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1.  Conventional NK cells can produce IL-22 and promote host defense in K. pneumoniae pneumonia1 
It has been reported that host defense against pulmonary K. pneumoniae infection requires IL-22, which has been proposed to be of T cell origin. Supporting a role for IL-22, we found that Il22−/− mice had decreased survival as compared with wild type mice after intratracheal infection with K. pneumoniae. Surprisingly, however, Rag2−/− mice did not differ from wild type mice in survival or levels of IL-22 in the lungs after infection with K. pneumoniae. By contrast, K. pneumoniae-infected Rag2−/−Il2rg−/− mice failed to produce IL-22. These data suggested a possible role for NK cells or other innate lymphoid cells (ILC) in host defense and production of IL-22. Unlike NK cell-like ILCs that produce IL-22 and display a surface phenotype of NK1.1−NKp46+CCR6+, lung NK cells showed the conventional phenotype, NK1.1+NKp46+CCR6−. Mice depleted of NK cells using anti-asialo GM1 showed decreased survival and higher lung bacterial counts as well as increased dissemination of K. pneumoniae to blood and liver as compared with control-treated mice. NK cell depletion also led to decreased production of IL-22 in the lung. Within one day after infection, although there was no increase in the number of lung NK cells, a subset of lung NK cells became competent to produce IL-22, and such cells were found in both wild type and Rag2−/− mice. Our data suggest that during pulmonary infection of mice with K. pneumoniae, conventional NK cells are required for optimal host defense, which includes the production of IL-22.
PMCID: PMC3995347  PMID: 24442439
2.  Determinants and Coverage of Vaccination in Children in Western Kenya from a 2003 Cross-Sectional Survey 
This study assesses full and timely vaccination coverage and factors associated with full vaccination in children ages 12–23 months in Gem, Nyanza Province, Kenya in 2003. A simple random sample of 1,769 households was selected, and guardians were invited to bring children under 5 years of age to participate in a survey. Full vaccination coverage was 31.1% among 244 children. Only 2.2% received all vaccinations in the target month for each vaccination. In multivariate logistic regression, children of mothers of higher parity (odds ratio [OR] = 0.27, 95% confidence interval [95% CI] = 0.13–0.65, P ≤ 0.01), children of mothers with lower maternal education (OR = 0.35, 95% CI = 0.13–0.97, P ≤ 0.05), or children in households with the spouse absent versus present (OR = 0.40, 95% CI = 0.17–0.91, P ≤ 0.05) were less likely to be fully vaccinated. These data serve as a baseline from which changes in vaccination coverage will be measured as interventions to improve vaccination timeliness are introduced.
PMCID: PMC3919223  PMID: 24343886
3.  Forceps Delivery Volumes in Teaching and Nonteaching Hospitals: Are Volumes Sufficient for Physicians to Acquire and Maintain Competence? 
The decline in the use of forceps in operative deliveries over the last two decades raises questions about teaching hospitals' ability to provide trainees with adequate experience in the use of forceps. The authors examined: (1) the number of operative deliveries performed in teaching and nonteaching hospitals, and (2) whether teaching hospitals performed a sufficient number of forceps deliveries for physicians to acquire and maintain competence.
The authors used State Inpatient Data from nine states to identify all women hospitalized for childbirth in 2008. They divided hospitals into three categories: major teaching, minor teaching, and nonteaching. They calculated delivery volumes (total operative, cesarean, vacuum, forceps, two or more methods) for each hospital and compared data across hospital categories.
The sample included 1,344,305 childbirths in 835 hospitals. The mean cesarean volumes for major teaching, minor teaching, and nonteaching hospitals were 969.8, 757.8, and 406.9. The mean vacuum volumes were 301.0, 304.2, and 190.4, and the mean forceps volumes were 25.2, 15.3, and 8.9. In 2008, 31 hospitals (3.7% of all hospitals) performed no vacuum extractions, and 320 (38.3%) performed no forceps deliveries. In 2008, 13 (23%) major teaching and 44 (44%) minor teaching hospitals performed five or fewer forceps deliveries.
Low forceps delivery volumes may preclude many trainees from acquiring adequate experience and proficiency. These findings highlighted broader challenges, faced by many specialties, in ensuring that trainees and practicing physicians acquire and maintain competence in infrequently performed, highly technical procedures.
PMCID: PMC4317267  PMID: 24280847
4.  A Targeted Health Risk Assessment Following the Deepwater Horizon Oil Spill: Polycyclic Aromatic Hydrocarbon Exposure in Vietnamese-American Shrimp Consumers 
Environmental Health Perspectives  2014;123(2):152-159.
Background: The Deepwater Horizon oil spill of 2010 prompted concern about health risks among seafood consumers exposed to polycyclic aromatic hydrocarbons (PAHs) via consumption of contaminated seafood.
Objective: The objective of this study was to conduct population-specific probabilistic health risk assessments based on consumption of locally harvested white shrimp (Litopenaeus setiferus) among Vietnamese Americans in southeast Louisiana.
Methods: We conducted a survey of Vietnamese Americans in southeast Louisiana to evaluate shrimp consumption, preparation methods, and body weight among shrimp consumers in the disaster-impacted region. We also collected and chemically analyzed locally harvested white shrimp for 81 individual PAHs. We combined the PAH levels (with accepted reference doses) found in the shrimp with the survey data to conduct Monte Carlo simulations for probabilistic noncancer health risk assessments. We also conducted probabilistic cancer risk assessments using relative potency factors (RPFs) to estimate cancer risks from the intake of PAHs from white shrimp.
Results: Monte Carlo simulations were used to generate hazard quotient distributions for noncancer health risks, reported as mean ± SD, for naphthalene (1.8 × 10–4 ± 3.3 × 10–4), fluorene (2.4 × 10–5 ± 3.3 × 10–5), anthracene (3.9 × 10–6 ± 5.4 × 10–6), pyrene (3.2 × 10–5 ± 4.3 × 10–5), and fluoranthene (1.8 × 10–4 ± 3.3 × 10–4). A cancer risk distribution, based on RPF-adjusted PAH intake, was also generated (2.4 × 10–7 ± 3.9 × 10–7).
Conclusions: The risk assessment results show no acute health risks or excess cancer risk associated with consumption of shrimp containing the levels of PAHs detected in our study, even among frequent shrimp consumers.
Citation: Wilson MJ, Frickel S, Nguyen D, Bui T, Echsner S, Simon BR, Howard JL, Miller K, Wickliffe JK. 2015. A targeted health risk assessment following the Deepwater Horizon Oil Spill: polycyclic aromatic hydrocarbon exposure in Vietnamese-American shrimp consumers. Environ Health Perspect 123:152–159;
PMCID: PMC4314254  PMID: 25333566
5.  Reactive Arrays of Colorimetric Sensors for Metabolite and Steroid Identification 
Journal of sensor technology  2014;4(1):43398.
The work described herein examines a rapid mix-and-measure method called DETECHIP suitable for screening of steroids and metabolites. The addition of steroids and metabolites to reactive arrays of colorimetric sensors generated characteristic color “fingerprints” that were used to identify the analyte. A color analysis tool was used to identify the analyte pool that now includes biologically relevant analytes. The mix-and-measure arrays allowed the detection of disease metabolites, orotic acid and argininosuccinic acid; and the steroids androsterone, 1,4-androstadiene, testosterone, stanozolol, and estrone. The steroid 1,4-androstadiene was also detected by this method while dissolved in synthetic urine. Some of the steroids, such as androstadiene, stanozolol, and androsterone were co-dissolved with (2-hydroxypropyl)-β-cyclodextrin in order to increase solubility in aqueous buffered solutions. The colorimetric arrays do not intend to eliminate ELISA or mass spectroscopy based screening, but to possibly provide an alternative analytical detection method for steroids and metabolites.
PMCID: PMC4091918  PMID: 25019034
Colorimetric Arrays; Sensors; Color Changes; Steroids; Metabolic Disease, Metabolites, Detection
6.  Patterns of hepatocellular carcinoma incidence in Egypt from a population-based cancer registry 
Hepatocellular carcinoma (HCC) is increasing worldwide, and is frequently attributed to rising rates of hepatitis C virus infection and interactions between viral and environmental risk factors. Because of Egypt’s unique risk factor profile, we analyzed data from the Gharbiah Population-Based Cancer Registry for the period 1999–2003 to characterize demographic and geographic patterns of cases in this province.
We calculated age- and sex-specific and age- and sex-standardized HCC incidence rates for the eight districts in Gharbiah. We also compared rates from Gharbiah with the USA (US Surveillance Epidemiology and End Results [SEER] database).
The analysis revealed a higher incidence in males than in females, significant geographic variations among districts, and a higher incidence in Gharbiah than that reported by SEER.
The findings of this study document the heterogeneous distribution of HCC at regional and international levels. This population-based registry offers the opportunity for careful representative studies of various etiologies, particularly infectious and/or environmental factors that may contribute to risk.
PMCID: PMC4276031  PMID: 18042228
age-specific rates; developing countries; geographic variation; liver cancer; USA
7.  The changing patterns of bladder cancer in Egypt over the past 26 years 
Cancer causes & control : CCC  2008;19(4):421-429.
To evaluate temporal changes in histopathological types of bladder cancer and to assess associated changes in demographic, epidemiologic, and lifestyle risk factors.
We abstracted data from all available medical records from the National Cancer Institute of Cairo University (NCI-Cairo). Six calendar years representing 5-year periods between 1980 and 2005 were evaluated. Information on demographics, schistosomal infection, clinical symptoms of bladder cancer, and tumor pathology was abstracted.
During this 26-year period, important changes in the frequency of histopathological types of bladder cancer occurred. We found a statistically significant association between time period of diagnosis and histopathological type. Patients diagnosed in 2005 had a sixfold higher odds associated with transitional cell carcinoma compared to those patients diagnosed in 1980 (odds ratio (OR) 6.00 (95% CI 4.00–8.97)).
These data strongly suggest that the histopathological profile of bladder cancer in Egypt has changed significantly over the past 26 years. Historically, squamous cell carcinoma was the predominant form of bladder cancer in Egypt; however transitional cell carcinoma has become the most frequent type. These results corroborate findings from a few small-scale hospital-based studies which conclude that the etiology of bladder cancer in Egypt has changed significantly over the past 26 years.
PMCID: PMC4274945  PMID: 18188671
Bladder cancer; Schistosomiasis; Histopathology; Epidemiologic trends; Egypt
8.  Magnetic resonance imaging and multi-detector computed tomography assessment of extracellular compartment in ischemic and non-ischemic myocardial pathologies 
World Journal of Cardiology  2014;6(11):1192-1208.
Myocardial pathologies are major causes of morbidity and mortality worldwide. Early detection of loss of cellular integrity and expansion in extracellular volume (ECV) in myocardium is critical to initiate effective treatment. The three compartments in healthy myocardium are: intravascular (approximately 10% of tissue volume), interstitium (approximately 15%) and intracellular (approximately 75%). Myocardial cells, fibroblasts and vascular endothelial/smooth muscle cells represent intracellular compartment and the main proteins in the interstitium are types I/III collagens. Microscopic studies have shown that expansion of ECV is an important feature of diffuse physiologic fibrosis (e.g., aging and obesity) and pathologic fibrosis [heart failure, aortic valve disease, hypertrophic cardiomyopathy, myocarditis, dilated cardiomyopathy, amyloidosis, congenital heart disease, aortic stenosis, restrictive cardiomyopathy (hypereosinophilic and idiopathic types), arrythmogenic right ventricular dysplasia and hypertension]. This review addresses recent advances in measuring of ECV in ischemic and non-ischemic myocardial pathologies. Magnetic resonance imaging (MRI) has the ability to characterize tissue proton relaxation times (T1, T2, and T2*). Proton relaxation times reflect the physical and chemical environments of water protons in myocardium. Delayed contrast enhanced-MRI (DE-MRI) and multi-detector computed tomography (DE-MDCT) demonstrated hyper-enhanced infarct, hypo-enhanced microvascular obstruction zone and moderately enhanced peri-infarct zone, but are limited for visualizing diffuse fibrosis and patchy microinfarct despite the increase in ECV. ECV can be measured on equilibrium contrast enhanced MRI/MDCT and MRI longitudinal relaxation time mapping. Equilibrium contrast enhanced MRI/MDCT and MRI T1 mapping is currently used, but at a lower scale, as an alternative to invasive sub-endomyocardial biopsies to eliminate the need for anesthesia, coronary catheterization and possibility of tissue sampling error. Similar to delayed contrast enhancement, equilibrium contrast enhanced MRI/MDCT and T1 mapping is completely noninvasive and may play a specialized role in diagnosis of subclinical and other myocardial pathologies. DE-MRI and when T1-mapping demonstrated sub-epicardium, sub-endocardial and patchy mid-myocardial enhancement in myocarditis, Behcet’s disease and sarcoidosis, respectively. Furthermore, recent studies showed that the combined technique of cine, T2-weighted and DE-MRI technique has high diagnostic accuracy for detecting myocarditis. When the tomographic techniques are coupled with myocardial perfusion and left ventricular function they can provide valuable information on the progression of myocardial pathologies and effectiveness of new therapies.
PMCID: PMC4244616  PMID: 25429331
Myocardial viability; Ischemic/non-ischemic heart diseases; Magnetic resonance imaging; Multi-detector computed tomography; Cellular compartments; Contrast media
9.  Synthesis of a Fluorophore with Improved Optical Brightness 
The synthesis and characterization of a novel fluorophore(1), with potential application as an optical brightener are reported. This compound was prepared by reacting 4,4-diaminostilbene-2,2-disulfonic acid with cyanuric chloride in the presence of Na2CO3 followed by the addition of trityl aniline. Solution and solid state fluorescence demonstrated a strong blue/purple emission centered at 450 nm. 1H-NMR spectroscopy, mass spectrometry analysis, elemental analysis, and DOSY-NMR were used for the characterization of the fluorophore.
PMCID: PMC4241686  PMID: 25429353
Optical Brightener; Fluorophore; Diaminostilbene; Cyanuric Chloride; Optical Brightness
10.  Sequestration and histopathology in Plasmodium chabaudi malaria are influenced by the immune response in an organ-specific manner 
Cellular Microbiology  2013;16(5):687-700.
Infection with the malaria parasite, Plasmodium, is associated with a strong inflammatory response and parasite cytoadhesion (sequestration) in several organs. Here, we have carried out a systematic study of sequestration and histopathology during infection of C57Bl/6 mice with Plasmodium chabaudi AS and determined the influence of the immune response. This parasite sequesters predominantly in liver and lung, but not in the brain, kidney or gut. Histopathological changes occur in multiple organs during the acute infection, but are not restricted to the organs where sequestration takes place. Adaptive immunity, and signalling through the IFNγ receptor increased sequestration and histopathology in the liver, but not in the lung, suggesting that there are differences in the adhesion molecules and/or parasite ligands utilized and mechanisms of pathogenesis in these two organs. Exacerbation of pro-inflammatory responses during infection by deletion of the il10 gene resultsin the aggravation of damage to lung and kidney irrespective of the degree of sequestration. The immune response therefore affected both sequestration and histopathology in an organ-specific manner. P. chabaudi AS provides a good model to investigate the influence of the host response on the sequestration and specific organ pathology, which is applicable to human malaria.
PMCID: PMC4234010  PMID: 24003897
11.  CRH receptor antagonism reverses the effect of social subordination upon central GABAA receptor binding in estradiol-treated ovariectomized female rhesus monkeys 
Neuroscience  2013;250:10.1016/j.neuroscience.2013.07.002.
Persistent exposure to environmental stressors causes dysregulation of the limbic-hypothalamic-pituitary-adrenal (LHPA) axis and alters GABAA receptor (GABAAR) levels throughout the brain. Social subordination in socially housed female rhesus results in distinctive stress-related physiological and behavioral phenotypes that are dependent on the ovarian hormone estradiol (E2). In the present study, we utilized ovariectomized adult female rhesus monkeys undergoing hormone replacement with E2 to test the hypothesis that the chronic psychosocial stress of subordination alters GABAAR binding potential (GABAAR BPND) in limbic regions implicated in emotional processing including the prefrontal cortex, temporal lobe (amygdala and hippocampus), and hypothalamus. Furthermore, we tested the hypothesis that peripheral administration of a corticotropin-releasing hormone receptor (CRHR) antagonist (astressin B) would reverse the alterations in GABAAR binding within these regions in subordinate females. After subjects received astressin B or saline for three consecutive days, GABAAR BPND was determined by positron emission tomography (PET) using 18F-flumazenil as a radioligand. T1-weighted structural MRI scans were also acquired for PET scan co-registration, in order to perform a region of interest analysis using the pons as a reference region. Compared to socially dominant females, subordinate females exhibited increased GABAAR BPND in the prefrontal cortex but not in the temporal lobe or the hypothalamus. Administration of astressin B eliminated the status difference in GABAAR BPND in the prefrontal cortex, suggesting that the chronic stressor of social subordination modulates GABAergic tone via effects on CRH and the LHPA axis, at least in prefrontal regions.
PMCID: PMC3821982  PMID: 23856065
estradiol; social subordination; stress; flumazenil; Astressin B; GABAA receptor; monkeys
12.  Spatial Clustering of Aedes aegypti Related to Breeding Container Characteristics in Coastal Ecuador: Implications for Dengue Control 
Mosquito management within households remains central to the control of dengue virus transmission. An important factor in these management decisions is the spatial clustering of Aedes aegypti. We measured spatial clustering of Ae. aegypti in the town of Borbón, Ecuador and assessed what characteristics of breeding containers influenced the clustering. We used logistic regression to assess the spatial extent of that clustering. We found strong evidence for juvenile mosquito clustering within 20 m and for adult mosquito clustering within 10 m, and stronger clustering associations for containers ≥ 40 L than those < 40 L. Aedes aegypti clusters persisted after adjusting for various container characteristics, suggesting that patterns are likely attributable to short dispersal distances rather than shared characteristics of containers in cluster areas. These findings have implications for targeting Ae. aegypti control efforts.
PMCID: PMC3795109  PMID: 24002483
13.  Functional convergence of structurally distinct thioesterases from cyanobacteria and plants involved in phylloquinone biosynthesis 
The crystal structures of two 1,4-dihydroxy-2-naphthoyl-CoA thioesterases of plant and cyanobacterial origin that are involved in the biosynthesis of phylloquinone are presented. The divergent structures of these two functionally similar enzymes indicate convergent evolution.
The synthesis of phylloquinone (vitamin K1) in photosynthetic organisms requires a thioesterase that hydrolyzes 1,4-di­hydroxy-2-naphthoyl-CoA (DHNA-CoA) to release 1,4-dihydroxy-2-naphthoate (DHNA). Cyanobacteria and plants contain distantly related hotdog-fold thioesterases that catalyze this reaction, although the structural basis of these convergent enzymatic activities is unknown. To investigate this, the crystal structures of hotdog-fold DHNA-CoA thio­esterases from the cyanobacterium Synechocystis (Slr0204) and the flowering plant Arabidopsis thaliana (AtDHNAT1) were determined. These enzymes form distinct homotetramers and use different active sites to catalyze hydrolysis of DHNA-CoA, similar to the 4-­hydroxybenzoyl-CoA (4-HBA-CoA) thio­esterases from Pseudomonas and Arthrobacter. Like the 4-­HBA-CoA thio­esterases, the DHNA-CoA thioesterases contain either an active-site aspartate (Slr0204) or glutamate (AtDHNAT1) that are predicted to be catalytically important. Computational modeling of the substrate-bound forms of both enzymes indicates the residues that are likely to be involved in substrate binding and catalysis. Both enzymes are selective for DHNA-CoA as a substrate, but this selectivity is achieved using divergent predicted binding strategies. The Slr0204 binding pocket is predominantly hydrophobic and closely conforms to DHNA, while that of AtDHNAT1 is more polar and solvent-exposed. Considered in light of the related 4-­HBA-CoA thioesterases, these structures indicate that hotdog-fold thioesterases using either an active-site aspartate or glutamate diverged into distinct clades prior to the evolution of strong substrate specificity in these enzymes.
PMCID: PMC3792638  PMID: 24100308
thioesterases; hotdog fold; vitamin K; phylloquinone; Synechocystis; Arabidopsis thaliana
14.  Digital Image Analysis for DETCHIP® Code Determination 
DETECHIP® is a molecular sensing array used for identification of a large variety of substances. Previous methodology for the analysis of DETECHIP® used human vision to distinguish color changes induced by the presence of the analyte of interest. This paper describes several analysis techniques using digital images of DETECHIP®. Both a digital camera and flatbed desktop photo scanner were used to obtain Jpeg images. Color information within these digital images was obtained through the measurement of red-green-blue (RGB) values using software such as GIMP, Photoshop and ImageJ. Several different techniques were used to evaluate these color changes. It was determined that the flatbed scanner produced in the clearest and more reproducible images. Furthermore, codes obtained using a macro written for use within ImageJ showed improved consistency versus pervious methods.
PMCID: PMC4176695  PMID: 25267940
DETECHIP®; Molecular Sensing Array; Narcotics Detection; Image Analysis; RGB Color Signal
15.  The Cochrane Collaboration 20 years in 
PMCID: PMC3778497  PMID: 23979868
16.  Imaging assessment of a portable hemodialysis device: detection of possible failure modes and monitoring of functional performance 
Medical instrumentation (Luton, England)  2014;2(2):10.7243/2052-6962-2-2.
The purpose of this study was to investigate the utility and limitations of various imaging modalities in the noninvasive assessment of a novel compact hemodialyzer under development for renal replacement therapy, with specific aim towards monitoring its functional performance.
The prototype is a 4×3×6 cm aluminum cartridge housing “blood” and “dialysate” flow paths arranged in parallel. A sheet of semipermeable silicon nanopore membranes forms the blood-dialysate interface, allowing passage of small molecules. Blood flow was simulated using a peristaltic pump to instill iodinated contrast through the blood compartment, while de-ionized water was instilled through the dialysate compartment at a matched rate in the countercurrent direction. Images were acquired under these flow conditions using multi-detector computed tomography (MDCT), fluoroscopy, high-resolution quantitative computed tomography (HR-QCT), and magnetic resonance imaging (MRI). MDCT was used to monitor contrast diffusion efficiency by plotting contrast density as a function of position along the path of flow through the cartridge during steady state infusion at 1 and 20 mL/min. Both linear and exponential regressions were used to model contrast decay along the flow path.
Both linear and exponential models of contrast decay appeared to be reasonable approximations, yielding similar results for contrast diffusion during a single pass through the cartridge. There was no measurable difference in contrast diffusion when comparing 1 mL/min and 20 mL/min flow rates. Fluoroscopy allowed a gross qualitative assessment of flow within the device, and revealed flow inhomogeneity within the corner of the cartridge opposite the blood inlet port. MRI and HR-QCT were both severely limited due to the paramagnetic properties and high atomic number of the target material, respectively. During testing, we encountered several causes of device malfunction, including leak formation, trapped gas, and contrast-mediated nanopore clogging. We illustrate the imaging manifestations of each.
Despite the inherent challenges in imaging a predominantly metallic device, some modalities show potential in the non-invasive assessment of a novel compact hemodialyzer. The approaches described here could potentially be translated to device evaluation in the implanted setting.
PMCID: PMC4101171  PMID: 25045526
End-stage renal disease; renal replacement therapy; hemodialysis device; multi-detector computed tomography
17.  MicroRNA-Containing T-Regulatory-Cell-Derived Exosomes Suppress Pathogenic T Helper 1 Cells 
Immunity  2014;41(1):89-103.
Foxp3+ T regulatory (Treg) cells prevent inflammatory disease but the mechanistic basis of suppression is not understood completely. Gene silencing by RNA interference can act in a cell-autonomous and non-cell-autonomous manner, providing mechanisms of intercellular regulation. Here, we demonstrate that non-cell-autonomous gene silencing, mediated by miRNA-containing exosomes, is a mechanism employed by Treg cells to suppress T-cell-mediated disease. Treg cells transferred microRNAs (miRNA) to various immune cells, including T helper 1 (Th1) cells, suppressing Th1 cell proliferation and cytokine secretion. Use of Dicer-deficient or Rab27a and Rab27b double-deficient Treg cells to disrupt miRNA biogenesis or the exosomal pathway, respectively, established a requirement for miRNAs and exosomes for Treg-cell-mediated suppression. Transcriptional analysis and miRNA inhibitor studies showed that exosome-mediated transfer of Let-7d from Treg cell to Th1 cells contributed to suppression and prevention of systemic disease. These studies reveal a mechanism of Treg-cell-mediated suppression mediated by miRNA-containing exosomes.
•Foxp3+ Treg-cell-derived exosomes contain distinct miRNAs•miRNAs and the exosomal pathway are required for proficient Treg cell function•Treg-cell-derived exosomes suppress Th1 cells in a Let-7d-dependent manner
The mechanisms through which T regulatory (Treg) cells prevent inflammation are not fully understood. Okoye et al. show that Treg cells release exosomes that transfer miRNAs to target T helper cells and suppress T-cell-mediated disease.
PMCID: PMC4104030  PMID: 25035954
18.  TLR4 Signaling Augments Monocyte Chemotaxis by Regulating G Protein-Coupled Receptor Kinase 2 (GRK2) Translocation 
Monocytes are critical effector cells of the innate immune system that protect the host by migrating to inflammatory sites, differentiating to macrophages and dendritic cells, eliciting immune responses, and killing pathogenic microbes. Monocyte chemoattractant protein 1(MCP-1), also known as CCL2, plays an important role in monocyte activation and migration. Chemotactic function of MCP-1 is mediated by binding to the CCR2 receptor, a member of the G protein-coupled receptor (GPCR) family. Desensitization of GPCR chemokine receptors is an important regulator of the intensity and duration of chemokine stimulation. G protein-coupled receptor kinases (GRKs) induce GPCR phosphorylation, and this leads to GPCR desensitization. Regulation of subcellular localization of GRKs is considered an important early regulatory mechanism of GRK function and subsequent GPCR desensitization. Chemokines and LPS are both present during Gram-negative bacterial infection, and LPS often synergistically exaggerates leukocyte migration in response to chemokines. In this study, we investigated the role of, and mechanism of, LPS-TLR4 signaling on the regulation of monocyte chemotaxis. We demonstrate that LPS augments MCP-1-induced monocyte migration. We also show that LPS, through p38 MAPK signaling, induces phosphorylation of GRK2 at serine 670, which, in turn, suppresses GRK2 translocation to the membrane, thereby preventing GRK2-initiated internalization and desensitization of CCR2 in response to MCP-1. This therefore results in enhanced monocyte migration. These findings reveal a novel function for TLR4 signaling in promoting innate immune cell migration.
PMCID: PMC3702632  PMID: 23772028
CCR2; GPCR; leukocyte migration; MCP-1
19.  Wireless Monitoring of Liver Hemodynamics In Vivo 
PLoS ONE  2014;9(7):e102396.
Liver transplants have their highest technical failure rate in the first two weeks following surgery. Currently, there are limited devices for continuous, real-time monitoring of the graft. In this work, a three wavelengths system is presented that combines near-infrared spectroscopy and photoplethysmography with a processing method that can uniquely measure and separate the venous and arterial oxygen contributions. This strategy allows for the quantification of tissue oxygen consumption used to study hepatic metabolic activity and to relate it to tissue stress. The sensor is battery operated and communicates wirelessly with a data acquisition computer which provides the possibility of implantation provided sufficient miniaturization. In two in vivo porcine studies, the sensor tracked perfusion changes in hepatic tissue during vascular occlusions with a root mean square error (RMSE) of 0.135 mL/min/g of tissue. We show the possibility of using the pulsatile wave to measure the arterial oxygen saturation similar to pulse oximetry. The signal is also used to extract the venous oxygen saturation from the direct current (DC) levels. Arterial and venous oxygen saturation changes were measured with an RMSE of 2.19% and 1.39% respectively when no vascular occlusions were induced. This error increased to 2.82% and 3.83% when vascular occlusions were induced during hypoxia. These errors are similar to the resolution of a commercial oximetry catheter used as a reference. This work is the first realization of a wireless optical sensor for continuous monitoring of hepatic hemodynamics.
PMCID: PMC4097065  PMID: 25019160
20.  Intermolecular Interactions between Eosin Y and Caffeine Using 1H-NMR Spectroscopy 
DETECHIP has been used in testing analytes including caffeine, cocaine, and tetrahydrocannabinol (THC) from marijuana, as well as date rape and club drugs such as flunitrazepam, gamma-hydroxybutyric acid (GHB), and methamphetamine. This study investigates the intermolecular interaction between DETECHIP sensor eosin Y (DC1) and the analyte (caffeine) that is responsible for the fluorescence and color changes observed in the actual array. Using 1H-NMR, 1H-COSY, and 1H-DOSY NMR methods, a proton exchange from C-8 of caffeine to eosin Y is proposed.
PMCID: PMC4091800  PMID: 25018772
23.  Pervasive alterations of emotional and neuroendocrine responses to an acute stressor after neonatal amygdala lesions in rhesus monkeys 
Psychoneuroendocrinology  2012;38(7):1021-1035.
The current study examined the long-term effects of neonatal amygdala lesions on emotional and hypothalamic-pituitary-adrenal (HPA) axis reactivity to an acute stressor in rhesus monkeys. Rhesus monkeys received either bilateral MRI-guided ibotenic acid amygdala (Neo-Aibo; n = 6) or sham (Neo-C; n = 7) lesions between 7–14 days of age. Emotional reactivity was assessed using the Human Intruder paradigm at 2 months, 4.5 months, and 6–8 years of age, whereas stress neuroendocrine response was only assessed in adulthood (6–8 years). The modulation of defensive and emotional behaviors based on the gaze direction of the intruder emerged between 2–4 months of age in surrogate-peer reared sham-operated infant monkeys, as already shown for mother-reared infants. Although neonatal amygdala lesions did not impair the ability to exhibit defensive and emotional behaviors, it altered the modulation of these responses based on the intruder’s gaze direction. The changes in emotional reactivity after neonatal amygdala lesions emerged in infancy and persisted throughout adulthood when they were associated with a reduction of basal cortisol levels and a blunted cortisol response to the stressor. These changes are reminiscent of those found after adult-onset amygdala lesions, demonstrating little functional compensation following early amygdala damage.
PMCID: PMC3593974  PMID: 23148887
Amygdala; Emotion; Development; HPA-axis
24.  Using a Delphi Technique to Seek Consensus Regarding Definitions, Descriptions and Classification of Terms Related to Implicit and Explicit Forms of Motor Learning 
PLoS ONE  2014;9(6):e100227.
Motor learning is central to domains such as sports and rehabilitation; however, often terminologies are insufficiently uniform to allow effective sharing of experience or translation of knowledge. A study using a Delphi technique was conducted to ascertain level of agreement between experts from different motor learning domains (i.e., therapists, coaches, researchers) with respect to definitions and descriptions of a fundamental conceptual distinction within motor learning, namely implicit and explicit motor learning.
A Delphi technique was embedded in multiple rounds of a survey designed to collect and aggregate informed opinions of 49 international respondents with expertise related to motor learning. The survey was administered via an online survey program and accompanied by feedback after each round. Consensus was considered to be reached if ≥70% of the experts agreed on a topic.
Consensus was reached with respect to definitions of implicit and explicit motor learning, and seven common primary intervention strategies were identified in the context of implicit and explicit motor learning. Consensus was not reached with respect to whether the strategies promote implicit or explicit forms of learning.
The definitions and descriptions agreed upon may aid translation and transfer of knowledge between domains in the field of motor learning. Empirical and clinical research is required to confirm the accuracy of the definitions and to explore the feasibility of the strategies that were identified in research, everyday practice and education.
PMCID: PMC4072669  PMID: 24968228
25.  Magnetically Assisted Remote-controlled Endovascular Catheter for Interventional MR Imaging: In Vitro Navigation at 1.5 T versus X-ray Fluoroscopy 
Radiology  2014;271(3):862-869.
To compare in vitro navigation of a magnetically assisted remote-controlled (MARC) catheter under real-time magnetic resonance (MR) imaging with manual navigation under MR imaging and standard x-ray guidance in endovascular catheterization procedures in an abdominal aortic phantom.
Materials and Methods
The 2-mm-diameter custom clinical-grade microcatheter prototype with a solenoid coil at the distal tip was deflected with a foot pedal actuator used to deliver 300 mA of positive or negative current. Investigators navigated the catheter into branch vessels in a custom cryogel abdominal aortic phantom. This was repeated under MR imaging guidance without magnetic assistance and under conventional x-ray fluoroscopy. MR experiments were performed at 1.5 T by using a balanced steady-state free precession sequence. The mean procedure times and percentage success data were determined and analyzed with a linear mixed-effects regression analysis.
The catheter was clearly visible under real-time MR imaging. One hundred ninety-two (80%) of 240 turns were successfully completed with magnetically assisted guidance versus 144 (60%) of 240 turns with nonassisted guidance (P < .001) and 119 (74%) of 160 turns with standard x-ray guidance (P = .028). Overall mean procedure time was shorter with magnetically assisted than with nonassisted guidance under MR imaging (37 seconds ± 6 [standard error of the mean] vs 55 seconds ± 3, P < .001), and time was comparable between magnetically assisted and standard x-ray guidance (37 seconds ± 6 vs 44 seconds ± 3, P = .045). When stratified by angle of branch vessel, magnetic assistance was faster than nonassisted MR guidance at turns of 45°, 60°, and 75°.
In this study, a MARC catheter for endovascular navigation under real-time MR imaging guidance was developed and tested. For catheterization of branch vessels arising at large angles, magnetically assisted catheterization was faster than manual catheterization under MR imaging guidance and was comparable to standard x-ray guidance.
PMCID: PMC4065602  PMID: 24533872

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