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1.  Accelerated Aortic Flow Assessment with Compressed Sensing With and Without Use of the Sparsity of the Complex Difference Image 
Phase contrast (PC) cardiac MR (CMR) is widely used for the clinical assessment of blood flow in cardiovascular disease. One of the challenges of PC CMR is the long scan time which limits both spatial and temporal resolution. Compressed sensing (CS) reconstruction with accelerated PC acquisitions is a promising technique to increase the scan efficiency. In this study, we sought to utilize the sparsity of the complex difference (CD) of the two flow-encoded images as an additional constraint term to improve the CS reconstruction of the corresponding accelerated PC data acquisition. Using retrospectively under-sampled data, the proposed reconstruction technique was optimized and validated in-vivo on 15 healthy subjects. Then, prospectively under-sampled data was acquired on 11 healthy subjects and reconstructed with the proposed technique. The results show that there is good agreement between the cardiac output measurements from the fully-sampled data and the proposed CS reconstruction method using CD sparsity up to acceleration rate 5. In conclusion, we have developed and evaluated an improved reconstruction technique for accelerated PC CMR that utilizes the sparsity of the CD of the two flow-encoded images.
doi:10.1002/mrm.24514
PMCID: PMC3604074  PMID: 23065722
phase contrast MR; blood flow assessment; compressed sensing; accelerated imaging; cardiac MR
2.  Pharmacokinetic and In Vivo Efficacy Studies of the Mycobactin Biosynthesis Inhibitor Salicyl-AMS in Mice 
Antimicrobial Agents and Chemotherapy  2013;57(10):5138-5140.
Mycobactin biosynthesis in Mycobacterium tuberculosis facilitates iron acquisition, which is required for growth and virulence. The mycobactin biosynthesis inhibitor salicyl-AMS [5′-O-(N-salicylsulfamoyl)adenosine] inhibits M. tuberculosis growth in vitro under iron-limited conditions. Here, we conducted a single-dose pharmacokinetic study and a monotherapy study of salicyl-AMS with mice. Intraperitoneal injection yielded much better pharmacokinetic parameter values than oral administration did. Monotherapy of salicyl-AMS at 5.6 or 16.7 mg/kg significantly inhibited M. tuberculosis growth in the mouse lung, providing the first in vivo proof of concept for this novel antibacterial strategy.
doi:10.1128/AAC.00918-13
PMCID: PMC3811451  PMID: 23856770
3.  The Cytokines IL-21 and GM-CSF have Opposing Regulatory Roles in the Apoptosis of Conventional Dendritic Cells 
Immunity  2013;38(3):514-527.
Interleukin-21 (IL-21) has broad actions on T- and B-cells, but its actions in innate immunity are poorly understood. Here we show that IL-21 induced apoptosis of conventional dendritic cells (cDCs) via STAT3 and Bim, and this was inhibited by granulocyte-macrophage colony-stimulating factor (GM-CSF). ChIP-Seq analysis revealed genome-wide binding competition between GM-CSF-induced STAT5 and IL-21-induced STAT3. Expression of IL-21 in vivo decreased cDC numbers, and this was prevented by GM-CSF. Moreover, repetitive α-galactosylceramide injection of mice induced IL-21 but decreased GM-CSF production by natural killer T (NKT) cells, correlating with decreased cDC numbers. Furthermore, adoptive-transfer of wild-type CD4+ T cells caused more severe colitis with increased DCs and interferon (IFN)-γ producing CD4+ T cells in Il21r−/−Rag2−/− mice (which lack T cells and have IL-21-unresponsive DCs) than in Rag2−/− mice. Thus, IL-21 and GM-CSF exhibit cross-regulatory actions on gene regulation and apoptosis, regulating cDC numbers and thereby the magnitude of the immune response.
doi:10.1016/j.immuni.2013.02.011
PMCID: PMC3705920  PMID: 23453633
IL-21; GM-CSF; apoptosis; dendritic cells
4.  Regulatory B Cell (B10 Cell) Expansion During Listeria Infection Governs Innate and Cellular Immune Responses In Mice 
Pathogens use numerous methods to subvert host immune responses, including the modulation of host IL-10 production by diverse cell types. However, the B cell sources of IL-10 and their overall influence on innate and cellular immune responses have not been well characterized during infections. Using Listeria as a model pathogen, infection drove the acute expansion of a small subset of regulatory B cells (B10 cells) that potently suppress inflammation and autoimmunity through the production of IL-10. Unexpectedly, spleen bacteria loads were 92–97% lower in B10 cell-deficient CD19−/− mice, in mice depleted of mature B cells, and in mice treated with CD22 mAb to preferentially deplete B10 cells before infection. By contrast, the adoptive transfer of wild type B10 cells reduced bacterial clearance by 38-fold in CD19−/− mice through IL-10-dependent pathways. B10 cell depletion using CD22 mAb significantly enhanced macrophage phagocytosis of Listeria and their production of IFN-γ, TNF-α, and nitric oxide ex vivo. Accelerated bacteria clearance following B10 cell depletion significantly reduced Ag-specific CD4+ T cell proliferation and cytokine production, but did not alter CD8+ T cell responses. B10 cell regulatory function during innate immune responses was nonetheless dependent on cognate interactions with CD4+ T cells since B10 cells deficient in IL-10, MHC-II or IL-21 receptor expression did not influence Listeria clearance. Thus, Listeria manipulates immune responses through a strategy of immune evasion that involves the preferential expansion of endogenous B10 cells that regulate the magnitude and duration of both innate and cellular immune responses.
doi:10.4049/jimmunol.1201427
PMCID: PMC3552111  PMID: 23275601
B cells; Listeria monocytogenes; innate immunity; regulatory B cells; B10 cells
5.  Improved Fat Water Separation with Water Selective Inversion Pulse for Inversion Recovery Imaging in Cardiac MRI 
Purpose
To develop an improved chemical shift-based water-fat separation sequence using a water-selective inversion pulse for inversion-recovery 3D contrast-enhanced cardiac MR.
Materials and Methods
In inversion-recovery sequences, the fat signal is substantially reduced due to the application of a non-selective inversion pulse. Therefore, for simultaneous visualization of water, fat, and myocardial enhancement in inversion-recovery based sequences such as late Gadolinium enhancement imaging, two separate scans are used. To overcome this, the non-selective inversion pulse is replaced with a water-selective inversion pulse. Imaging was performed in phantoms, 9 healthy subjects and 9 patients with suspected arrhythmogenic right ventricular cardiomyopathy plus 1 patient for tumor/mass imaging. In patients, images with conventional turbo-spin echo (TSE) with and without fat saturation were acquired prior to contrast injection for fat assessment. Subjective image scores (1=poor, 4=excellent) were used for image assessment.
Results
Phantom experiments showed a fat SNR increase between 1.7 to 5.9 times for inversion times of 150 and 300ms, respectively. The water-selective inversion pulse retains the fat signal in contrast-enhanced cardiac MR, allowing improved visualization of fat in the water-fat separated images of healthy subjects with a score of 3.7 ± 0.6. Patient images acquired with the proposed sequence were scored higher when compared with TSE sequence (3.5 ± 0.7 vs. 2.2 ± 0.5, p<0.05).
Conclusion
The water-selective inversion pulse retains the fat signal in inversion-recovery based contrast-enhanced cardiac MR, allowing simultaneous visualization of water and fat.
doi:10.1002/jmri.23779
PMCID: PMC3557547  PMID: 22927327
water-fat separation; cardiac MRI; coronary MRI; late gadolinium enhancement
6.  Interleukin-2 at the Crossroads of Effector Responses, Tolerance, and Immunotherapy 
Immunity  2013;38(1):13-25.
Interleukin-2 is a pleiotropic cytokine produced after antigen activation that plays pivotal roles in the immune response. Discovered as a T-cell growth factor, IL-2 additionally promotes CD8+ T cell and NK cell cytolytic activity, and modulates T cell differentiation programs in response to antigen, promoting naïve CD4+ T cell differentiation into T helper-1 (Th1) and T helper-2 (Th2) cells while inhibiting T helper-17 (Th17) and T follicular helper (Tfh) cell differentiation. Moreover, IL-2 is essential for the development and maintenance of T regulatory (Treg) cells and for activation-induced cell death, thereby mediating tolerance and limiting inappropriate immune reactions. In this review, we focus on the molecular mechanisms and complex cellular actions of IL-2, its cooperative and opposing effects with other cytokines, and how both promoting and blocking the actions of IL-2 are being utilized in clinical medicine.
doi:10.1016/j.immuni.2013.01.004
PMCID: PMC3610532  PMID: 23352221
7.  Adventitial Nab-Rapamycin Injection Reduces Porcine Femoral Artery Luminal Stenosis Induced by Balloon Angioplasty via Inhibition of Medial Proliferation and Adventitial Inflammation 
Background
Endovascular interventions on peripheral arteries are limited by high rates of restenosis. Our hypothesis was that adventitial injection of rapamycin nanoparticles would be safe and reduce luminal stenosis in a porcine femoral artery balloon angioplasty model.
Methods and Results
Eighteen juvenile male crossbred swine were included. Single-injury (40%–60% femoral artery balloon overstretch injury; n=2) and double-injury models (endothelial denudation injury 2 weeks before a 20%–30% overstretch injury; n=2) were compared. The double-injury model produced significantly more luminal stenosis at 28 days, P=0.002, and no difference in medial fibrosis or inflammation. Four pigs were randomized to the double-injury model and adventitial injection of saline (n=2) or 500 μg of nanoparticle albumin-bound rapamycin (nab-rapamycin; n=2) with an endovascular microinfusion catheter. There was 100% procedural success and no difference in endothelial regeneration. At 28 days, nab-rapamycin led to significant reductions in luminal stenosis, 17% (interquartile range, 12%–35%) versus 10% (interquartile range, 8.3%–14%), P=0.001, medial cell proliferation, P<0.001, and fibrosis, P<0.001. There were significantly fewer adventitial leukocytes at 3 days, P<0.001, but no difference at 28 days. Pharmacokinetic analysis (single-injury model) found rapamycin concentrations 1500× higher in perivascular tissues than in blood at 1 hour. Perivascular rapamycin persisted ≥8 days and was not detectable at 28 days.
Conclusions
Adventitial nab-rapamycin injection was safe and significantly reduced luminal stenosis in a porcine femoral artery balloon angioplasty model. Observed reductions in early adventitial leukocyte infiltration and late medial cell proliferation and fibrosis suggest an immunosuppressive and antiproliferative mechanism. An intraluminal microinfusion catheter for adventitial injection represents an alternative to stent- or balloon-based local drug delivery.
doi:10.1161/CIRCINTERVENTIONS.113.000195
PMCID: PMC3888086  PMID: 24221390
coronary restenosis; drug delivery systems; peripheral arterial disease; sirolimus
8.  Compressed Sensing Reconstruction for Whole-Heart Imaging with 3D Radial Trajectories: A GPU Implementation 
A disadvantage of 3D isotropic acquisition in whole-heart coronary MRI is the prolonged data acquisition time. Isotropic 3D radial trajectories allow undersampling of k-space data in all three spatial dimensions, enabling accelerated acquisition of the volumetric data. Compressed sensing (CS) reconstruction can provide further acceleration in the acquisition by removing the incoherent artifacts due to undersampling and improving the image quality. However, the heavy computational overhead of the CS reconstruction has been a limiting factor for its application. In this paper, a parallelized implementation of an iterative CS reconstruction method for 3D radial acquisitions using a commercial graphics processing unit (GPU) is presented. The execution time of the GPU-implemented CS reconstruction was compared with that of the C++ implementation and the efficacy of the undersampled 3D radial acquisition with CS reconstruction was investigated in both phantom and whole-heart coronary data sets. Subsequently, the efficacy of CS in suppressing streaking artifacts in 3D whole-heart coronary MRI with 3D radial imaging and its convergence properties were studied. The CS reconstruction provides improved image quality (in terms of vessel sharpness and suppression of noise-like artifacts) compared with the conventional 3D gridding algorithm and the GPU implementation greatly reduces the execution time of CS reconstruction yielding 34–54 times speed-up compared with C++ implementation.
doi:10.1002/mrm.24234
PMCID: PMC3371294  PMID: 22392604
compressed sensing; accelerated imaging; GPU implementation; 3D radial acquisition; cardiac MR
9.  Early (30 day) vein remodeling is predictive of mid-term graft patency following lower extremity bypass 
Journal of vascular surgery  2012;57(1):9-18.
OBJECTIVES
Successful adaptation of a vein graft to an arterial environment is incompletely understood. We sought to investigate whether early vein graft remodeling is predictive of subsequent patency.
METHODS
A prospective longitudinal study of 67 patients undergoing lower extremity bypass with autologous vein between February 2004 and April 2008. Preoperative blood samples were drawn for biomarkers. During the bypass operation, a 5 cm index segment of the graft was registered for serial lumen diameter measurements (0, 1, 3, 6, 9, and 12 months) using duplex ultrasound. Patients with at least 2 study ultrasounds were included in this analysis.
RESULTS
The median age was 70 years (IQR 59-76y) and the median follow-up was 32 months (IQR 15-47mo). Over half (55%) of the subjects were male, 40% had diabetes mellitus, 49% had critical limb ischemia, and most were on a statin (75%) and antiplatelet medication (91%). The median baseline high-sensitivity C-reactive protein level (hsCRP) for the cohort was 3.2mg/L (IQR 1.4-9.7mg/L). The average intraoperative, post-implantation vein lumen diameter was 3.9 ± 1.0mm, increasing to 4.7 ± 1.1mm at 1 month, an average 24 ± 27% change per subject. By 3 months, the average lumen diameter was 5.1 ± 1.6mm, with little subsequent change observed to 12 months. Non-white race, baseline hsCRP ≥5mg/L, statin use and initial lumen diameter were significantly associated with early (0-1 month) vein remodeling in a multivariable regression model. The primary patency rate for the cohort was 60 ±6.3% at 2 years. Initial lumen diameter of the index segment was not associated with primary patency, whereas larger lumen diameter achieved at 1 month (≥5.1mm) was positively associated with primary patency (P=.03, log-rank). Early (30 day) remodeling behavior was used to divide subjects into “poor remodelers” (< −5% lumen diameter change, N=6), “modest remodelers” (−5 to +25% change, N=29) and “robust remodelers” (>+25% change, N=30). Early remodeling category was significantly associated with primary patency rate at 2 years P=.02, log-rank). A multi-variable Cox proportional hazards model showed that modest (HR 3.9, 95% CI 1.02-15, P=.04) and poor (HR 13, 95% CI 1.9-89, P=.008) remodelers had significantly higher hazard ratios for graft failure than robust early remodelers.
CONCLUSIONS
Early remodeling of the arterialized vein appears to predict mid-term bypass graft patency. In addition to baseline diameter, race, inflammation, CRP, and statin use are associated with early adaptive remodeling, but the mechanism for these observations are not understood.
doi:10.1016/j.jvs.2012.06.098
PMCID: PMC3529790  PMID: 22960020
10.  Bathing the brain 
The Journal of Clinical Investigation  2013;123(3):1013-1015.
The brain and spinal cord are surrounded by cerebrospinal fluid, which provides a mechanically stable environment for these delicate structures against the forces of gravity and sudden acceleration and deceleration. Neurons and glia comprising the parenchyma of the brain are enveloped in their microenvironment by interstitial fluid. Interstitial fluid has long been considered to be unaffected by the production and flow of cerebrospinal fluid outside the brain parenchyma. However, two recent papers by Iliff et al. demonstrate that cerebrospinal fluid enters the deep substance of the brain, mixes with the interstitial fluid surrounding neurons and glia, and plays an important role in the exchange and clearance of molecules in the interstitial space of the central nervous system.
doi:10.1172/JCI68241
PMCID: PMC3582153  PMID: 23434595
12.  Impact of New Therapeutics for Hepatitis C Virus Infection in Incarcerated Populations 
Topics in antiviral medicine  2013;21(1):27-35.
Inmate populations bear a disproportionate share of the burden of hepatitis C virus (HCV) infection. With more than 90% of prisoners released back to their communities within a few years of sentencing, incarceration can be viewed as an opportunity to provide HCV screening and therapeutic interventions to benefit the individual, reduce the costs of HCV management to the health care system from a societal perspective, and improve overall public health. Although optimal medical management of HCV within prison settings would increase the current cost of correctional health care, it could decrease transmission within the community, reduce overall disease burden, and lower the future societal health care costs associated with end-stage liver disease. Nonetheless, most prison systems treat only a small fraction of infected inmates. Current and emerging therapeutic agents will cure HCV infection in the vast majority of patients. Mathematical modeling also shows that expanded HCV screening and treatment are cost-effective from the societal perspective. In this article, we will describe appropriate treatment regimens, propose strategies to lessen the burden of these costly HCV therapies on correctional health care systems, and address the challenges of expanded HCV screening in correctional settings.
PMCID: PMC3875217  PMID: 23596276
13.  TSLP: A Key Regulator of Asthma Pathogenesis 
Drug discovery today. Disease mechanisms  2012;9(3-4):10.1016/j.ddmec.2012.09.003.
Asthma is a complex disorder of the airways that is characterized by T helper type 2 (Th2) inflammation. The pleiotrophic cytokine TSLP has emerged as an important player involved in orchestrating the inflammation seen in asthma and other atopic diseases. Early research elucidated the role of TSLP on CD4+ T cells, and recent work has revealed the impact of TSLP on multiple cell types. Furthermore, TSLP plays an important role in the sequential progression of atopic dermatitis to asthma, clarifying the key role of TSLP in the pathogenesis of asthma, a finding with therapeutic implications.
doi:10.1016/j.ddmec.2012.09.003
PMCID: PMC3859144  PMID: 24348685
14.  Free-Breathing Cardiac MR with a Fixed Navigator Efficiency Using Adaptive Gating Window Size 
A respiratory navigator with a fixed acceptance gating window is commonly used to reduce respiratory motion artifacts in cardiac MR. This approach prolongs the scan time and occasionally yields an incomplete dataset due to respiratory drifts. To address this issue, we propose an adaptive gating window approach in which the size and position of the gating window are changed adaptively during the acquisition based on the individual’s breathing pattern. The adaptive gating window tracks the breathing pattern of the subject throughout the scan and adapts the size and position of the gating window such that the gating efficiency is always fixed at a constant value. To investigate the image quality and acquisition time, free breathing cardiac MRI, including both targeted coronary MRI and late gadolinium enhancement (LGE) imaging, was performed in 67 subjects using the proposed navigator technique. Targeted coronary MRI was acquired from eleven healthy adult subjects using both the conventional and proposed adaptive gating window techniques. Fifty-six patients referred for cardiac MRI were also imaged using LGE with the proposed adaptive gating window technique. Subjective and objective image assessments were used to evaluate the proposed method. The results demonstrate that the proposed technique allows free-breathing cardiac MRI in a relatively fixed time without compromising imaging quality due to respiratory motion artifacts.
doi:10.1002/mrm.24210
PMCID: PMC3371297  PMID: 22367715
Free-breathing cardiovascular MRI; respiratory motion compensation; diaphragmatic navigators; gating window
15.  Atherosclerotic Biomarkers and Aortic Atherosclerosis by Cardiovascular Magnetic Resonance Imaging in the Framingham Heart Study 
Background
The relations between subclinical atherosclerosis and inflammatory biomarkers have generated intense interest but their significance remains unclear. We sought to determine the association between a panel of biomarkers and subclinical aortic atherosclerosis in a community‐based cohort.
Methods and Results
We evaluated 1547 participants of the Framingham Heart Study Offspring cohort who attended the 7th examination cycle and underwent both cardiovascular magnetic resonance imaging (CMR) and assays for 10 biomarkers associated with atherosclerosis: high‐sensitivity C‐reactive protein, fibrinogen, intercellular adhesion molecule‐1, interleukin‐6, interleukin‐18, lipoprotein‐associated phospholipase‐A2 activity and mass, monocyte chemoattractant protein‐1, P‐selectin, and tumor necrosis factor receptor‐2. In logistic regression analysis, we found no significant association between the biomarker panel and the presence of aortic plaque (global P=0.53). Using Tobit regression with aortic plaque as a continuous variable, we noted a modest association between biomarker panel and aortic plaque volume in age‐ and sex‐adjusted analyses (P=0.003). However, this association was attenuated after further adjustment for clinical covariates (P=0.09).
Conclusions
In our community‐based cohort, we found no significant association between our multibiomarker panel and aortic plaque. Our results underscore the strengths and limitations of the use of biomarkers for the identification of subclinical atherosclerosis and the importance of traditional risk factors.
doi:10.1161/JAHA.113.000307
PMCID: PMC3886740  PMID: 24242683
aorta; atherosclerosis; biomarkers; cardiovascular magnetic resonance imaging
16.  Resveratrol Preserves Myocardial Function and Perfusion in Remote Non-Ischemic Myocardium in a Swine Model of Metabolic Syndrome 
Background
Resveratrol has been shown to reverse some of the detrimental affects of metabolic syndrome (MetS). We sought to define the impact of supplemental resveratrol on normal myocardium remote from an ischemic territory in a swine model of MetS and chronic myocardial ischemia.
Study Design
Yorkshire swine were fed either a normal diet (control), high cholesterol diet (HCD), or high cholesterol diet with orally supplemented resveratrol (HCD-R; 100mg/kg/day). Four weeks after diet modification myocardial ischemia was induced by ameroid constrictor placement. Seven weeks later myocardial tissue from a territory remote from the ischemia was harvested. Animals in the HCD and HCD-R groups underwent functional cardiac MRI before ischemia and prior to sacrifice. Tissue was harvested for protein expression analysis.
Results
After 7 weeks of ischemia, regional left ventricular systolic function was significantly increased in HCD-R as compared to HCD. During ventricular pacing the HCD group had significantly decreased flow (p=0.03), while perfusion in the HCD-R was preserved as compared to the control. There was no difference in microvascular relaxation. Expression of metabolic proteins Sirt-1 (p=0.002), AMPkinase (p=0.02), and Carnitine palmitoyltransferase-I (p=0.002) were upregulated in the HCD-R group. Levels of protein oxidative stress were significantly increased in the HCD and HCD-R groups, as compared to the control (p=0.003). Acitvated eNOS was increased in HCD-R (p=0.01). There was no difference in myocardial endothelial cell density between the groups, however dividing endothelial cells were decreased in the HCD and HCD-R groups (p=0.006).
Conclusions
Resveratrol supplementation improves regional left ventricular function and preserves perfusion to myocardium remote from an area of ischemia in an animal model of metabolic syndrome and chronic myocardial ischemia.
doi:10.1016/j.jamcollsurg.2012.06.417
PMCID: PMC3478418  PMID: 22867714
17.  Left Ventricular Trabeculae and Papillary Muscles: Correlation With Clinical and Cardiac Characteristics and Impact on Cardiovascular Magnetic Resonance Measures of Left Ventricular Anatomy and Function 
JACC. Cardiovascular imaging  2012;5(11):1115-1123.
Objective
We sought to assess the relationship of left ventricular (LV) trabeculae and papillary muscles (TPM) with clinical characteristics in a community-based, free living adult cohort and to determine the effect of TPM on quantitative measures of LV volume, mass and ejection fraction (EF).
Background
Hypertrabeculation has been associated with adverse cardiovascular events, but the distribution and clinical correlates of the volume and mass of the TPM in a normal left ventricle have not been well characterized.
Methods
Short-axis cine cardiovascular magnetic resonance (CMR) images, obtained using a steady-state free precession sequence, from 1494 members of the Framingham Offspring cohort were analyzed using software that automatically segments TPM. Absolute TPM volume, TPM as a fraction of end-diastolic volume (TPM/EDV), and TPM mass as a fraction of LV mass (TPMm/LVM) were determined on all Offspring and in a referent group of Offspring free of clinical cardiovascular disease and hypertension.
Results
In the referent group (aged 61±9 years, with 262 men and 423 women) TPM was 23±3 % of LV EDV in both sexes (p=0.9). TPM/EDV decreased with age (p<0.02) but was not associated with body mass index (BMI). TPMm/LVM was inversely correlated with age (p<0.0001), BMI (p<0.018) and systolic blood pressure (p<0.0001). Among all 1494 participants (699 men) LV volumes decreased 23%, LV mass increased 28% and EF increased by 7.5 EF units (p<0.0001) when TPM were considered myocardial mass rather than part of the LV blood pool.
Conclusions
Global CMR LV parameters are significantly affected by whether TPM are considered as part of the LV blood pool or as part of LV mass. Our cross-sectional data from a healthy referent group of adults free of clinical cardiovascular disease demonstrate that TPM/EDV decreases with increasing age in both sexes, but is not related to hypertension or obesity.
doi:10.1016/j.jcmg.2012.05.015
PMCID: PMC3502069  PMID: 23153911
magnetic resonance imaging; population study; trabeculae; papillary muscle; left ventricular ejection fraction
18.  Professional Language Interpretation and Inpatient Length of Stay and Readmission Rates 
Journal of General Internal Medicine  2012;27(10):1294-1299.
Background
The population of persons seeking medical care is linguistically diverse in the United States. Language barriers can adversely affect a patient’s ability to explain their symptoms. Among hospitalized patients, these barriers may lead to higher readmission rates and longer hospitalizations. Trained interpreters help overcome communication barriers; however, interpreter usage among patients is suboptimal.
Objective
To investigate differences among patients with limited English proficiency (LEP) in their length of stay (LOS) and 30-day readmission rate associated with their receiving professional interpretation at admission or discharge.
Design
We analyzed the rates of interpretation at admission and discharge of all LEP patients admitted to a tertiary care hospital over a three-year period. We calculated length of stay in days and as log of LOS. We also examined 30-day readmission. Using multivariable regression models, we explored differences among patients who received interpretation at admission, discharge, or both, controlling for patient characteristics, including age, illness severity, language, and gender.
Participants
All LEP patients admitted between May 1, 2004 and April 30, 2007.
Main Measures
Length of hospital stay as related to use of professional interpreters; readmission to the hospital within 30 days.
Key Results
Of the 3071 patients included in the study, 39 % received language interpretation on both admission and discharge date. Patients who did not receive professional interpretation at admission or both admission/discharge had an increase in their LOS of between 0.75 and 1.47 days, compared to patients who had an interpreter on both day of admission and discharge (P < 0.02). Patients receiving interpretation at admission and/or discharge were less likely than patients receiving no interpretation to be readmitted with 30 days.
Conclusions
The length of a hospital stay for LEP patients was significantly longer when professional interpreters were not used at admission or both admission/discharge.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-012-2041-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s11606-012-2041-5
PMCID: PMC3445680  PMID: 22528618
low English proficient (LEP); interpreters; length of stay (LOS)
19.  Presymptomatic studies in genetic frontotemporal dementia 
Revue Neurologique  2013;169(10):820-824.
Approximately 20% of patients with the neurodegenerative disorder frontotemporal dementia (FTD) have an autosomal dominant pattern of inheritance. Genetic FTD is caused by mutations in three genes in most cases (progranulin, microtubule-associated protein tau and chromosome 9 open reading frame 72) although a number of other genes are rare causes. Studies of other neurodegenerative diseases have shown imaging and biomarker evidence of disease onset many years prior to the development of symptoms. Similar studies in genetic FTD are now revealing evidence of a series of presymptomatic changes, initially in plasma biomarkers followed by MR imaging abnormalities of functional and structural connectivity and then grey matter atrophy. Lastly, neuropsychometric tests become abnormal in proximity to the onset of symptoms. Such studies have been relatively small until now but research centres with an expertise in genetic FTD are now forming consortia such as the Genetic Frontotemporal Dementia Initiative (GenFI) to create larger cohorts that can form the basis of future clinical trials.
doi:10.1016/j.neurol.2013.07.010
PMCID: PMC3878569  PMID: 24012408
Frontotemporal dementia; Primary progressive aphasia; Progranulin; Tau; C9orf72; Dégénérescence lobaire frontotemporale; Démence frontotemporale; Aphasie progressive primaire; Progranuline; MAPT; C9ORF72
20.  An integrated biochemical prediction model of all-cause mortality in patients undergoing lower extremity bypass surgery for advanced peripheral artery disease 
Background
Patients with advanced peripheral artery disease (PAD) have a high prevalence of cardiovascular (CV) risk factors and shortened life expectancy. However, CV risk factors poorly predict midterm (<5 years) mortality in this population. This study was designed to test the hypothesis that baseline biochemical parameters would add clinically meaningful predictive information in patients undergoing lower extremity bypass.
Methods
This was a prospective cohort study of subjects with clinically advanced PAD undergoing lower extremity bypass surgery. The Cox proportional hazard was used to assess the main outcome of all-cause mortality. A clinical model was constructed with known cardiovascular risk factors and the incremental value of the addition of clinical chemistry, lipid, and a panel of 11 inflammatory parameters were investigated using c-statistic, the integrated discrimination improvement (IDI) index and Akaike information criterion (AIC).
Results
225 subjects were followed for a median 893 days; IQR 539–1315 days). In this study 50 (22.22%) subjects died during the follow-up period. By life table analysis (expressed as percent surviving ± standard error), survival at 1, 2, 3, 4, and 5 years respectively was 90.5 ± 1.9%, 83.4 ± 2.5%, 77.5 ± 3.1%, 71.0 ± 3.8%, and 65.3 ± 6.5%. Compared with survivors, decedents were older, diabetic, had extant CAD, and were more likely to present with CLI as their indication for bypass surgery, P<.05. After adjustment for the above, clinical chemistry and inflammatory parameters significant for all cause mortality were albumin, HR .43 (95% CI .26–.71); P=.001, estimated glomerular filtration rate (eGFR), HR .98 (95% CI .97–.99), P=.023, high sensitivity C-reactive protein (hsCRP), HR 3.21 (95% CI 1.21–8.55), P=.019, and soluble vascular cell adhesion molecule (sVCAM), HR 1.74 (1.04–2.91), P=.034. Of all inflammatory molecules investigated, hsCRP proved most robust and representative of the integrated inflammatory response. Albumin, eGFR, and hsCRP improved the c-statistic and IDI beyond that of the clinical model and produced a final c-statistic of .82.
Conclusions
A risk prediction model including traditional risk factors and parameters of inflammation, renal function and nutrition had excellent discriminatory ability in predicting all cause mortality in patients with clinically advanced PAD undergoing bypass surgery.
doi:10.1016/j.jvs.2012.02.034
PMCID: PMC3413780  PMID: 22554422
21.  Correction: Whole Cell Screen for Inhibitors of pH Homeostasis in Mycobacterium tuberculosis 
PLoS ONE  2013;8(8):10.1371/annotation/760b5b07-4922-42c4-b33a-162c1e9ae188.
doi:10.1371/annotation/760b5b07-4922-42c4-b33a-162c1e9ae188
PMCID: PMC3782195  PMID: 24098606
22.  Th17 cell-derived IL-17 is dispensable for B cell antibody production 
Cytokine  2012;59(1):108-114.
IL-17, which is preferentially produced by Th17 cells, is important for host defense against pathogens and is also involved in the development of autoimmune and allergic disorders. Antibody (Ab) production was shown to be impaired in IL-17-deficient mice, suggesting that IL-17 may promote B cell activation and direct secretion of Ab. However, the precise role of IL-17 in Ab production by B cells remains unclear. In the present study, we found constitutive expression of IL-17R in murine splenic B cells. Nevertheless, IL-17, IL-17F or IL-25 alone could not induce Ab production by B cells even in the presence of agonistic anti-CD40 Ab. IL-17 also could not affect IFN-γ-, IL-4- or TGF-β1-mediated Ig class-switching. Furthermore, in cocultures of B cells and IL-17−/− CD4+ T cells or IL-17−/− Th17 cells, IL-17 deficiency did not influence Ab production by B cells in vitro, suggesting that Th17 cell-derived IL-17 was not required for B cell Ab production through T-B cell interaction in vitro. Thus, in vivo, IL-17 may be indirectly involved in Ab production by enhancing production of B cell activator(s) by other immune cells.
doi:10.1016/j.cyto.2012.03.018
PMCID: PMC3746348  PMID: 22503615
interleukin-17; Th17 cells; B cells; antibody production
23.  On the Mechanisms of Cyanine Fluorophore Photostabilization 
Cyanine fluorophores exhibit greatly improved photostability when covalently linked to stabilizers, such as cyclooctatetraene (COT), nitrobenzyl alcohol (NBA) or Trolox. However, the mechanism by which photostabilization is mediated has yet to be determined. Here we present spectroscopic evidence that COT, when covalently linked to Cy5, substantially reduces the lifetime of the Cy5 triplet state, and that the degree of triplet state quenching correlates with enhancements in photostability observed in single-molecule fluorescence measurements. By contrast, NBA and Trolox did not quench the Cy5 triplet state under our conditions suggesting that their mechanism of photostabilization is different from COT and does not target the fluorophore triplet state directly. These findings provide insights into the mechanisms of fluorophore photostabilization that may lead to improved fluorophore designs for biological imaging applications.
doi:10.1021/jz300670p
PMCID: PMC3439216  PMID: 22984636
Laser flash photolysis; single-molecule spectroscopy; Cy5; COT
24.  Usefulness of the Left Ventricular Myocardial Contraction Fraction in Healthy Men and Women to Predict Cardiovascular Morbidity and Mortality 
The American journal of cardiology  2012;109(10):1454-1458.
We sought to determine whether depressed myocardial contraction fraction (MCF, the ratio of left ventricular (LV) stroke volume to myocardial volume) predicts cardiovascular disease (CVD) events in initially healthy adults. A subset (N=318, 60±9 yrs, 158 men) of the Framingham Heart Study Offspring cohort free of clinical CVD underwent volumetric cardiovascular magnetic resonance (CMR) imaging in 1998–1999. LV ejection fraction (EF), mass and MCF were determined. “Hard” CVD events comprised cardiovascular death, myocardial infarction, stroke or new heart failure. A Cox proportional hazards model adjusting for Framingham Coronary Risk Score (FCRS) was used to estimate hazard ratios for incident hard CVD events for sex-specific quartiles of MCF, LV mass and LVEF. The lowest quartile of LV mass and highest quartiles of MCF and EF served as referent. Kaplan-Meier survival plots and the log rank test were used to compare event-free survival. MCF was greater in women (0.58±0.13) than men (0.52±0.11), p<0.01. Nearly all (99%) participants had EF ≥ 0.55. Over up to 9-year (median 5.2) follow-up, 31 participants (10%) experienced an incident hard CVD event. Lowest-quartile MCF was 7 times more likely to develop hard CVD (hazard ratio 7.11, p=0.010) compared to the lowest quartile, and the elevated hazards persisted even after adjustment for LV mass (hazard ratio=6.09, p=0.020). The highest-quartile LV mass/height2.7 had nearly five-fold risk (hazard ratio 4.68, p=0.016). Event-free survival was shorter in lowest-quartile MCF, p = 0.0006, but not in lowest-quartile LVEF. Conclusion: In a cohort of adults initially without clinical CVD, lowest-quartile MCF conferred an increased hazard for hard CVD events after adjustment for traditional CVD risk factors and LV mass.
doi:10.1016/j.amjcard.2012.01.357
PMCID: PMC3742100  PMID: 22381161
magnetic resonance imaging; myocardial contraction fraction; risk factors; left ventricular function
25.  Long-term outcomes after a strategy of percutaneous coronary intervention of the infarct-related artery with drug-eluting stents or bare metal stents vs medical therapy alone in the Occluded Artery Trial (OAT) 
American heart journal  2012;163(6):1011-1018.
Background
The OAT, a randomized study of routine percutaneous coronary intervention or optimal medical therapy (MED) alone for the treatment of a totally occluded infarct-related artery in the subacute phase after myocardial infarction, showed similar rates of death, reinfarction and congestive heart failure (CHF) between study groups. Although most percutaneous coronary intervention patients were treated with bare metal stents (BMS), drug-eluting stents (DES) were also implanted in the latter part of the study. The aim of the study was to conduct an exploratory analysis of long-term outcomes for DES vs. BMS deployment vs. MED in the OAT.
Methods
Patients enrolled after February 2003 (when first DES was implanted) were followed (DES n = 79, BMS n = 393, MED n = 552) up to a maximum of 6 years (mean survivor follow-up 5.1 years).
Results
The 6-year occurrence of the composite end point of death, reinfarction and class IV CHF was similar [20.4% of DES, 18.9% of BMS and 18.4% of MED (P = .66)] as were the rates of the components of the primary end point. During the follow-up period, 33.4% of DES, 44.4% of BMS and 48.1% of MED patients, developed angina (P = .037). The rate of revascularization during follow up was 11.3%, 20.5% and 22.5% among these groups, respectively (P = .045).
Conclusions
There is no suggestion of reduced long-term risk of death, reinfarction or class IV CHF with DES usage compared to BMS or medical treatment alone. An association between DES use and freedom from angina and revascularization relative to medical therapy is suggested.
doi:10.1016/j.ahj.2012.03.008
PMCID: PMC3735135  PMID: 22709754

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