were treatment description by the treating physician (33.1%), Internet sites (18.9%) and books (18.1%). In multiple variable models patient age (p = 0.005) and information provided by the physician regarding outcomes in their patients (p = 0.01) were independently associated with patient satisfaction with the information provided.
Various information sources were used and endorsed as helpful by subjects, although results for physician patients was the only source independently associated with satisfaction with information. Providing patients with information about possible or expected courses of care and outcomes may improve satisfaction.
PMCID: PMC4283586  PMID: 24333514
prostate; prostatic neoplasms; consumer health information; consumer satisfaction; questionnaires
13.  Early Expression of Mitral Valve Prolapse in the Framingham Offspring: Phenotypic Spectrum 
Mitral valve prolapse (MVP) is a common disorder associated with mitral regurgitation (MR), endocarditis, heart failure and sudden death. In the familial context, prior studies have described non-diagnostic mitral valve morphologies (‘prodromal forms’ and ‘minimal superior displacement’ [MSD]) that may represent early expression of MVP in those genetically predisposed. Our objective was to explore the spectrum of MVP abnormalities in the community and compare their clinical and echocardiographic features.
Phenotypic heterogeneity of MVP was assessed by measuring annular diameter (D), leaflet displacement (Dis), thickness (T), anterior/posterior leaflet projections (A, P) onto the annulus, coaptation height (C or P/D), and MR jet height (JH) in a sample of 296 individuals of the Framingham Offspring Study who were identified as having MVP (n=77) or its prodromal form (N=11) or MSD (N=57), with 151 controls with no feature of MVP or its non-diagnostic forms.
The prodromal form did not meet diagnostic criteria but resembled fully diagnostic MVP with regards to D, T and JH (all p > 0.05); they were similar to individuals with posterior MVP with regard to leaflet asymmetry and coaptation height (p = 0.91). Compared to MSDs and controls, prodromals had greater C, T, D and JH (all p < 0.05). MSDs shared the posterior leaflet asymmetry with classic MVP, but their coaptation point was more posterior (C = 31% versus 42%, p<0.0001).
Non-diagnostic morphologies of MVP are observed in the community and share the common feature of posterior leaflet asymmetry with fully affected individuals. Prodromal morphology and MSD may represent early expressions of MVP and additional studies are warranted to elucidate the natural history of these phenotypes.
PMCID: PMC4239996  PMID: 24206636
mitral valve prolapse; echocardiography
14.  Relation between soluble ST2, GDF-15 and hsTnI and Incident Atrial Fibrillation 
American heart journal  2013;167(1):10.1016/j.ahj.2013.10.003.
We investigated whether circulating concentrations of soluble ST2, growth differentiation factor-15 (GDF-15), and high-sensitivity troponin I (hsTnI) are associated with incident atrial fibrillation (AF), and whether these biomarkers, improve current risk prediction models including AF risk factors, B-type natriuretic peptide (BNP) and C-reactive protein (CRP).
We studied the relation between soluble ST2, GDF-15, and hsTnI and development of AF in Framingham Heart Study participants without prevalent AF. We used Cox proportional hazard regression analysis to examine the relation of incident AF during a 10-year follow-up period with each biomarker. We adjusted for standard AF clinical risk factors, BNP, and CRP.
The mean age of the 3,217 participants was 59±10 years and 54% were women. During 10 years of follow-up, 242 participants developed AF. In age- and sex-adjusted models, GDF-15 and hsTnI were associated with risk of incident AF; however, after including the AF risk factors and BNP and CRP, only hsTnI was significantly associated with AF (hazard ratio per 1 standard deviation of loge hsTnI, 1.12; 95%CI, 1.00-1.26; P=0.045). The C-statistic of the base model including AF risk factors, BNP and CRP was 0.803 (95% CI 0.777–0.830), and did not improve by adding individual or all 3 biomarkers. None of the discrimination and reclassification statistics was significant compared to the base model.
In a community-based cohort, circulating hsTnI concentrations were associated with incident AF. None of the novel biomarkers evaluated improved AF risk discrimination or reclassification beyond standard clinical AF risk factors and biomarkers.
PMCID: PMC3884900  PMID: 24332149
atrial fibrillation; biomarker; risk factor
15.  High incidence of multiple antibiotic resistant cells in cultures of in enterohemorrhagic Escherichia coli O157:H7 
The spontaneous incidence of chloramphenicol (Cam) resistant mutant bacteria is at least ten-fold higher in cultures of enterohemorrhagic E. coli O157:H7 strain EDL933 than in E. coli K-12. It is at least 100-fold higher in the dam (DNA adenine methyltransferase) derivative of EDL933, compared to the dam strain of E. coli K-12, thereby preventing the use of Cam resistance as a marker in gene replacement technology. Genome sequencing of Cam-resistant isolates of EDL933 and its dam derivatives showed that the marR (multiple antibiotic resistance) gene was mutated in every case but not in the Cam-sensitive parental strains. As expected from mutation in the marR gene, the Cam-resistant bacteria were also found to be resistant to tetracycline and nalidixic acid. The marR gene in strain EDL933 is annotated as a shorter open reading frame than that in E. coli K-12 but the longer marR+ open reading frame was more efficient at complementing the marR antibiotic-resistance phenotype of strain EDL933. Beta-lactamase-tolerant derivatives were present at frequencies 10–100 times greater in cultures of marR derivatives of strain EDL933 than the parent strain. Spontaneous mutation frequency to rifampicin, spectinomycin and streptomycin resistance was the same in E. coli O157:H7 and E. coli K-12 strains.
PMCID: PMC3913999  PMID: 24361397
Escherichia coli O157; multiple antibiotic resistance; mutation; genes; repressor protein; DNA
16.  Burn Wound γδ T-Cells Support a Th2 and Th17 Immune Response 
Major burn triggers immune dysfunction, which is associated with wound healing complications. Gamma delta T-cells have been shown to be important in post-burn inflammation and wound healing; however their cytokine phenotype at the burn wound site is unknown.
C57BL/6 male mice were subjected to a major burn (25% TBSA, 3rd degree) or sham treatment. At 3 h, 3 days and 7 days thereafter, skin samples were collected and subjected to dispase and trypsin digestion to isolate single cells. The cells were phenotyped and evaluated for cytokine profiles by flow cytometry. Th-1 cells were defined as IFNγ positive, Th-2 cells were defined IL-10 positive and Th-17 cells were defined as IL-17 positive.
At 7 days after burn a shift towards Th-2 and Th-17 positive T-cells at the wound site was observed. Further analysis revealed that at 3 h post-injury the percentage of γδ T-cells positive for IFNγ, IL-10 and IL-17 where comparable between sham and burn skin samples. At 3 days and 7 days post-injury the percentage of cells positive for each cytokine increased; however, the increase was significantly greater for IL-10 and IL-17, as compared with IFNγ (i.e., 9-20 fold vs. 3-fold). Skin αβ T-cells preferentially produced IFNγ (~20%), which was unaffected by burn injury.
These data demonstrate that burn wound γδ T-cells are activated for enhanced cytokine production and display a shift towards a Th-2 and/or Th-17 phenotype. In contrast, burn wound αβ T-cells were not activated for enhanced cytokine production.
PMCID: PMC4098707  PMID: 24270084
Injury; Cytokines; Inflammation
17.  Prospective, Multi-Center Evaluation of the Beckman Coulter Prostate Health Index Using WHO Calibration 
The Journal of urology  2012;189(5):1702-1706.
Reported prostate-specific antigen (PSA) values may differ substantially between assays with the Hybritech and World Health Organization (WHO) standardization. [-2]proPSA (p2PSA) and the Beckman Coulter prostate health index (phi) are newly approved serum markers, which are associated with prostate cancer risk and aggressiveness. Our objective was to study the influence of assay standardization on these markers.
Materials and Methods
PSA, % free PSA (%fPSA), and p2PSA were measured using the Hybritech calibration in 892 men undergoing prostate biopsy from a prospective multicenter study. Phi was calculated as: [p2PSA/ fPSA) × (square root of PSA)]. Performance characteristics of phi for prostate cancer detection were then determined using re-calculated WHO calibration PSA values.
The median phi was significantly higher in men with prostate cancer compared to those with negative biopsies using the WHO values (47.4 vs 39.8, p<0.001). Phi offered improved discrimination of prostate cancer detection on biopsy (AUC 0.704) compared to %fPSA or total PSA using the WHO calibration.
Phi can be calculated using Hybritech or WHO standardized assays, and significantly improved the prediction of biopsy outcome over %fPSA or PSA alone.
PMCID: PMC4273580  PMID: 23206426
prostate cancer screening; proPSA; phi; prostate health index; assay
18.  Noninvasive Molecular Imaging of Tuberculosis-Associated Inflammation With Radioiodinated DPA-713 
The Journal of Infectious Diseases  2013;208(12):2067-2074.
Background. Increased expression of translocator protein (TSPO) is a feature of microglial and macrophage activation. Since activated macrophages are key components of tuberculosis-associated inflammation, we evaluated radioiodinated DPA-713, a synthetic ligand of TSPO, for in vivo imaging of host response.
Methods. Mice were infected with aerosolized Mycobacterium tuberculosis and evaluated using whole-body [125I]iodo-DPA-713 single-photon emission computed tomography (SPECT). Ex vivo biodistribution and correlative immunofluorescence studies were also performed.
Results. [125I]Iodo-DPA-713 SPECT imaging clearly delineated tuberculosis-associated pulmonary inflammation in live animals. Biodistribution studies confirmed radiotracer specificity for inflamed pulmonary tissues. Immunofluorescence studies demonstrated that TSPO is highly expressed in CD68+ macrophages and phagocytic cells within tuberculosis lesions and that [125I]DPA-713 specifically accumulates within these cells. Coadministration of excess unlabelled DPA-713 abrogated both the SPECT and ex vivo fluorescence signals. Lesion-specific signal-to-noise ratios were significantly higher with [125I]iodo-DPA-713 SPECT (4.06 ± 0.52) versus [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) (2.00 ± 0.28) performed in the same mice (P = .004).
Conclusions. [125I]Iodo-DPA-713 accumulates specifically in tuberculosis-associated inflammatory lesions by selective retention within macrophages and phagocytic cells. [125I]Iodo-DPA-713 SPECT provides higher lesion-specific signal-to-noise ratios than [18F]FDG PET and may prove to be a more specific biomarker to monitor tuberculosis in situ.
PMCID: PMC3836460  PMID: 23901092
translocator protein; molecular imaging; tuberculosis; PET; pyrazolopyrimidine; macrophage
19.  Leptin and IL-6 Family Cytokines Synergize to Stimulate Müller Glia Reprogramming and Retina Regeneration 
Cell reports  2014;9(1):272-284.
Unlike mammals, zebrafish can regenerate a damaged retina. This remarkable regenerative response is mediated by Müller glia (MG) that undergo a reprogramming event that drives their proliferation and the generation of multipotent progenitors for retinal repair. The mechanisms driving MG reprogramming are poorly understood. Here we report that Leptin and Gp130-coupled receptors, acting via a Jak/Stat signaling pathway, stimulate MG reprogramming and progenitor formation in the injured retina. Importantly, we found that ascl1a gene expression, which drives MG reprogramming in fish and mammals, is regulated in a Jak/Stat-dependent manner and requires consensus Stat binding sites for injury-dependent activation. Finally, we identified cytokines that are induced by retinal injury and exhibit a remarkable synergy in their ability to activate Jak/Stat signaling and MG reprogramming in the uninjured retina. Our study not only furthers our understanding of retina regeneration in zebrafish, but also suggests new strategies for awakening retina regeneration in mammals.
PMCID: PMC4194149  PMID: 25263554
20.  Where does the carbon go? A model–data intercomparison of vegetation carbon allocation and turnover processes at two temperate forest free-air CO2 enrichment sites 
The New Phytologist  2014;203(3):883-899.
Elevated atmospheric CO2 concentration (eCO2) has the potential to increase vegetation carbon storage if increased net primary production causes increased long-lived biomass. Model predictions of eCO2 effects on vegetation carbon storage depend on how allocation and turnover processes are represented.We used data from two temperate forest free-air CO2 enrichment (FACE) experiments to evaluate representations of allocation and turnover in 11 ecosystem models.Observed eCO2 effects on allocation were dynamic. Allocation schemes based on functional relationships among biomass fractions that vary with resource availability were best able to capture the general features of the observations. Allocation schemes based on constant fractions or resource limitations performed less well, with some models having unintended outcomes. Few models represent turnover processes mechanistically and there was wide variation in predictions of tissue lifespan. Consequently, models did not perform well at predicting eCO2 effects on vegetation carbon storage.Our recommendations to reduce uncertainty include: use of allocation schemes constrained by biomass fractions; careful testing of allocation schemes; and synthesis of allocation and turnover data in terms of model parameters. Data from intensively studied ecosystem manipulation experiments are invaluable for constraining models and we recommend that such experiments should attempt to fully quantify carbon, water and nutrient budgets.
PMCID: PMC4260117  PMID: 24844873
allocation; carbon (C); climate change; CO2 fertilisation; elevated CO2; free-air CO2 enrichment (FACE); models; phenology
21.  Intimal hyperplasia following implantation of helical-centreline and straight-centreline stents in common carotid arteries in healthy pigs: influence of intraluminal flow† 
Intimal hyperplasia (IH) is a leading cause of obstruction of vascular interventions, including arterial stents, bypass grafts and arteriovenous grafts and fistulae. Proposals to account for arterial stent-associated IH include wall damage, low wall shear stress (WSS), disturbed flow and, although not widely recognized, wall hypoxia. The common non-planarity of arterial geometry and flow, led us to develop a bare-metal, nitinol, self-expanding stent with three-dimensional helical-centreline geometry. This was deployed in one common carotid artery of healthy pigs, with a straight-centreline, but otherwise identical (conventional) stent deployed contralaterally. Both stent types deformed the arteries, but the helical-centreline device additionally deformed them helically and caused swirling of intraluminal flow. At sacrifice, one month post stent deployment, histology revealed significantly less IH in the helical-centreline than straight-centreline stented vessels. Medial cross-sectional area was not significantly different in helical-centreline than straight-centreline stented vessels. By contrast, luminal cross-sectional area was significantly larger in helical-centreline than straight-centreline stented vessels. Mechanisms considered to account for those results include enhanced intraluminal WSS and enhanced intraluminal blood–vessel wall mass transport, including of oxygen, in the helical-centreline stented vessels. Consistent with the latter proposal, adventitial microvessel density was lower in the helical-centreline stented than straight-centreline stented vessels.
PMCID: PMC3808545  PMID: 24132200
helical-centreline arterial stent; swirling intraluminal blood flow; intimal hyperplasia; vessel wall hypoxia; wall shear stress; blood–wall oxygen transport
22.  Leptin Mediates the Increase in Blood Pressure Associated with Obesity 
Cell  2014;159(6):1404-1416.
Obesity is associated with increased blood pressure (BP), which in turn increases the risk of cardiovascular diseases. We found that the increase in leptin levels seen in diet-induced obesity (DIO) drives an increase in BP in rodents, an effect that was not seen in animals deficient in leptin or leptin receptors (LepR). Furthermore, humans with loss-of-function mutations in leptin and the LepR have low BP despite severe obesity. Leptin’s effects on BP are mediated by neuronal circuits in the dorsomedial hypothalamus (DMH), as blocking leptin with a specific antibody, antagonist, or inhibition of the activity of LepR-expressing neurons in the DMH caused a rapid reduction of BP in DIO mice, independent of changes in weight. Re-expression of LepRs in the DMH of DIO LepR-deficient mice caused an increase in BP. These studies demonstrate that leptin couples changes in weight to changes in BP in mammalian species.
Graphical Abstract
•Leptin is the link between obesity and increased blood pressure•Leptin acts through the dorsomedial hypothalamus to increase blood pressure•Blockade of leptin signaling reduces blood pressure in obese mice•Humans with defects in leptin signaling are protected from obesity hypertension
Leptin is found to be the link between obesity and increased blood pressure. Blocking leptin action reduces blood pressure in obese mice with clinical studies in humans, suggesting that defects in leptin signaling may protect against hypertension associated with obesity.
PMCID: PMC4259491  PMID: 25480301
23.  A Parabrachial-Hypothalamic Cholecystokinin Neurocircuit Controls Counterregulatory Responses to Hypoglycemia 
Cell Metabolism  2014;20(6):1030-1037.
Hypoglycemia engenders an autonomically mediated counterregulatory (CR)-response that stimulates endogenous glucose production to maintain concentrations within an appropriate physiological range. Although the involvement of the brain in preserving normoglycemia has been established, the neurocircuitry underlying centrally mediated CR-responses remains unclear. Here we demonstrate that lateral parabrachial nucleus cholecystokinin (CCKLPBN) neurons are a population of glucose-sensing cells (glucose inhibited) with counterregulatory capacity. Furthermore, we reveal that steroidogenic-factor 1 (SF1)-expressing neurons of the ventromedial nucleus of the hypothalamus (SF1VMH) are the specific target of CCKLPBN glucoregulatory neurons. This discrete CCKLPBN→SF1VMH neurocircuit is both necessary and sufficient for the induction of CR-responses. Together, these data identify CCKLPBN neurons, and specifically CCK neuropeptide, as glucoregulatory and provide significant insight into the homeostatic mechanisms controlling CR-responses to hypoglycemia.
Graphical Abstract
•CCKLPBN neurons are glucose inhibited and activated by hypoglycemia•CCKLPBN neurons are necessary and sufficient for counterregulatory (CR)-responses•CCK neuropeptide is the key mediator of CCKLPBN neuron-mediated CR-responses•CCKLPBN neuron-induced CR-responses require downstream SF1VMH neurons
The counterregulatory response (CRR) to hypoglycemia is critical for the maintenance of normoglycemia and governed by the brain. Garfield et al. identify a population of brainstem CCK neurons that directly sense extracellular glucose concentrations and, via their connection to SF1 hypothalamic neurons, promote CRR.
PMCID: PMC4261079  PMID: 25470549
24.  Neoadjuvant androgen deprivation therapy (NADT) Leads to Immediate Impairment of Vitality/ Hormonal and Sexual Quality of Life: Results of a Multi-Center, Prospective Study 
Urology  2013;82(6):1363-1368.
To evaluate the immediate effects of neoadjuvant androgen depravation therapy (NADT) on health-related quality of life (HRQOL) among patients undergoing RT for newly diagnosed prostate cancer.
The Prostate Cancer Outcomes and Satisfaction with Treatment Quality Assessment (PROST-QA) Consortium is a prospective, multi-institutional study. HRQOL is measured with the EPIC-26 questionnaire. Differences in patient reported HRQOL were observed between pre-treatment and 2 months after NADT start (and before definitive RT) with significant differences evaluated by paired t-test.
From among 450 subjects who completed the EPIC-26 before and 2-months after NADT start, 71 received NADT prior to proceeding with definitive RT. Patients receiving NADT experienced significant impairment in vitality/hormonal (p<0.0001) and sexual (p<0.0001) HRQOL after NADT initiation. The mean ± standard deviation vitality/hormonal score fell from an average of 94.1 ± 9.7 before NADT to 78.7 ± 16.3 two months after NADT initiation; and sexual HRQOL fell from a mean of 51.7 ± 31.1 pre-treatment to 32.3 ± 26.1 after NADT initiation. Both of these HRQOL domain changes exceeded the thresholds for clinical significance. Patients receiving NADT also experienced a significant impairment in urinary continence (p=0.024), although this difference did not meet criteria for clinical significance.
In this analysis, patients receiving NADT experience significant impairment in sexual and vitality/hormonal HRQOL even before starting definitive radiation therapy. The significant impact of this therapy on HRQOL needs to be considered before initiating NADT in men where there is no clear evidence of clinical benefit.
PMCID: PMC3904352  PMID: 24139340
PROST-QA; neoadjuvant androgen deprivation therapy; quality of life; radiotherapy; prostate cancer
25.  Impact of Ventilatory Modes on the Breathing Variability in Mechanically Ventilated Infants 
Objectives: Reduction of breathing variability is associated with adverse outcome. During mechanical ventilation, the variability of ventilatory pressure is dependent on the ventilatory mode. During neurally adjusted ventilatory assist (NAVA), the support is proportional to electrical activity of the diaphragm (EAdi), which reflects the respiratory center output. The variability of EAdi is, therefore, translated into a similar variability in pressures. Contrastingly, conventional ventilatory modes deliver less variable pressures. The impact of the mode on the patient’s own respiratory drive is less clear. This study aims to compare the impact of NAVA, pressure-controlled ventilation (PCV), and pressure support ventilation (PSV) on the respiratory drive patterns in infants. We hypothesized that on NAVA, EAdi variability resembles most of the endogenous respiratory drive pattern seen in a control group.
Methods: Electrical activity of the diaphragm was continuously recorded in 10 infants ventilated successively on NAVA (5 h), PCV (30 min), and PSV (30 min). During the last 10 min of each period, the EAdi variability pattern was assessed using non-rhythmic to rhythmic (NRR) index. These variability profiles were compared to the pattern of a control group of 11 spontaneously breathing and non-intubated infants.
Results: In control infants, NRR was higher as compared to mechanically ventilated infants (p < 0.001), and NRR pattern was relatively stable over time. While the temporal stability of NRR was similar in NAVA and controls, the NRR profile was less stable during PCV. PSV exhibited an intermediary pattern.
Perspectives: Mechanical ventilation impacts the breathing variability in infants. NAVA produces EAdi pattern resembling most that of control infants. NRR can be used to characterize respiratory variability in infants. Larger prospective studies are necessary to understand the differential impact of the ventilatory modes on the cardio-respiratory variability and to study their impact on clinical outcomes.
PMCID: PMC4242927  PMID: 25505779
pediatric intensive care; mechanical ventilation; neurally adjusted ventilatory support; diaphragm; children

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