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1.  Assessing and improving acoustic radiation force image quality using a 1.5D transducer design 
A 1.5D transducer array was developed to improve acoustic radiation force impulse (ARFI) imaging signal-to-noise ratio (SNRARFI) and image contrast relative to a conventional 1D array. To predict performance gains from the proposed 1.5D transducer array, an analytical model for SNRARFI upper bound was derived. The analytical model and 1.5D ARFI array were validated using a finite element model-based numerical simulation framework. The analytical model demonstrated good agreement with numerical results (correlation coefficient = 0.995), and simulated lesion images yielded a significant (2.92 dB; p < 0.001) improvement in contrast-to-noise ratio when rendered using the 1.5D ARFI array.
PMCID: PMC4047991  PMID: 22828855
Acoustic Radiation Force Impulse Imaging; ARFI; Echo Decorrelation; 1.5D Array
2.  Estimating the Burden of Paratyphoid A in Asia and Africa 
Despite the increasing availability of typhoid vaccine in many regions, global estimates of mortality attributable to enteric fever appear stable. While both Salmonella enterica serovar Typhi (S. Typhi) and serovar Paratyphi (S. Paratyphi) cause enteric fever, limited data exist estimating the burden of S. Paratyphi, particularly in Asia and Africa.
We performed a systematic review of both English and Chinese-language databases to estimate the regional burden of paratyphoid within Africa and Asia. Distinct from previous reviews of the topic, we have presented two separate measures of burden; both incidence and proportion of enteric fever attributable to paratyphoid. Included articles reported laboratory-confirmed Salmonella serovar classification, provided clear methods on sampling strategy, defined the age range of participants, and specified the time period of the study.
A total of 64 full-text articles satisfied inclusion criteria and were included in the qualitative synthesis. Paratyphoid A was commonly identified as a cause of enteric fever throughout Asia. The highest incidence estimates in Asia came from China; four studies estimated incidence rates of over 150 cases/100,000 person-years. Paratyphoid A burden estimates from Africa were extremely limited and with the exception of Nigeria, few population or hospital-based studies from Africa reported significant Paratyphoid A burden.
While significant gaps exist in the existing population-level estimates of paratyphoid burden in Asia and Africa, available data suggest that paratyphoid A is a significant cause of enteric fever in Asia. The high variability in documented incidence and proportion estimates of paratyphoid suggest considerable geospatial variability in the burden of paratyphoid fever. Additional efforts to monitor enteric fever at the population level will be necessary in order to accurately quantify the public health threat posed by S. Paratyphi A, and to improve the prevention and treatment of enteric fever.
Author Summary
Enteric fever due to Salmonella enterica serovar Typhi (S. Typhi) and serovar Paratyphi (S. Paratyphi A, B, C) remains a global public health concern. While numerous studies have estimated the levels or burden of S. Typhi, there are only limited data estimating the burden of S. Paratyphi A, particularly in Asia and Africa. We reviewed both English and Chinese-language databases for estimates of the regional burden within Africa and Asia, including new paratyphoid A cases/year and proportion of enteric fever cases attributable to paratyphoid A. S. Paratyphi A appears to constitute a significant proportion of all cases of enteric fever in Asia, though population level estimates are limited, especially in Africa. There was high variability in reported paratyphoid A burden estimates, which suggests considerable geospatial variability in the burden of paratyphoid fever. Improved efforts to monitor enteric fever at the population level are warranted in order to correctly measure the public health threat posed by S. Paratyphi A and to determine the potential need for S. Paratyphi specific prevention and treatment interventions.
PMCID: PMC4046978  PMID: 24901439
3.  Medical Treatment of Essential Tremor 
Essential tremor (ET) is the most common pathological tremor characterized by upper limb action—postural tremor (PT)/kinetic tremor (KT). There are no specific neuropathological or biochemical abnormalities in ET. The disability is consequent to amplitude of KT, which may remain mild without handicap or may become disabling. The most effective drugs for sustained tremor control are propranolol and primidone. Symptomatic drug treatment must be individualized depending on the circumstances that provoke the tremor-related disability. Broad guidelines for treatment are discussed in this review. Patients may be treated intermittently only on stressful occasions with propranolol, clonazepam, or primidone monotherapy, or an alcoholic drink. Those with persistently disabling tremor need continued treatment.
PMCID: PMC3999812  PMID: 24812533
essential tremor; medical treatment; diagnosis; pathophysiology; drugs; individualized treatment
4.  Nox4 NADPH oxidase contributes to smooth muscle cell phenotypes associated with unstable atherosclerotic plaques 
Redox Biology  2014;2:642-650.
Plaque instability associated with acute coronary syndromes results in part from apoptosis and senescence of cells within the atherosclerotic (AS) lesion. Increased cellular oxidative stress has been proposed to contribute to plaque progression and changes in composition, leading to plaque instability. Our objective was to examine the role of NADPH oxidase in smooth muscle cell (SMC) phenotypes associated with an unstable plaque. Aortae were isolated from pre-lesion (8 weeks of age) and post-lesion (35 weeks of age) hypercholesterolemic mice (ApoE-/-/LDLR-/-, AS), and age-matched normal C57BL/6J mice. We observed an age-dependent increase in reactive oxygen species (ROS) in aorta from AS mice, with evidence for elevated ROS prior to lesion development. Whereas macrophage infiltration was restricted to the lesion, oxidized lipids extended beyond the plaque and into the vessel wall. Consistent with these findings, we observed dynamic changes in the expression of NADPH oxidases in AS vessels. Specifically, Nox1 expression was increased early and decreased with lesion progression, while induction of Nox4 was a late event. Nox2 and p22phox were elevated throughout lesion development. Similar to observations in aortae, SMCs isolated from the lesion of AS aortae had decreased Nox1 and increased Nox4 levels as compared to SMCs from normal mice. AS SMCs demonstrated increased generation of ROS, cell cycle arrest, evidence of senescence, and increased susceptibility to apoptosis. Overexpression of Nox4 in normal SMCs recapitulated the phenotypes of the AS SMCs. We conclude that increased expression of Nox4 in AS may drive SMC phenotypes that lead to the plaque instability and rupture responsible for myocardial infarction and stroke.
•Increases in ROS and Nox1 expression precede atherosclerotic lesion development.•Development of atherosclerotic plaque is associated with expression of Nox4.•SMCs derived from atherosclerotic vessels have elevated Nox4 expression and ROS.•Nox4 contributes to the senescent phenotype and apoptosis in plaque SMCs.•Increased Nox4 may play a role in plaque rupture and myocardial infarction.
Graphical abstract
PMCID: PMC4052526  PMID: 24936437
Atherosclerosis; Smooth muscle; Reactive oxygen species; NADPH oxidase; Oxidative stress
5.  Establishing Magnetic Resonance Imaging as an Accurate and Reliable Tool to Diagnose and Monitor Esophageal Cancer in a Rat Model 
PLoS ONE  2014;9(4):e93694.
To assess the reliability of magnetic resonance imaging (MRI) for detection of esophageal cancer in the Levrat model of end-to-side esophagojejunostomy.
The Levrat model has proven utility in terms of its ability to replicate Barrett’s carcinogenesis by inducing gastroduodenoesophageal reflux (GDER). Due to lack of data on the utility of non-invasive methods for detection of esophageal cancer, treatment efficacy studies have been limited, as adenocarcinoma histology has only been validated post-mortem. It would therefore be of great value if the validity and reliability of MRI could be established in this setting.
Chronic GDER reflux was induced in 19 male Sprague-Dawley rats using the modified Levrat model. At 40 weeks post-surgery, all animals underwent endoscopy, MRI scanning, and post-mortem histological analysis of the esophagus and anastomosis. With post-mortem histology serving as the gold standard, assessment of presence of esophageal cancer was made by five esophageal specialists and five radiologists on endoscopy and MRI, respectively.
The accuracy of MRI and endoscopic analysis to correctly identify cancer vs. no cancer was 85.3% and 50.5%, respectively. ROC curves demonstrated that MRI rating had an AUC of 0.966 (p<0.001) and endoscopy rating had an AUC of 0.534 (p = 0.804). The sensitivity and specificity of MRI for identifying cancer vs. no-cancer was 89.1% and 80% respectively, as compared to 45.5% and 57.5% for endoscopy. False positive rates of MRI and endoscopy were 20% and 42.5%, respectively.
MRI is a more reliable diagnostic method than endoscopy in the Levrat model. The non-invasiveness of the tool and its potential to volumetrically quantify the size and number of tumors likely makes it even more useful in evaluating novel agents and their efficacy in treatment studies of esophageal cancer.
PMCID: PMC3976303  PMID: 24705451
6.  A retrospective analysis of survival and prognostic factors of male breast cancer from a single center 
BMC Cancer  2014;14:227.
Less than 1% of all breast cancer cases are found in men, who reportedly have inferior outcomes compared with matched women patients. Ethnic differences may also affect their prognosis. Here, we investigated overall survival (OS) and major prognostic factors for male breast cancer (MBC) in a cohort of Egyptian patients.
We retrospectively analyzed OS in a cohort of 69 male patients with MBC who were surgically treated at the Mansoura Cancer Center, Egypt between 2000 and 2007. We registered demographic data, age, height, weight and body mass index, tumor size, histology, number of infiltrated axillary lymph nodes, hormone receptor (HR) status and metastatic presence, and TNM staging. Patients’ OS was the primary endpoint. Patients received treatment to the medical standards at the time of their diagnosis.
In the 69 patients who met the inclusion criteria and had complete stored patient data, tumors ranged from T1c to T3. We could gather cancer-related survival data from only 56 patients. The collective 5-year survival in this cohort was 46.4%. Only five patients had distant metastasis at diagnosis, but they showed a null percent 5-year survival, whereas those with no lymph node infiltration showed a 100% 5-year survival. Lymph node status and tumor grading were the only prognostic factors that significantly affected OS.
Lymph node status and tumor grade are the most important prognostic factors for overall survival of MBC in Egyptian male patients; whereas even remarkably low HR expression in MBC did not significantly affect OS. Further research is needed to understand the factors that affect this disease.
PMCID: PMC3987167  PMID: 24673740
Male breast cancer; Overall survival; Prognostic factors; Hormone receptor status
7.  Cigarette smoking prevalence in US counties: 1996-2012 
Cigarette smoking is a leading risk factor for morbidity and premature mortality in the United States, yet information about smoking prevalence and trends is not routinely available below the state level, impeding local-level action.
We used data on 4.7 million adults age 18 and older from the Behavioral Risk Factor Surveillance System (BRFSS) from 1996 to 2012. We derived cigarette smoking status from self-reported data in the BRFSS and applied validated small area estimation methods to generate estimates of current total cigarette smoking prevalence and current daily cigarette smoking prevalence for 3,127 counties and county equivalents annually from 1996 to 2012. We applied a novel method to correct for bias resulting from the exclusion of the wireless-only population in the BRFSS prior to 2011.
Total cigarette smoking prevalence varies dramatically between counties, even within states, ranging from 9.9% to 41.5% for males and from 5.8% to 40.8% for females in 2012. Counties in the South, particularly in Kentucky, Tennessee, and West Virginia, as well as those with large Native American populations, have the highest rates of total cigarette smoking, while counties in Utah and other Western states have the lowest. Overall, total cigarette smoking prevalence declined between 1996 and 2012 with a median decline across counties of 0.9% per year for males and 0.6% per year for females, and rates of decline for males and females in some counties exceeded 3% per year. Statistically significant declines were concentrated in a relatively small number of counties, however, and more counties saw statistically significant declines in male cigarette smoking prevalence (39.8% of counties) than in female cigarette smoking prevalence (16.2%). Rates of decline varied by income level: counties in the top quintile in terms of income experienced noticeably faster declines than those in the bottom quintile.
County-level estimates of cigarette smoking prevalence provide a unique opportunity to assess where prevalence remains high and where progress has been slow. These estimates provide the data needed to better develop and implement strategies at a local and at a state level to further reduce the burden imposed by cigarette smoking.
PMCID: PMC3987818  PMID: 24661401
Smoking; Tobacco; Disparities; BRFSS; Geographic patterns; Small area estimation
8.  Metabotropic Glutamate Receptor-1 as a Novel Target for the Antiangiogenic Treatment of Breast Cancer 
PLoS ONE  2014;9(3):e88830.
Metabotropic glutamate receptors (mGluRs) are normally expressed in the central nervous system, where they mediate neuronal excitability and neurotransmitter release. Certain cancers, including melanoma and gliomas, express various mGluR subtypes that have been implicated as playing a role in disease progression. Recently, we detected metabotropic glutamate receptor-1 (gene: GRM1; protein: mGluR1) in breast cancer and found that it plays a role in the regulation of cell proliferation and tumor growth. In addition to cancer cells, brain endothelial cells express mGluR1. In light of these studies, and because angiogenesis is both a prognostic indicator in cancer correlating with a poorer prognosis and a potential therapeutic target, we explored a potential role for mGluR1 in mediating endothelial cell (EC) proliferation and tumor-induced angiogenesis. GRM1 and mGluR1 were detected in various types of human ECs and, using mGluR1-specific inhibitors or shRNA silencing, we demonstrated that EC growth and Matrigel tube formation are dependent on mGluR1 signaling. In addition, loss of mGluR1 activity leads to reduced angiogenesis in a murine Matrigel sponge implant model as well as a murine tumor model. These results suggest a role for mGluR1 in breast cancer as a pro-angiogenic factor as well as a mediator of tumor progression. They also suggest mGluR1 as a potential new molecular target for the anti-angiogenic therapy of breast cancer.
PMCID: PMC3954556  PMID: 24633367
9.  Epigenetic mechanisms and models in the origins of asthma 
Purpose of the review
Epigenetic mechanisms have the ability to alter the phenotype without changing the genetic code. The science of epigenetics has grown considerably in recent years, and future epigenetically-based treatments or prevention strategies are likely. Epigenetic associations with asthma have received growing interest because genetic and environmental factors have been unable to independently explain the etiology of asthma.
Recent Findings
Recent findings suggest that both the environment and underlying genetic sequence variation influence DNA methylation, which in turn seems to modify the risk conferred by genetic variants for various asthma phenotypes. In particular DNA methylation may act as an archive of a variety of early developmental exposures which then can modify the risk related to genetic variants.
Current asthma treatments may control the symptoms of asthma but do not modify its natural history. Epigenetic mechanisms and novel explanatory models provide burgeoning approaches to significantly increase our understanding of the initiation and progression of asthma. This will lead to critical information to prevent or treat asthma not only in the current generation, but due to the epigenetic inheritance may also prevent asthma in future generations.
PMCID: PMC3952069  PMID: 23242116
Asthma; Epigenetics; DNA methylation; methylation quantitative trait loci; modifiable genetic variants
10.  Nonarteritic ischemic optic neuropathy developed after capsular block syndrome 
Indian Journal of Ophthalmology  2014;62(3):346-348.
A 65-year-old man developed capsular block syndrome in the early postoperative period, following phacoemulsification surgery. After neodymium-doped yttrium aluminum garnet (Nd:YAG) laser anterior capsulotomy, the intraocular pressure remained elevated for 4 days despite antiglaucomatous medication. On the postoperative fifth day, nonarteritic ischemic optic neuropathy was diagnosed. To the best of our knowledge, this is the first report of a case with nonarteritic ischemic optic neuropathy associated with early postoperative capsular block syndrome after phacoemulsification surgery.
PMCID: PMC4061678  PMID: 23619487
Capsular block syndrome; optic neuropathy; phacoemulsification
11.  Focused Ultrasound-Mediated Drug Delivery from Microbubbles Reduces Drug Dose Necessary for Therapeutic Effect on Neointima Formation 
We hypothesized that 1) neointimal formation in a rat carotid balloon injury model could be reduced in vivo following targeted ultrasound delivery of rapamycin-loaded microbubbles (RMBs), and 2) the addition of dual mode ultrasound decreases the total amount of drug needed to reduce neointima formation.
Methods and Results
Balloon injury was performed in rat carotids to induce neointima formation. High or low doses of RMBs were injected I.V. and ruptured at the site of injury with ultrasound. Compared to non-treated injured arteries, neointima formation was reduced by 0% and 35.9% with 108 RMBs, and by 28.7% and 34.9% in arteries treated with 109 RMBs with and without ultrasound respectively.
Without ultrasound, 10-fold higher concentrations of RMBs were needed to reduce neointima formation by at least 28%, whereas 108 RMBs combined with ultrasound were sufficient to achieve the same therapeutic effect demonstrating that this technology may have promise for localized potent drug therapy.
PMCID: PMC3935345  PMID: 21960561
Balloon Injury; Ultrasound; Microbubbles; Drug Delivery; Rats
12.  Astronomical algorithms for automated analysis of tissue protein expression in breast cancer 
British Journal of Cancer  2013;108(3):602-612.
High-throughput evaluation of tissue biomarkers in oncology has been greatly accelerated by the widespread use of tissue microarrays (TMAs) and immunohistochemistry. Although TMAs have the potential to facilitate protein expression profiling on a scale to rival experiments of tumour transcriptomes, the bottleneck and imprecision of manually scoring TMAs has impeded progress.
We report image analysis algorithms adapted from astronomy for the precise automated analysis of IHC in all subcellular compartments. The power of this technique is demonstrated using over 2000 breast tumours and comparing quantitative automated scores against manual assessment by pathologists.
All continuous automated scores showed good correlation with their corresponding ordinal manual scores. For oestrogen receptor (ER), the correlation was 0.82, P<0.0001, for BCL2 0.72, P<0.0001 and for HER2 0.62, P<0.0001. Automated scores showed excellent concordance with manual scores for the unsupervised assignment of cases to ‘positive' or ‘negative' categories with agreement rates of up to 96%.
The adaptation of astronomical algorithms coupled with their application to large annotated study cohorts, constitutes a powerful tool for the realisation of the enormous potential of digital pathology.
PMCID: PMC3593538  PMID: 23329232
image analysis; immunohistochemistry; breast cancer; systems pathology; digital pathology
13.  Aspirin use and knowledge in the community: a population- and health facility based survey for measuring local health system performance 
Little is known about the relationship between cardiovascular risk, disease and actual use of aspirin in the community.
The Measuring Disparities in Chronic Conditions (MDCC) study is a community and health facility-based survey designed to track disparities in the delivery of health interventions for common chronic diseases. MDCC includes a survey instrument designed to collect detailed information about aspirin use. In King County, WA between 2011 and 2012, we surveyed 4633 white, African American, or Hispanic adults (45% home address-based sample, 55% health facility sample). We examined self-reported counseling on, frequency of use and risks of aspirin for all respondents. For a subgroup free of CAD or cerebral infarction that underwent physical examination, we measured 10-year coronary heart disease risk and blood salicylate concentration.
Two in five respondents reported using aspirin routinely while one in five with a history of CAD or cerebral infarction and without contraindication did not report routine use of aspirin. Women with these conditions used less aspirin than men (65.0% vs. 76.5%) and reported more health problems that would make aspirin unsafe (29.4% vs. 21.2%). In a subgroup undergoing phlebotomy a third of respondents with low cardiovascular risk used aspirin routinely and only 4.6% of all aspirin users had no detectable salicylate in their blood.
In this large urban county where health care delivery should be of high quality, there is insufficient aspirin use among those with high cardiovascular risk or disease and routine aspirin use by many at low risk. Further efforts are needed to promote shared-decision making between patients and clinicians as well as inform the public about appropriate use of routine aspirin to reduce the burden of atherosclerotic vascular disease.
PMCID: PMC3922250  PMID: 24507089
Aspirin; Prevention; Coronary disease
14.  Analytical modeling of glucose biosensors based on carbon nanotubes 
In recent years, carbon nanotubes have received widespread attention as promising carbon-based nanoelectronic devices. Due to their exceptional physical, chemical, and electrical properties, namely a high surface-to-volume ratio, their enhanced electron transfer properties, and their high thermal conductivity, carbon nanotubes can be used effectively as electrochemical sensors. The integration of carbon nanotubes with a functional group provides a good and solid support for the immobilization of enzymes. The determination of glucose levels using biosensors, particularly in the medical diagnostics and food industries, is gaining mass appeal. Glucose biosensors detect the glucose molecule by catalyzing glucose to gluconic acid and hydrogen peroxide in the presence of oxygen. This action provides high accuracy and a quick detection rate. In this paper, a single-wall carbon nanotube field-effect transistor biosensor for glucose detection is analytically modeled. In the proposed model, the glucose concentration is presented as a function of gate voltage. Subsequently, the proposed model is compared with existing experimental data. A good consensus between the model and the experimental data is reported. The simulated data demonstrate that the analytical model can be employed with an electrochemical glucose sensor to predict the behavior of the sensing mechanism in biosensors.
PMCID: PMC3898395  PMID: 24428818
Carbon nanotube; SWCNT FET; Glucose detection; Biosensor; Analytical model; I-V characteristics; PBS; Glucose oxide
15.  Combined choroidal neovascularization and hypopituitarism in a patient with homozygous mutation in methylenetetrahydrofolate reductase gene 
We report a case of choroidal neovascularization (CNV) secondary to methylenetetrahydrofolate reductase (MTHFR) gene mutation in a 20-year-old male patient with hypopituitarism. Treatment with three consecutive injections of intravitreal ranibizumab (anti-vascular endothelial growth factor) resulted in significant improvement of the patient's vision and the appearance of the macula. A search of the literature produced no previously reported case of MTHFR gene mutation associated both CNV and possibly hypopituitarism. With hormone replacement therapy of hypopituitarism, acetyl salicylic acid 100 mg/day also was started. The patient was clinically stable both for CNV and other thromboembolic disorders over a 6-month follow-up and also 1-year follow-up period.
PMCID: PMC3963328  PMID: 24672570
Choroidal neovascularization; drug therapy; hypopituitarism; intravitreal injections; methylenetetrahydrofolate reductase deficiency; MTHFR; ranibizumab; vascular endothelial growth factor
16.  Primary Subcutaneous Hydatid Cyst with Palisading Granulomatous Reaction 
Case Reports in Pathology  2013;2013:126541.
Palisading granulomatous reactions are prominent microscopic characteristics that are seen in many diseases. Isolated subcutaneous cystic echinococcosis is rarely documented. Palisading granuloma as a host immune reaction to Echinococcus granulosus in an isolated primary subcutaneous hydatid cyst has been reported only once before. In this report, we are describing a 53-year-old male who developed a slowly growing subcutaneous thigh mass. Light microscopy confirmed the presence of hydatid cyst. Further radiological workup for liver and lung has not shown any visceral hydatid focus.
PMCID: PMC3872406  PMID: 24386579
17.  Disparities in HIV Screening among Pregnant Women – El Salvador, 2011 
PLoS ONE  2013;8(12):e82760.
To provide an accurate estimate of antenatal HIV screening and its determinants among pregnant women in El Salvador and help local authorities make informed decisions for targeted interventions around mother-to-child transmission (MTCT).
A total sample of 4,730 women aged 15-49 years were interviewed from a random sample of 3,625 households. We collected data on antenatal care services, including HIV screening, during last pregnancy through a pre-established questionnaire. We used a backward elimination multivariate logistic regression model to examine the association between HIV screening and sociodemographic and health care-related factors.
A total of 2,929 women were included in this analysis. About 98% of participants reported receiving antenatal care, but only 83% of these reported being screened for HIV. Screening was lower in geographic areas with higher HIV incidence and ranged from 69.1% among women who were not seen by a physician during antenatal care, to 93.7% among those who attended or completed college. Odds for screening varied also by age, employment status, household economic expenditure, possession of health care coverage, health care settings, and number of antenatal care visits.
We found disparities in HIV screening during antenatal care at the environmental, social, demographic, and structural levels despite a high uptake of antenatal care in El Salvador. Our findings should urge health authorities to tailor and enhance current strategies implemented to eliminate MTCT and reduce inequities and HIV morbidity among women in El Salvador.
PMCID: PMC3857257  PMID: 24349356
Hand‐held dynamometers are commonly used to assess plantarflexor strength during rehabilitation. The purpose of this study was to determine the concurrent validity of measuring plantarflexion force using a hand‐held dynamometer (HHD) as compared to an electromechanical dynamometer as the gold standard. The hypothesis was that plantarflexor forces obtained using a hand‐held dynamometer would not show absolute agreement with a criterion standard.
Concurrent validity assessment for a diagnostic strength testing device.
Institutional clinic and research laboratory
Volunteer sample of healthy university students (N=20, 10 women, 10 men; 25.9±4.1 years).
Main Outcome Measure(s):
Maximal plantarflexion strength was measured using both a HHD and an electromechanical dynamometer (EMD) as a criterion measure.
Plantarflexor force measures with the HHD were significantly different (p<0.01) and not correlated with plantarflexor forces measured using the EMD for either limb (R2 ≤ 0.09).
Plantarflexor strength measurements acquired using HHD are different from those acquired using an EMD and are likely influenced by the strength of the examiner.
Level of Evidence:
Prospective cohort study, level II
PMCID: PMC3867075  PMID: 24377068
Diagnostic strength; triceps surae; concurrent validity
19.  Brain Iron Detected by SWI High Pass Filtered Phase Calibrated with Synchrotron X-Ray Fluorescence 
Journal of magnetic resonance imaging : JMRI  2010;31(6):10.1002/jmri.22201.
To test the ability of susceptibility weighted images (SWI) and high pass filtered phase images to localize and quantify brain iron.
Materials and Methods
Magnetic resonance (MR) images of human cadaver brain hemispheres were collected using a gradient echo based SWI sequence at 1.5T. For X-ray fluorescence (XRF) mapping, each brain was cut to obtain slices that reasonably matched the MR images and iron was mapped at the iron K-edge at 50 or 100 μm resolution. Iron was quantified using XRF calibration foils. Phase and iron XRF were averaged within anatomic regions of one slice, chosen for its range of iron concentrations and nearly perfect anatomic correspondence. X-ray absorption spectroscopy (XAS) was used to determine if the chemical form of iron was different in regions with poorer correspondence between iron and phase.
Iron XRF maps, SWI, and high pass filtered phase data in nine brain slices from five subjects were visually very similar, particularly in high iron regions. The chemical form of iron could not explain poor matches. The correlation between the concentration of iron and phase in the cadaver brain was estimated as cFe [μg/g tissue] = 850Δφ + 110.
The phase shift Δφ was found to vary linearly with iron concentration with the best correspondence found in regions with high iron content.
PMCID: PMC3843009  PMID: 20512886 CAMSID: cams3710
iron; phase imaging; x-ray fluorescence; susceptibility weighted imaging; human
20.  Epidemiologic Methods of Assessing Asthma and Wheezing Episodes in Longitudinal Studies: Measures of Change and Stability 
Journal of Epidemiology  2013;23(6):399-410.
In settings in which diseases wax and wane, there is a need to measure disease dynamics in longitudinal studies. Traditional measures of disease occurrence (eg, cumulative incidence) do not address change or stability or are limited to stable cohorts (eg, incidence) and may thus lead to erroneous conclusions. To illustrate how different measures can be used to detect disease dynamics, we investigated sex differences in the occurrence of asthma and wheezing, using a population-based study cohort that covered the first 18 years of life.
In the Isle of Wight birth cohort (n = 1456), prevalence, incidence, cumulative incidence, positive and negative transitions, and remission were determined at ages 1 or 2, 4, 10, and 18 years. Latent transition analysis was used to simultaneously identify classes of asthma and wheezing (related phenotypes) and characterize transition probabilities over time. Trajectory analysis was used to characterize the natural history of asthma and wheezing.
Regarding time-specific changes, positive and negative transition probabilities were more informative than other measures of associations because they revealed a sex switchover in asthma prevalence (P < 0.05). Transition probabilities were able to identify the origin of a sex-specific dynamic; in particular, prior wheezing transitioned to asthma at age 18 years among girls but not among boys. In comparison with latent transition analysis, trajectory analysis did not directly identify a switchover in prevalence among boys and girls.
In longitudinal analyses, transition analyses that impose minimal restrictions on data are needed in order to produce appropriate information on disease dynamics.
PMCID: PMC3834276  PMID: 23994864
asthma; cohort study; incidence; prevalence; trajectory; transition probability
21.  Prognostic Value and Targeted Inhibition of Survivin Expression in Esophageal Adenocarcinoma and Cancer-Adjacent Squamous Epithelium 
PLoS ONE  2013;8(11):e78343.
Survivin is an inhibitor of apoptosis and its over expression is associated with poor prognosis in several malignancies. While several studies have analyzed survivin expression in esophageal squamous cell carcinoma, few have focused on esophageal adenocarcinoma (EAC) and/or cancer-adjacent squamous epithelium (CASE). The purpose of this study was 1) to determine the degree of survivin up regulation in samples of EAC and CASE, 2) to evaluate if survivin expression in EAC and CASE correlates with recurrence and/or death, and 3) to examine the effect of survivin inhibition on apoptosis in EAC cells.
Fresh frozen samples of EAC and CASE from the same patient were used for qRT-PCR and Western blot analysis, and formalin-fixed, paraffin-embedded tissue was used for immunohistochemistry. EAC cell lines, OE19 and OE33, were transfected with small interfering RNAs (siRNAs) to knockdown survivin expression. This was confirmed by qRT-PCR for survivin expression and Western blot analysis of cleaved PARP, cleaved caspase 3 and survivin. Survivin expression data was correlated with clinical outcome.
Survivin expression was significantly higher in EAC tumor samples compared to the CASE from the same patient. Patients with high expression of survivin in EAC tumor had an increased risk of death. Survivin expression was also noted in CASE and correlated with increased risk of distant recurrence. Cell line evaluation demonstrated that inhibition of survivin resulted in an increase in apoptosis.
Higher expression of survivin in tumor tissue was associated with increased risk of death; while survivin expression in CASE was a superior predictor of recurrence. Inhibition of survivin in EAC cell lines further showed increased apoptosis, supporting the potential benefits of therapeutic strategies targeted to this marker.
PMCID: PMC3817247  PMID: 24223792
22.  Platelet-derived CD154: ultrastructural localization and clinical correlation in organ transplantation 
CD154 is an immunostimulatory ligand for CD40 that markedly influences alloimmunity. Its presence in platelets suggests that its release and subsequent immune effects are driven by trauma and thus could be relevant following organ transplantation. However, the release of platelet derived CD154 and its consequences have not been investigated in a clinical transplant setting. To better characterize the relationship between platelet activation and CD154 release, we investigated CD154 release by platelets obtained from normal individuals, and patients with two genetic defects that influence platelet granule development. Using these unique patient populations and immune-electron microscopy, we confirmed that CD154 was an alpha granule and not a cell surface protein, and thereafter optimized the methods for its in vivo measurement in humans. We then investigated plasma CD154 levels in kidney and liver transplant recipients and found no evidence that CD154 levels fluctuated systemically as a result of kidney or liver transplant procedures. Paradoxically, we found that kidney transplant patients had significantly lower systemic CD154 levels during episodes of rejection. These data suggest that the immune effects of CD154 are likely mediated through local and not systemic mechanisms, and discourage the use of CD154 as a peripheral biomarker in organ transplantation.
PMCID: PMC3484197  PMID: 22947105
platelets; co-stimulation; trauma
23.  Post-translational regulation enables robust p53 regulation 
BMC Systems Biology  2013;7:83.
The tumor suppressor protein p53 plays important roles in DNA damage repair, cell cycle arrest and apoptosis. Due to its critical functions, the level of p53 is tightly regulated by a negative feedback mechanism to increase its tolerance towards fluctuations and disturbances. Interestingly, the p53 level is controlled by post-translational regulation rather than transcriptional regulation in this feedback mechanism.
We analyzed the dynamics of this feedback to understand whether post-translational regulation provides any advantages over transcriptional regulation in regard to disturbance rejection. When a disturbance happens, even though negative feedback reduces the steady-state error, it can cause a system to become less stable and transiently overshoots, which may erroneously trigger downstream reactions. Therefore, the system needs to balance the trade-off between steady-state and transient errors. Feedback control and adaptive estimation theories revealed that post-translational regulation achieves a better trade-off than transcriptional regulation, contributing to a more steady level of p53 under the influence of noise and disturbances. Furthermore, post-translational regulation enables cells to respond more promptly to stress conditions with consistent amplitude. However, for better disturbance rejection, the p53- Mdm2 negative feedback has to pay a price of higher stochastic noise.
Our analyses suggest that the p53-Mdm2 feedback favors regulatory mechanisms that provide the optimal trade-offs for dynamic control.
PMCID: PMC3844394  PMID: 23992617
Feedback control theory; p53-Mdm2 feedback loop; Robustness; Disturbance rejection
After unilateral total knee arthroplasty (TKA), osteoarthritis (OA) in the non-operated often progresses. The altered gait mechanics exhibited by patients after TKA increase the loading on the non-operated knee and predispose it to disease progression. Therefore, our objective was to examine the potentially detrimental changes in frontal plane kinetics and kinematics during walking in patients who underwent unilateral TKA. Thirty one subjects six months after TKA, forty four subjects one year after unilateral TKA and twenty control subjects were recruited. All subjects underwent three dimensional gait analysis. In the TKA groups, the non-operated knee had a higher adduction angle and higher dynamic loading, knee adduction moment and impulse, compared to the operated knee. This increased loading may be an underlying reason for OA progression in the non-operated knee. Measures of loading in the control knee did not differ from that of the non-operated knee in the TKA group, but the TKA group walked with shorter step length. Whilst the non-operated knee loading was not different from controls, there may be greater risk of cumulative loading in the non-operated knee of the TKA group given their shorter step length.
PMCID: PMC3754839  PMID: 21437943
Physics in medicine and biology  2012;57(16):5275-5293.
Ultrasound-based real-time molecular imaging in large blood vessels holds promise for early detection and diagnosis of various important and significant diseases, such as stroke, atherosclerosis, and cancer. Central to the success of this imaging technique is the isolation of ligand-receptor bound adherent microbubbles from free microbubbles and tissue structures. In this paper, we present an alternative approach, termed singular spectrum-based targeted molecular (SiSTM) imaging, which separates signal components using singular value spectra content over local regions of complex echo data. Simulations were performed to illustrate the effects of acoustic target motion and harmonic energy on SiSTM imaging-derived measurements of statistical dimensionality. In vitro flow phantom experiments were performed under physiologically realistic conditions (2.7 cm/s flow velocity and 4 mm diameter) with targeted and non-targeted phantom channels. Both simulation and experimental results demonstrated that the relative motion and harmonic characteristics of adherent microbubbles (i.e. low motion and large harmonics) yields echo data with dimensionality that is distinct from free microbubbles (i.e. large motion and large harmonics) and tissue (i.e. low motion and low harmonics). Experimental SiSTM images produced the expected trend of greater adherent microbubble signal in targeted versus non-targeted microbubble experiments (P < 0.05, n = 4). The location of adherent microbubbles was qualitatively confirmed via optical imaging of fluorescent DiI signal along the phantom channel walls after SiSTM imaging. In comparison with two frequency-based real-time molecular imaging strategies, SiSTM imaging provided significantly higher image contrast (P < 0.001, n = 4) and larger area under the receiver operating characteristic curve (P < 0.05, n = 4).
PMCID: PMC3440015  PMID: 22853933

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