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1.  New insights into heterogeneity of peritoneal B-1a cells 
Peritoneal B-1a cells are characterized by their expression of CD5 and enrichment for germ line–encoded IgM B cell receptors (BCRs). Early studies showing expression of a diverse array of VDJ sequences among purified B-1a cells provided a molecular basis for understanding the heterogeneity of the B-1a cell repertoire. Antigen-driven positive selection and the identification of B-1a specific progenitors suggest multiple origins of B-1a cells. The introduction of new markers such as PD-L2, CD25, CD73, and PC1 (plasma cell alloantigen 1, also known as ectonucleotide phosphodiesterase/pyrophosphatase 1 (ENPP1)) further helped to identify phenotypically and functionally distinct B-1a subsets. Among many B-1a subsets defined by these new markers, PC1 is unique in that it subdivides B-1a cells into PC1hi and PC1lo subpopulations with distinct functions, such as production of natural IgM and gut IgA, response to the pneumococcal antigen PPS-3, secretion of interleukin (IL)-10, and support for T helper 1 (TH1) cell differentiation. RNA sequencing (RNA-seq) of these subsets revealed differential expression of genes involved in cellular movement and immune cell trafficking. We will discuss these new insights underlying the heterogeneous nature of the B-1a cell repertoire.
PMCID: PMC4651667  PMID: 25988856
B-1a; PC1; IL-10; lymphocyte trafficking
2.  Vascular Inflammation in a Growing Iliac Artery Aneurysm 
Clinical nuclear medicine  2015;40(6):e323-e324.
We have used a multimodality imaging approach to assess the inflammatory component of a growing iliac artery aneurysm in a 53-year-old man who presented with related ureteral obstruction. Research suggests that episodic and heterogeneous inflammatory processes are important for the progression of aneurysms. The combined PET and MRI evaluation of inflammation that we present here is a novel approach to vascular imaging that is well suited for emerging hybrid PET/MRI systems.
PMCID: PMC5127266  PMID: 25674872
vascular inflammation; aneurysm; PET/MRI; macrophage imaging
3.  Top 100 cited articles in cardiovascular magnetic resonance: a bibliometric analysis 
With limited health care resources, bibliometric studies can help guide researchers and research funding agencies towards areas where reallocation or increase in research activity is warranted. Bibliometric analyses have been published in many specialties and sub-specialties but our literature search did not reveal a bibliometric analysis on Cardiovascular Magnetic Resonance (CMR). The main objective of the study was to identify the trends of the top 100 cited articles on CMR research.
Web of Science (WOS) search was used to create a database of all English language scientific journals. This search was then cross-referenced with a similar search term query of Scopus® to identify articles that may have been missed on the initial search. Articles were ranked by citation count and screened by two independent reviewers.
Citations for the top 100 articles ranged from 178 to 1925 with a median of 319.5. Only 17 articles were cited more than 500 times, and the vast majority (n = 72) were cited between 200–499 times. More than half of the articles (n = 52) were from the United States of America, and more than one quarter (n = 21) from the United Kingdom. More than four fifth (n = 86) of the articles were published between the time period 2000–2014 with only 1 article published before 1990. Circulation and Journal of the American College of Cardiology made up more than half (n = 62) of the list. We found 10 authors who had greater than 5 publications in the list.
Our study provides an insight on the characteristics and quality of the most highly cited CMR literature, and a list of the most influential references related to CMR.
Electronic supplementary material
The online version of this article (doi:10.1186/s12968-016-0303-9) contains supplementary material, which is available to authorized users.
PMCID: PMC5116819  PMID: 27866473
Bibliometrics; Cardiac; MRI; Web of Science; Scopus
4.  Relationship between native papillary muscle T1 time and severity of functional mitral regurgitation in patients with non-ischemic dilated cardiomyopathy 
Functional mitral regurgitation is one of the severe complications of non-ischemic dilated cardiomyopathy (DCM). Non-contrast native T1 mapping has emerged as a non-invasive method to evaluate myocardial fibrosis. We sought to evaluate the potential relationship between papillary muscle T1 time and mitral regurgitation in DCM patients.
Forty DCM patients (55 ± 13 years) and 20 healthy adult control subjects (54 ± 13 years) were studied. Native T1 mapping was performed using a slice interleaved T1 mapping sequence (STONE) which enables acquisition of 5 slices in the short-axis plane within a 90 s free-breathing scan. We measured papillary muscle diameter, length and shortening. DCM patients were allocated into 2 groups based on the presence or absence of functional mitral regurgitation.
Papillary muscle T1 time was significantly elevated in DCM patients with mitral regurgitation (n = 22) in comparison to those without mitral regurgitation (n = 18) (anterior papillary muscle: 1127 ± 36 msec vs 1063 ± 16 msec, p < 0.05; posterior papillary muscle: 1124 ± 30 msec vs 1062 ± 19 msec, p < 0.05), but LV T1 time was similar (1129 ± 38 msec vs 1134 ± 58 msec, p = 0.93). Multivariate linear regression analysis showed that papillary muscle native T1 time (β = 0.10, 95 % CI: 0.05–0.17, p < 0.05) is significantly correlated with mitral regurgitant fraction. Elevated papillary muscle T1 time was associated with larger diameter, longer length and decreased papillary muscle shortening (all p values <0.05).
In DCM, papillary muscle native T1 time is significantly elevated and related to mitral regurgitant fraction.
PMCID: PMC5111188  PMID: 27846845
5.  BACH2 regulates CD8+ T cell differentiation by controlling access of AP-1 factors to enhancers 
Nature immunology  2016;17(7):851-860.
T cell antigen receptor (TCR) signaling drives distinct responses depending upon the differentiation state and context of CD8+ T cells. We hypothesized that access of signal-dependent transcription factors (TFs) to enhancers is dynamically regulated to shape transcriptional responses to TCR signaling. We found that the TF BACH2 restrains terminal differentiation to enable generation of long-lived memory cells and protective immunity following viral infection. BACH2 was recruited to enhancers where it limited expression of TCR-driven genes by attenuating the availability of activator protein 1 (AP-1) sites to Jun family signal-dependent TFs. In naïve cells, this prevented TCR-driven induction of genes associated with terminal differentiation. Upon effector differentiation, reduced expression of BACH2 and its phosphorylation enabled unrestrained induction of TCR-driven effector programs.
PMCID: PMC4918801  PMID: 27158840
6.  Culprit lesion thrombus burden after manual thrombectomy or percutaneous coronary intervention-alone in ST-segment elevation myocardial infarction: the optical coherence tomography sub-study of the TOTAL (ThrOmbecTomy versus PCI ALone) trial 
European heart journal  2015;36(29):1892-1900.
Manual thrombectomy has been proposed as a strategy to reduce thrombus burden during primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI). However, the effectiveness of manual thrombectomy in reducing thrombus burden is uncertain. In this substudy of the TOTAL (ThrOmbecTomy versus PCI ALone) trial, we compared the thrombus burden at the culprit lesion using optical coherence tomography (OCT) in patients treated with thrombectomy vs. PCI-alone.
Methods and results
The TOTAL trial (N = 10 732) was an international, multicentre, randomized trial of thrombectomy (using the Export catheter, Medtronic Cardiovascular, Santa Rosa, CA, USA) in STEMI patients treated with primary PCI. The OCT sub-study prospectively enrolled 214 patients from 13 sites in 5 countries. Optical coherence tomography was performed immediately after thrombectomy or PCI-alone and then repeated after stent deployment. Thrombus quantification was performed by an independent core laboratory blinded to treatment assignment. The primary outcome of pre-stent thrombus burden as a percentage of segment analysed was 2.36% (95% CI: 1.73–3.22) in the thrombectomy group and 2.88% (95% CI: 2.12–3.90) in the PCI-alone group (P = 0.373). Absolute pre-stent thrombus volume was not different (2.99 vs. 3.74 mm3, P = 0.329). Other secondary outcomes of pre-stent quadrants of thrombus, post–stent atherothrombotic burden, and post-stent atherothrombotic volume were not different between groups.
Manual thrombectomy did not reduce pre-stent thrombus burden at the culprit lesion compared with PCI-alone. Both strategies were associated with low thrombus burden at the lesion site after the initial intervention to restore flow.
PMCID: PMC5061563  PMID: 25994742 CAMSID: cams5777
Myocardial infarction; STEMI; Optical coherence tomography; Thrombectomy; Thrombus
7.  Statistical Design Features of the Healthy Communities Study 
The Healthy Communities Study is designed to assess relationships between characteristics of community programs and policies targeting childhood obesity and children’s BMI, diet, and physical activity. The study involved a complex data collection protocol implemented over a 2-year period (2013–2015) across a diverse sample of up to 125 communities, defined as public high school catchment areas. The protocol involved baseline assessment within each community that included in-person or telephone interviews regarding community programs and policies and in-home collection of BMI, nutritional, and physical activity outcomes from a sample of up to 81 children enrolled in kindergarten through eighth grade in public schools. The protocol also involved medical record reviews to establish a longitudinal trajectory of BMI for an estimated 70% of participating children. Staged sampling was used to collect less detailed measures of physical activity and nutrition across the entire sample of children, with a subset assessed using more costly, burdensome, and detailed measures. Data from the Healthy Community Study will be analyzed using both cross-sectional and longitudinal models that account for the complex design and correct for measurement error and bias using a likelihood-based Markov chain Monte Carlo methodology. This methods paper provides insights into the complex design features of the Healthy Communities Study and may serve as an example for future large-scale studies that assess the relationship between community-based programs and policies and health outcomes of community residents.
PMCID: PMC4575768  PMID: 26384932
8.  Left Atrial Late Gadolinium Enhancement with Water-Fat Separation: the Importance of Phase-encoding Order 
To compare two late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) methods: a Dixon LGE sequence with sequential phase-encoding order, reconstructed using water-fat separation, and standard fat-saturated LGE.
Materials and Methods
We have implemented a dual-echo Dixon LGE method for reconstructing water-only images, and compared it to fat-saturated LGE in twelve patients prior to their first pulmonary vein isolation (PVI) procedure. Images were analyzed for quality and fat-suppression. Regions of the left atrium were evaluated by a blinded observer (1=prominent enhancement, 0=mild or absent enhancement) on two sets of images (fat-saturated and water-only LGE), and agreement was assessed.
Water-only LGE showed a trend toward better fat-suppression (p=0.06), with a significantly more homogeneous blood pool signal and reduced inflow artifacts (both p<0.01). Agreement between fat-saturated LGE and water-only methods was found in 84% of regions, significantly correlated by chi-squared test (p<0.001). The kappa value was 0.52 (moderate). The average number of enhancing segments was higher for fat-saturated LGE than water-only LGE (4.2 ±2.7 vs. 3.2±2.9, p=0.03).
The two-point Dixon LGE technique reduces artifacts due to a centric k-space order. A similar enhancement pattern was observed irrespective of the LGE technique, with more enhancement detected by fat-saturated LGE.
PMCID: PMC5036388  PMID: 24105717
Late gadolinium enhancement; Dixon; atrial fibrillation; delayed enhancement; pulmonary vein isolation; fat-water separation; left atrium
9.  Impact of school-based vegetable garden and physical activity coordinated health interventions on weight status and weight-related behaviors of ethnically diverse, low-income students: Study design and baseline data of the Texas, Grow! Eat! Go! (TGEG) cluster-randomized controlled trial 
BMC Public Health  2016;16(1):973.
Coordinated, multi-component school-based interventions can improve health behaviors in children, as well as parents, and impact the weight status of students. By leveraging a unique collaboration between Texas AgriLife Extension (a federal, state and county funded educational outreach organization) and the University of Texas School of Public Health, the Texas Grow! Eat! Go! Study (TGEG) modeled the effectiveness of utilizing existing programs and volunteer infrastructure to disseminate an enhanced Coordinated School Health program. The five-year TGEG study was developed to assess the independent and combined impact of gardening, nutrition and physical activity intervention(s) on the prevalence of healthy eating, physical activity and weight status among low-income elementary students. The purpose of this paper is to report on study design, baseline characteristics, intervention approaches, data collection and baseline data.
The study design for the TGEG study consisted of a factorial group randomized controlled trial (RCT) in which 28 schools were randomly assigned to one of 4 treatment groups: (1) Coordinated Approach to Child Health (CATCH) only (Comparison), (2) CATCH plus school garden intervention [Learn, Grow, Eat & Go! (LGEG)], (3) CATCH plus physical activity intervention [Walk Across Texas (WAT)], and (4) CATCH plus LGEG plus WAT (Combined). The outcome variables include student’s weight status, vegetable and sugar sweetened beverage consumption, physical activity, and sedentary behavior. Parents were assessed for home environmental variables including availability of certain foods, social support of student health behaviors, parent engagement and behavior modeling.
Descriptive data are presented for students (n = 1369) and parents (n = 1206) at baseline. The sample consisted primarily of Hispanic and African American (53 % and 18 %, respectively) and low-income (i.e., 78 % eligible for Free and Reduced Price School Meals program and 43 % food insecure) students. On average, students did not meet national guidelines for vegetable consumption or physical activity. At baseline, no statistical differences for demographic or key outcome variables among the 4 treatment groups were observed.
The TGEG study targets a population of students and parents at high risk of obesity and related chronic conditions, utilizing a novel and collaborative approach to program formulation and delivery, and a rigorous, randomized study design.
PMCID: PMC5022204  PMID: 27624139
School garden intervention; Physical activity intervention; JMG; LGEG; WAT; Randomized controlled trial; Low-income children; Hispanic; African American
10.  Outcomes after thrombus aspiration for ST elevation myocardial infarction: 1-year follow-up of the prospective randomised TOTAL trial 
Lancet (London, England)  2015;387(10014):127-135.
Two large trials have reported contradictory results at 1 year after thrombus aspiration in ST elevation myocardial infarction (STEMI). In a 1-year follow-up of the largest randomised trial of thrombus aspiration, we aimed to clarify the longer-term benefits, to help guide clinical practice.
The trial of routine aspiration ThrOmbecTomy with PCI versus PCI ALone in Patients with STEMI (TOTAL) was a prospective, randomised, investigator-initiated trial of routine manual thrombectomy versus percutaneous coronary intervention (PCI) alone in 10 732 patients with STEMI. Eligible adult patients (aged ≥18 years) from 87 hospitals in 20 countries were enrolled and randomly assigned (1:1) within 12 h of symptom onset to receive routine manual thrombectomy with PCI or PCI alone. Permuted block randomisation (with variable block size) was done by a 24 h computerised central system, and was stratified by centre. Participants and investigators were not masked to treatment assignment. The trial did not show a difference at 180 days in the primary outcome of cardiovascular death, myocardial infarction, cardiogenic shock, or heart failure. However, the results showed improvements in the surrogate outcomes of ST segment resolution and distal embolisation, but whether or not this finding would translate into a longer term benefit remained unclear. In this longer-term follow-up of the TOTAL study, we report the results on the primary outcome (cardiovascular death, myocardial infarction, cardiogenic shock, or heart failure) and secondary outcomes at 1 year. Analyses of the primary outcome were by modified intention to treat and only included patients who underwent index PCI. This trial is registered with, number NCT01149044.
Between Aug 5, 2010, and July 25, 2014, 10 732 eligible patients were enrolled and randomly assigned to thrombectomy followed by PCI (n=5372) or to PCI alone (n=5360). After exclusions of patients who did not undergo PCI in each group (337 in the PCI and thrombectomy group and 331 in the PCI alone group), the final study population comprised 10 064 patients (5035 thrombectomy and 5029 PCI alone). The primary outcome at 1 year occurred in 395 (8%) of 5035 patients in the thrombectomy group compared with 394 (8%) of 5029 in the PCI alone group (hazard ratio [HR] 1·00 [95% CI 0·87–1·15], p=0·99). Cardiovascular death within 1 year occurred in 179 (4%) of the thrombectomy group and in 192 (4%) of 5029 in the PCI alone group (HR 0·93 [95% CI 0·76–1·14], p=0·48). The key safety outcome, stroke within 1 year, occurred in 60 patients (1·2%) in the thrombectomy group compared with 36 (0·7%) in the PCI alone group (HR 1·66 [95% CI 1·10–2·51], p=0·015).
Routine thrombus aspiration during PCI for STEMI did not reduce longer-term clinical outcomes and might be associated with an increase in stroke. As a result, thrombus aspiration can no longer be recommended as a routine strategy in STEMI.
PMCID: PMC5007127  PMID: 26474811 CAMSID: cams5775
11.  Randomized Trial of Primary PCI with or without Routine Manual Thrombectomy 
The New England journal of medicine  2015;372(15):1389-1398.
During primary percutaneous coronary intervention (PCI), manual thrombectomy may reduce distal embolization and thus improve microvascular perfusion. Small trials have suggested that thrombectomy improves surrogate and clinical outcomes, but a larger trial has reported conflicting results.
We randomly assigned 10,732 patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI to a strategy of routine upfront manual thrombectomy versus PCI alone. The primary outcome was a composite of death from cardiovascular causes, recurrent myocardial infarction, cardiogenic shock, or New York Heart Association (NYHA) class IV heart failure within 180 days. The key safety outcome was stroke within 30 days.
The primary outcome occurred in 347 of 5033 patients (6.9%) in the thrombectomy group versus 351 of 5030 patients (7.0%) in the PCI-alone group (hazard ratio in the thrombectomy group, 0.99; 95% confidence interval [CI], 0.85 to 1.15; P = 0.86). The rates of cardiovascular death (3.1% with thrombectomy vs. 3.5% with PCI alone; hazard ratio, 0.90; 95% CI, 0.73 to 1.12; P = 0.34) and the primary outcome plus stent thrombosis or target-vessel revascularization (9.9% vs. 9.8%; hazard ratio, 1.00; 95% CI, 0.89 to 1.14; P = 0.95) were also similar. Stroke within 30 days occurred in 33 patients (0.7%) in the thrombectomy group versus 16 patients (0.3%) in the PCI-alone group (hazard ratio, 2.06; 95% CI, 1.13 to 3.75; P = 0.02).
In patients with STEMI who were undergoing primary PCI, routine manual thrombectomy, as compared with PCI alone, did not reduce the risk of cardiovascular death, recurrent myocardial infarction, cardiogenic shock, or NYHA class IV heart failure within 180 days but was associated with an increased rate of stroke within 30 days. (Funded by Medtronic and the Canadian Institutes of Health Research; TOTAL number, NCT01149044.)
PMCID: PMC4995102  PMID: 25853743 CAMSID: cams5774
12.  Molecular Models of STAT5A Tetramers Complexed to DNA Predict Relative Genome-Wide Frequencies of the Spacing between the Two Dimer Binding Motifs of the Tetramer Binding Sites 
PLoS ONE  2016;11(8):e0160339.
STAT proteins bind DNA as dimers and tetramers to control cellular development, differentiation, survival, and expansion. The tetramer binding sites are comprised of two dimer-binding sites repeated in tandem. The genome-wide distribution of the spacings between the dimer binding sites shows a distinctive, non-random pattern. Here, we report on estimating the feasibility of building possible molecular models of STAT5A tetramers bound to a DNA double helix with all possible spacings between the dimer binding sites. We found that the calculated feasibility estimates correlated well with the experimentally measured frequency of tetramer-binding sites. This suggests that the feasibility of forming the tetramer complex was a major factor in the evolution of this DNA sequence variation.
PMCID: PMC4990345  PMID: 27537504
13.  Interleukin-21 signaling in B cells, but not in T cells, is indispensable for the development of collagen-induced arthritis in mice 
Interleukin-21 (IL-21) is a T-cell-derived cytokine whose receptor is expressed on a variety of cells and therefore might have pleiotropic roles in the pathogenesis of rheumatoid arthritis (RA). In this study, we investigated the involvement of IL-21 signaling in the development of collagen-induced arthritis (CIA), an animal model of RA, using IL-21 receptor knockout (Il21r KO) mice.
Il21r KO mice or wild-type (WT) C57BL/6 mice were immunized with chicken type II collagen (CII) emulsified in complete Freund adjuvant on day 0 and were given a boost injection on day 21. The production of anti-CII antibody, development of T-cell and B-cell subsets, and T-cell responses to CII were analyzed. CIA was induced in Rag2 KO mice to which combinations of WT or Il21r KO CD4 T cells and WT or Il21r KO B cells had been transferred, in order to examine the role of IL-21 signaling in each cell subset.
Il21r KO mice were resistant to the development of CIA. CII-specific IgG but not IgM production was impaired in Il21r KO mice. This is consistent with a reduction of germinal center B cells in the draining lymph nodes. In contrast, CII-specific Th1 and Th17 responses were unaffected in Il21r KO mice. There was also no difference in the number of CII-specific follicular helper T cells between WT and Il21r KO mice. By analyzing the development of CIA in T-cell and B-cell mixed transfer experiments, we confirmed that IL-21 receptor expression on B cells, but not on T cells, was essential for the development of CIA.
IL-21 signaling in B cells, but not in T cells, plays essential roles in the production of pathogenic autoantibodies that induce CIA development.
PMCID: PMC4989522  PMID: 27535236
Interleukin-21; Collagen-induced arthritis; Rheumatoid arthritis; Cytokine; B cell
14.  In-hospital measurement of left ventricular ejection fraction and one-year outcomes in acute coronary syndromes: results from the IMMEDIATE Trial 
In patients with acute coronary syndrome (ACS), reduced left ventricular ejection fraction (LVEF) is a known marker for increased mortality. However, the relationship between LVEF measured during index ACS hospitalization and mortality and heart failure (HF) within 1 year are less well-defined.
We performed a retrospective analysis of 445 participants in the IMMEDIATE Trial who had LVEF measured by left ventriculography or echocardiogram during hospitalization.
Adjusting for age and coronary artery disease (CAD) history, lower LVEF was significantly associated with 1-year mortality or hospitalization for HF. For every 5 % LVEF reduction, the hazard ratio [HR] was 1.26 (95 % CI 1.15, 1.38, P < 0.001). Participants with LVEF < 40 % had higher hazard of 1-year mortality or HF hospitalization than those with LVEF > 40 (HR 3.59; 95 % CI 2.05, 6.27, P < 0.001). The HRs for the association of LVEF with the study outcomes were similar whether measured by left ventriculography or by echocardiography, (respectively, HR 1.32; 95 % CI 1.15, 1.51 and 1.21; 95 % CI 1.106, 1.35, interaction P = 0.32) and whether done within 24 h or not within 24 h (respectively, HR 1.28; 95 % CI 1.10, 1.50 and 1.23; 95 % CI 1.10, 1.38, interaction P = 0.67).
Among patients with ACS, lower in-hospital LVEF is associated with increased 1-year mortality or hospitalization for HF, regardless of the method or timing of the LVEF assessment. This has prognostic implications for clinical practice and suggests the possibility of using various methods of LVEF determination in clinical research.
PMCID: PMC4973066  PMID: 27488569
Acute coronary syndromes; Glucose-insulin-potassium; Left ventricular ejection fraction; Death; Hospitalization from heart failure
15.  Nuclear Spin Hyperpolarization of the Solvent Using Signal Amplification by Reversible Exchange (SABRE) 
Here we report the polarization of the solvent OH protons by SABRE using standard iridium-based catalysts under slightly acidic conditions. Solvent polarization was observed in the presence of a variety of structurally similar N-donor substrates while no solvent enhancement was observed in the absence of substrate or para-hydrogen (p-H2). Solvent polarization was sensitive to the polarizing field and catalyst:substrate ratio in a manner similar to that of substrate protons. SABRE experiments with pyridine-d5 suggest a mechanism where hyperpolarization is transferred from the free substrate to the solvent by chemical exchange while measured hyperpolaization decay times suggest a complimentary mechanism which occurs by direct coordination of the solvent to the catalytic complex. We found the solvent hyperpolarization to decay nearly 3 times more slowly than its characteristic spin-lattice relaxation time suggesting that the hyperpolarized state of the solvent may be sufficiently long lived (~20 s) to hyperpolarize biomolecules having exchangeable protons. This route may offer future opportunities for SABRE to impact metabolic imaging.
Graphical Abstract
PMCID: PMC4501889  PMID: 26037136
hyperpolarization; SABRE; solvent enhancement; iridium catalyst; MR imaging; chemical exchange
16.  Service-learning’s Impact on Dental Students’ Attitude toward Community Service 
This study evaluated service-learning program’s impact on senior dental students’ attitude toward community service at Virginia Commonwealth University (VCU) School of Dentistry. Experience gained through service-learning in dental school may positively impact dental students’ attitude toward community service that will eventually lead into providing care to the underserved.
Materials and methods
Two surveys (pre and post-test) were administered to 105 senior dental students. For the first survey (post-test), seventy six students out of 105 responded and reported their attitude toward community service immediately after the service-learning program completion. Three weeks later, fifty six students out of the 76 responded to the second survey (retrospective pre-test) and reported their recalled attitude prior to the program retrospectively.
A repeated-measure mixed-model analysis indicated that overall there was improvement between pre-test and post-test. Scales of connectedness, normative helping behavior, benefits1, career benefits, and intention showed a significant pre-test and post-test difference. An association between attitude toward community service and student characteristics such as age, gender, ethnicity, and volunteer activity was also examined. Only ethnicity showed an overall significant difference. White dental students appear to have a differing perception of the costs of community service.
The service-learning program at VCU School of Dentistry has positively impacted senior dental students’ attitude toward community service.
PMCID: PMC4336626  PMID: 25142286
Service-learning; attitude; community-based dental education
17.  The BioHub Knowledge Base: Ontology and Repository for Sustainable Biosourcing 
The motivation for the BioHub project is to create an Integrated Knowledge Management System (IKMS) that will enable chemists to source ingredients from bio-renewables, rather than from non-sustainable sources such as fossil oil and its derivatives.
The BioHubKB is the data repository of the IKMS; it employs Semantic Web technologies, especially OWL, to host data about chemical transformations, bio-renewable feedstocks, co-product streams and their chemical components. Access to this knowledge base is provided to other modules within the IKMS through a set of RESTful web services, driven by SPARQL queries to a Sesame back-end. The BioHubKB re-uses several bio-ontologies and bespoke extensions, primarily for chemical feedstocks and products, to form its knowledge organisation schema.
Parts of plants form feedstocks, while various processes generate co-product streams that contain certain chemicals. Both chemicals and transformations are associated with certain qualities, which the BioHubKB also attempts to capture. Of immediate commercial and industrial importance is to estimate the cost of particular sets of chemical transformations (leading to candidate surfactants) performed in sequence, and these costs too are captured. Data are sourced from companies’ internal knowledge and document stores, and from the publicly available literature. Both text analytics and manual curation play their part in populating the ontology. We describe the prototype IKMS, the BioHubKB and the services that it supports for the IKMS.
The BioHubKB can be found via
PMCID: PMC4888476  PMID: 27246819
Ontology; Repository; Environmental sustainability; Chemistry
18.  Interleukin-2 Activity can be Fine-Tuned with Engineered Receptor Signaling Clamps 
Immunity  2015;42(5):826-838.
Interleukin-2 (IL-2) regulates lymphocyte function by signaling through heterodimerization of the IL-2Rβ and γc receptor subunits. IL-2 is of considerable therapeutic interest, but harnessing its actions in a controllable manner remains a challenge. Previously, we have engineered an IL-2 “superkine” with enhanced affinity for IL-2Rβ. Here, we describe next-generation IL-2 variants that function as “receptor signaling clamps.” They retained high-affinity for IL-2Rβ, inhibiting binding of endogenous IL-2, but their interaction with γc was weakened, attenuating IL-2Rβ-γc heterodimerization. These IL-2 analogues acted as partial agonists and differentially affected lymphocytes poised at distinct activation thresholds. Moreover, one variant, H9-RETR, antagonized IL-2 and IL-15 better than blocking antibodies against IL-2Rα or IL-2Rβ. Furthermore, this mutein prolonged survival in a model of graft-versus-host disease and blocked spontaneous proliferation of smoldering adult T-cell leukemia (ATL) T cells. This receptor-clamping approach may be a general mechanism-based strategy for engineering cytokine partial agonists for therapeutic immunomodulation.
Graphical abstract
PMCID: PMC4560365  PMID: 25992859
19.  Loss of Interleukin-21 Receptor Activation in Hypoxic Endothelial Cells Impairs Perfusion Recovery after Hindlimb Ischemia 
Surgical hindlimb ischemia (HLI) in mice has become a valuable preclinical model to study peripheral arterial disease (PAD). We previously identified that the different phenotypical outcomes following HLI across inbred mouse strains is related a region on the short arm of mouse chromosome 7. The gene coding the interleukin-21 receptor (IL-21R) lies at the peak of association in this region.
Approach and Results
With quantitative RT-PCR, we found that a mouse strain with a greater ability to up-regulate IL-21R following HLI had better perfusion recovery than a strain with no up-regulation after HLI. Immunofluorescent staining of ischemic hind-limb tissue showed IL-21R expression on endothelial cells (EC) from these C57BL/6 mice. An EC-enriched fraction isolated from ischemic hind-limb muscle showed higher Il-21R levels than an EC-enriched fraction from non-ischemic limbs. In-vitro, human umbilical vein EC (HUVEC) showed elevated IL-21R expression after hypoxia and serum starvation. Under these conditions, IL-21 treatment increased cell viability, decreased cell apoptosis, and augmented tube formation. In-vivo, either knockout Il21r or blocking IL-21 signaling by treating with IL-21R-Fc (fusion protein that blocks IL-21 binding to its receptor) in C57BL/6 mice resulted in less perfusion recovery after HLI. Both in-vitro and in-vivo modulation of the IL-21/IL-21R axis under hypoxic conditions resulted in increasedSTAT3 phosphorylation and a subsequent increase in the BCL-2/BAX ratio.
Our data indicate that IL-21R up-regulation and ligand activation in hypoxic endothelial cells may help perfusion recovery by limiting/preventing apoptosis and/or favoring cell survival and angiogenesis through the STAT3 pathway.
PMCID: PMC4865891  PMID: 25838422
Interleukin 21 receptor; Peripheral arterial diseases; Angiogenesis; STAT3 pathway
20.  Low Cardiac Index is Associated with Incident Dementia and Alzheimer’s Disease: The Framingham Heart Study 
Circulation  2015;131(15):1333-1339.
Cross-sectional epidemiological and clinical research suggest lower cardiac index is associated with abnormal brain aging, including smaller brain volumes, increased white matter hyperintensities, and worse cognitive performances. Lower systemic blood flow may have implications for dementia among older adults.
Methods & Results
1039 Framingham Offspring Cohort participants free from clinical stroke, transient ischemic attack, or dementia formed our sample (69±6 years; 53% women). Multivariable-adjusted proportional hazard models adjusting for Framingham Stroke Risk Profile score (age, sex, systolic blood pressure, anti-hypertensive medication, diabetes, cigarette smoking, cardiovascular disease [CVD] history, atrial fibrillation), education, and apolipoprotein E4 status related cardiac MRI-assessed cardiac index (cardiac output/body surface area) to incident all-cause dementia and Alzheimer’s disease (AD). Over the median 7.7 year follow-up period, 32 participants developed dementia, including 26 cases of AD. Each one standard deviation unit decrease in cardiac index increased the relative risk of both dementia (HR=1.66; 95% confidence intervals [CI], 1.11–2.47; p=0.013) and AD (HR=1.65; 95% CI, 1.07–2.54; p=0.022). Compared to normal cardiac index, individuals with clinically low cardiac index had a higher relative risk of dementia (HR=2.07; 95% CI, 1.02–4.19; p=0.044). If participants with clinically prevalent CVD and atrial fibrillation were excluded (n=184), individuals with clinically low cardiac index had a higher relative risk of both dementia (HR=2.92; 95% CI, 1.34–6.36; p=0.007) and AD (HR=2.87; 95% CI, 1.21–6.80; p=0.016) compared to individuals with normal cardiac index.
Lower cardiac index is associated with an increased risk for the development of dementia and AD.
PMCID: PMC4398627  PMID: 25700178
blood circulation; brain; cardiac output; hemodynamics; dementia; Alzheimer disease
21.  Adaptive Registration of Varying Contrast-Weighted Images for Improved Tissue Characterization (ARCTIC): Application to T1 Mapping 
To propose and evaluate a novel non-rigid image registration approach for improved myocardial T1 mapping.
Myocardial motion is estimated as global affine motion refined by a novel local non-rigid motion estimation algorithm. A variational framework is proposed, which simultaneously estimates motion field and intensity variations, and uses an additional regularization term to constrain the deformation field using automatic feature tracking. The method was evaluated in 29 patients by measuring the DICE similarity coefficient (DSC) and the myocardial boundary error (MBE) in short axis and four chamber data. Each image series was visually assessed as “no motion” or “with motion”. Overall T1 map quality and motion artifacts were assessed in the 85 T1 maps acquired in short axis view using a 4-point scale (1-non diagnostic/severe motion artifact, 4-excellent/no motion artifact).
Increased DSC (0.78±0.14 to 0.87±0.03, p<0.001), reduced MBE (1.29±0.72mm to 0.84±0.20mm, p<0.001), improved overall T1 map quality (2.86±1.04 to 3.49±0.77, p<0.001), and reduced T1 map motion artifacts (2.51±0.84 to 3.61±0.64, p<0.001) were obtained after motion correction of “with motion” data (~56% of data).
The proposed non-rigid registration approach reduces the respiratory-induced motion that occurs during breath-hold T1 mapping, and significantly improves T1 map quality.
PMCID: PMC4221574  PMID: 24798588
Myocardial Tissue Characterization; T1 Mapping; Motion correction; Motion estimation; Image registration
22.  Impact of Age, Sex and Indexation Method on MR Left Ventricular Reference Values in the Framingham Heart Study Offspring Cohort 
To determine normative values for left ventricular (LV) volumes, mass, concentricity and ejection fraction (EF) and investigate associations between sex, age and body size with LV parameters in community dwelling adults.
Materials and Methods
1794 Framingham Heart Study Offspring cohort members underwent LV short-axis oriented, contiguous multislice ciné SSFP MR of the left ventricle; from these a healthy referent group (N=852, 61±9 years, 40% men) free of clinical cardiac disease and hypertension (SBP<140, DBP<90 mmHg, never used antihypertensive medication ≥ 30 years prior to scanning) was identified. Referent participants were stratified by sex and age group (≤55, 56-65, >65 years); LV parameters were indexed to measures of body size.
Men have greater LV volumes and mass than women both before and after indexation to height, powers of height, and body surface area (p<0.01 all), but indexation to fat-free mass yielded greater LV volume and mass in women. In both sexes, LV volumes and mass decrease with advancing age, though indexation attenuates this association. LVEF is greater in women than men (68±5% vs. 66±5%, p<0.01) and increases with age in both sexes (p<0.05).
Among non-hypertensive adults free of cardiac disease, men have greater LV volumes and mass with sex differences generally persisting after indexation to body size. LV volumes and mass tend to decrease with greater age in both sexes. Female sex and advanced age were both associated with greater LVEF.
PMCID: PMC4248013  PMID: 24817313
magnetic resonance imaging; left ventricle; aging; sex differences; population study; reference values
23.  Birt-Hogg-Dubé syndrome: a large single family cohort 
Respiratory Research  2016;17:22.
Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant condition characterized by dermatologic lesions, pulmonary manifestations, and renal tumors. The syndrome arises from germline mutations in the folliculin (FLCN) gene. We present findings from the single largest family BHD cohort described to date. Primary objectives were to characterize cystic lung changes on computed tomography (CT) chest scanning and identify features that stratify patients at higher risk of pneumothorax. Secondary objectives entailed description of the following: type and natural history of BHD-associated pneumothorax, pulmonary function characteristics, and relationship between cystic lung changes and pulmonary function.
The study was a retrospective chart review for a case series of a single family. Over 70 family members of a proband with documented BHD were identified, 68 of which consented to genetic testing. All those with confirmed BHD were offered a clinical assessment by the Medical Genetics and Pulmonary services which included a history, physical exam, complete pulmonary function tests, and computed tomography (CT) scan of the chest and abdomen.
Thirty-six individuals had a heterozygous mutation in the FLCN gene (c.59delT). Of these, 100 % (28/28) had pulmonary cysts, 41 % (13/32) had spontaneous pneumothoraces, 26 % (8/31) had kidney cysts, 3 % (1/31) had renal tumors, and 53 % (18/34) had dermatologic manifestations. Recurrent pneumothoraces were common (40 %). Cyst size (OR 3.23, 95 % CI 1.35–7.73) and extent of lower lung zone disease (OR 6.43, 95 % CI 1.41–29.2) were the only findings associated with pneumothorax. The size or extent of cystic disease did not correlate with lung function results.
This is the largest single family cohort of patients with BHD syndrome documented to date. We found that all individuals had pulmonary cysts, pneumothoraces were common, and cyst size and lower lobe predominant disease were associated with pneumothorax. Lung function was generally preserved and not affected by a high cyst burden.
PMCID: PMC4770529  PMID: 26928018
Cystic lung disease; Birt-Hogg- Dubé syndrome; Pneumothorax
24.  IL-21 Signaling in Immunity 
F1000Research  2016;5:F1000 Faculty Rev-224.
IL-21 is a type I cytokine produced by T cells and natural killer T cells that has pleiotropic actions on a wide range of immune and non-immune cell types. Since its discovery in 2000, extensive studies on the biological actions of IL-21 have been performed in vitro and in vivo. Recent reports describing patients with primary immunodeficiency caused by mutations of IL21 or IL21R have further deepened our knowledge of the role of this cytokine in host defense. Elucidation of the molecular mechanisms that mediate IL-21’s actions has provided the rationale for targeting IL-21 and IL-21 downstream mediators for therapeutic purposes. The use of next-generation sequencing technology has provided further insights into the complexity of IL-21 signaling and has identified transcription factors and co-factors involved in mediating the actions of this cytokine. In this review, we discuss recent advances in the biology and signaling of IL-21 and how this knowledge can be potentially translated into clinical settings.
PMCID: PMC4770986  PMID: 26966515
cytokine; IL-21; Immunosuppression; cancer immunotherapy; B-cell differentiation; T-cell differentiation
25.  IL-21-mediated non-canonical pathway for IL-1β production in conventional dendritic cells 
Nature communications  2015;6:7988.
The canonical pathway for IL-1β production requires TLR-mediated NF-κB-dependent Il1b gene induction, followed by caspase-containing inflammasome-mediated processing of pro-IL-1β. Here we show that IL-21 unexpectedly induces IL-1β production in conventional dendritic cells (cDCs) via a STAT3-dependent but NF-κB-independent pathway. IL-21 does not induce Il1b expression in CD4+ T cells, with differential histone marks present in these cells versus cDCs. IL-21-induced IL-1β processing in cDCs does not require caspase-1 or caspase-8 but depends on IL-21-mediated death and activation of serine protease(s). Moreover, STAT3-dependent IL-1β expression in cDCs at least partially explains the IL-21-mediated pathologic response occurring during infection with Pneumonia Virus of Mice. These results demonstrate lineage-restricted IL-21-induced IL-1β via a non-canonical pathway and provide evidence for its importance in vivo.
PMCID: PMC4555999  PMID: 26269257

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