Search tips
Search criteria

Results 1-25 (32)

Clipboard (0)

Select a Filter Below

Year of Publication
Document Types
1.  The E-MS Algorithm: Model Selection with Incomplete Data 
We propose a procedure associated with the idea of the E-M algorithm for model selection in the presence of missing data. The idea extends the concept of parameters to include both the model and the parameters under the model, and thus allows the model to be part of the E-M iterations. We develop the procedure, known as the E-MS algorithm, under the assumption that the class of candidate models is finite. Some special cases of the procedure are considered, including E-MS with the generalized information criteria (GIC), and E-MS with the adaptive fence (AF; Jiang et al. 2008). We prove numerical convergence of the E-MS algorithm as well as consistency in model selection of the limiting model of the E-MS convergence, for E-MS with GIC and E-MS with AF. We study the impact on model selection of different missing data mechanisms. Furthermore, we carry out extensive simulation studies on the finite-sample performance of the E-MS with comparisons to other procedures. The methodology is also illustrated on a real data analysis involving QTL mapping for an agricultural study on barley grains.
PMCID: PMC4714800  PMID: 26783375
backcross experiments; conditional sampling; consistency; convergence; missing data mechanism; model selection; regression
2.  Full scope of practice 
PMCID: PMC4813522  PMID: 27076815
3.  Small and large size for gestational age and neighborhood deprivation measured within increasing proximity to homes 
Health & place  2014;30:98-106.
Neighborhood deprivation is consistently associated with greater risk of low birthweight. However, large birth size is increasingly relevant but overlooked in neighborhood health research, and proximity within which neighborhood deprivation may affect birth outcomes is unknown. We estimated race/ethnic-specific effects of neighborhood deprivation index (NDI) within 1, 3, 5, and 8 km buffers around Oregon Pregnancy Risk Assessment Monitoring System (n=3,716; 2004-2007) respondents’ homes on small and large for gestational age (SGA, LGA). NDI was positively associated with LGA and SGA in most race/ethnic groups. The results varied little across the four buffer sizes.
PMCID: PMC4517430  PMID: 25240489
pregnancy outcome; neighborhood; socioeconomic factors; fetal growth
The Journal of pediatrics  2014;165(4):836-841.e1.
To quantitatively evaluate feeding impairment in children with Smith-Lemli-Opitz Syndrome (SLOS) and to correlate feeding impairment with clinical and biochemical indices of disease severity.
Study design
Subjects were 26 children with SLOS, 0.4 to 19 years age. Clinical severity was measured using an existing scoring system. We created a tool to quantitatively evaluate feeding. Plasma sterol concentrations were measured, and statistical associations (correlations) with feeding scores were calculated.
Oral hypo- or hypersensitivity, adverse behaviors, and risk for dysphagia were seen in ~65% of children with SLOS; 13/26 children experienced failure-to-thrive (FTT), and 10/26 required gastrostomy. 7DHC concentrations, as a measure of severity, correlated with Total Feeding Score and the Oral Function subcategory score (p<.001), less so with Oral Structure, adverse behaviors or dysphagia. Correlations with cholesterol concentrations were not statistically significant. 7DHC > 0.24 mmol/L or Chol < 1.95 mmol/L is predictive of gastrostomy use. Feeding impairments may improve with age.
Feeding impairment is common and complex in patients with SLOS. Findings confirm that oral sensitivities, adverse feeding behaviors and risk of oral phase dysphagia are amenable to quantitative evaluation and analysis. Feeding difficulties in children with SLOS are correlated with plasma sterol concentrations, suggesting a link between the biochemical severity in SLOS and feeding function. These findings expand the behavioral phenotype of SLOS and begin to provide insights into the biologic causes of feeding difficulties.
PMCID: PMC4177270  PMID: 25039049
Dysphagia; Feeding Impairment; Sterols; 7-Dehydrocholesterol; Cholesterol; Gastrostomy; Behavioral Phenotype; Smith-Lemli-Opitz Syndrome
5.  Background and Design of the Profiling Biobehavioral Responses to Mechanical Support in Advanced Heart Failure (PREMISE) Study 
Unexplained heterogeneity in response to ventricular assist device (VAD) implantation for the management of advanced heart failure impedes our ability to predict favorable outcomes, provide adequate patient and family education, and personalize monitoring and symptom management strategies. The purpose of this paper is to describe the background and design of a study entitled Profiling Biobehavioral Responses to Mechanical Support in Advanced Heart Failure (PREMISE).
Study Design and Methods
PREMISE is a prospective cohort study designed to a) identify common and distinct trajectories of change in physical and psychological symptom burden, b) characterize common trajectories of change in serum biomarkers of myocardial stress, systemic inflammation, and endothelial dysfunction, and c) quantify associations between symptoms and biomarkers of pathogenesis in adults undergoing VAD implantation. Latent growth mixture modeling, including parallel process and cross-classification modeling, will be used to address the study aims and will entail identifying trajectories, quantifying associations between trajectories and both clinical and quality-of-life outcomes, and identifying predictors of favorable symptom and biomarker responses to VAD implantation.
Research findings from PREMISE will be used to enhance shared patient and provider decision-making, and shape a much-needed new breed of interventions and clinical management strategies that are tailored to differential symptom and pathogenic responses to VAD implantation.
PMCID: PMC3885612  PMID: 23839571
6.  Radiographic and Clinical Outcomes of the Treatment of Immature Permanent Teeth by Revascularization or Apexification: A Pilot Retrospective Cohort Study 
Journal of endodontics  2014;40(8):1063-1070.
This retrospective cohort study compared clinical and radiographic outcomes of endodontic treatment performed in immature non-vital permanent teeth, by apexification (calcium hydroxide or apical barrier with Mineral Trioxide Aggregate (MTA)), versus revascularization.
A comprehensive chart review was performed to obtain a cohort of sequential previously completed cases with recalls. Clinical and radiographic data were collected for 31 treated teeth (19 revascularization and 12 apexification) with an average follow up time of 17 months and a recall rate of 63%. Tooth survival, success rate, and adverse events were analyzed. Changes in radiographic root length, width and area were quantified.
The majority of treated teeth survived throughout the study period with 30/31 (97%) teeth surviving (18/19 (95%) revascularization, 12/12 apexification). Most cases were also clinically successful with 27/31 (87%) meeting criteria for success, (15/19 (78%) revascularization and 12/12 apexification; non-significant difference). A greater incidence of adverse events was observed in the revascularization group (8/19 (42%) versus 1/12 (11%) in apexification (Risk Ratio= 5.1, p=0.04, 95%CI (0.719, 35.48)). Although more revascularization cases than apexification cases demonstrated an increase in radiographic root area and width, the effect was not statistically significant.
In this study, revascularization was not superior to other apexification techniques in either clinical or radiographic outcomes. Studies with large subject cohorts, and long follow up periods are needed to evaluate outcomes of revascularization and apexification, while accounting for important co-variants relevant to clinical success.
PMCID: PMC4159254  PMID: 25069909
7.  Genome-wide analysis of the regulatory function mediated by the small regulatory psm-mecRNA of methicillin-resistant Staphylococcus aureus 
Several methicillin resistance (SCCmec) clusters characteristic of hospital-associated methicillin-resistant Staphylococcus aureus (MRSA) strains harbor the psm-mec locus. In addition to encoding the cytolysin, phenol-soluble modulin (PSM)-mec, this locus has been attributed gene regulatory functions. Here we employed genome-wide transcriptional profiling to define the regulatory function of the psm-mec locus. The immune evasion factor protein A emerged as the primary conserved and strongly regulated target of psm-mec, an effect we show is mediated by the psm-mec RNA. Furthermore, the psm-mec locus exerted regulatory effects that were more moderate in extent. For example, expression of PSM-mec limited expression of mecA, thereby decreasing methicillin resistance. Our study shows that the psm-mec locus has a rare dual regulatory RNA and encoded cytolysin function. Furthermore, our findings reveal a specific mechanism underscoring the recently emerging concept that S. aureus strains balance pronounced virulence and high expression of antibiotic resistance.
PMCID: PMC4087065  PMID: 24877726
Staphylococcus aureus; MRSA; virulence; antibiotic resistance
8.  Fear of Falling Is Associated with Recurrent Falls in People with Multiple Sclerosis 
International Journal of MS Care  2015;17(4):164-170.
Background: People with multiple sclerosis (MS) fall frequently, and there are few clinically valid tools to measure the risk factors for falls. We assessed the unidimensionality of the 7-item Falls Efficacy Scale–International (FES-I), a measure of fear of falling, and determined whether the 7-item FES-I is associated with recurrent falls in people with MS.
Methods: Falls were counted prospectively for 6 months using fall calendars in 58 people with MS (age, 18–50 years; Expanded Disability Status Scale score, 0–6). The FES-I was administered at baseline, and its unidimensionality was assessed by confirmatory factor analysis. The relationship between FES-I score and future falls, after adjusting for recurrent falls in the past year, was assessed by logistic regression.
Results: Fifty-four participants who completed all assessments were included in the analysis. Goodness-of-fit indices confirmed a single-factor solution for the 7-item FES-I (discrepancy χ2, P = .101; Tucker-Lewis index, 0.953; comparative fit index, 0.969; root mean square error of approximation, 0.098). There was a significant association between fear of falling and falls in the following 3 months, independent of recurrent falls in the past year (odds ratio = 1.22, 95% confidence interval, 1.04–1.43, P = .016).
Conclusions: The 7-item FES-I demonstrates good construct validity, allowing the total score to be used as a measure of fear of falling in people with MS. Fear of falling, as measured by the 7-item FES-I, is associated with future recurrent falls independent of past recurrent falls in people with MS.
PMCID: PMC4542711  PMID: 26300702
9.  Clcn5 Knockout Mice Exhibit Novel Immunomodulatory Effects and Are More Susceptible to Dextran Sulfate Sodium-Induced Colitis 
Although the intracellular Cl−/H+ exchanger Clc-5 is expressed in apical intestinal endocytic compartments, its pathophysiological role in the gastrointestinal tract is unknown. In light of recent findings that CLC-5 is downregulated in active ulcerative colitis (UC), we tested the hypothesis that loss of CLC-5 modulates the immune response, thereby inducing susceptibility to UC. Acute dextran sulfate sodium (DSS) colitis was induced in Clcn5 knockout (KO) and wild-type (WT) mice. Colitis, monitored by disease activity index, histological activity index, and myeloperoxidase activity were significantly elevated in DSS-induced Clcn5 KO mice compared with those in WT mice. Comprehensive serum multiplex cytokine profiling demonstrated a heightened Th1–Th17 profile (increased TNF-α, IL-6, and IL-17) in DSS-induced Clcn5 KO mice compared with that in WT DSS colitis mice. Interestingly, Clcn5 KO mice maintained on a high vitamin D diet attenuated DSS-induced colitis. Immunofluorescence and Western blot analyses of colonic mucosa validated the systemic cytokine patterns and further revealed enhanced activation of the NF-κB pathway in DSS-induced Clcn5 KO mice compared with those in WT mice. Intriguingly, high baseline levels of IL-6 and phospho-IκB were observed in Clcn5 KO mice, suggesting a novel immunopathogenic role for the functional defects that result from the loss of Clc-5. Our studies demonstrate that the loss of Clc-5 1) exhibits IL-6–mediated immunopathogenesis, 2) significantly exacerbated DSS-induced colitis, which is influenced by dietary factors, including vitamin D, and 3) portrays distinct NF-κB–modulated Th1–Th17 immune dysregulation, implying a role for CLC-5 in the immunopathogenesis of UC.
PMCID: PMC4460988  PMID: 20181886
10.  Fence Methods for Backcross Experiments 
Model search strategies play an important role in finding simultaneous susceptibility genes that are associated with a trait. More particularly, model selection via the information criteria, such as the BIC with modifications, have received considerable attention in quantitative trait loci (QTL) mapping. However, such modifications often depend upon several factors, such as sample size, prior distribution, and the type of experiment, e.g., backcross, intercross. These changes make it difficult to generalize the methods to all cases. The fence method avoids such limitations with a unified approach, and hence can be used more broadly. In this paper, this method is studied in the case of backcross experiments throughout a series of simulation studies. The results are compared with those of the modified BIC method as well as some of the most popular shrinkage methods for model selection.
PMCID: PMC3891925  PMID: 24443613
high-dimensional variable seleciton; restricted fence (RF); model selection
11.  Self-denigrating terms 
PMCID: PMC4213264  PMID: 25364347
12.  Validity and Reliability of the European Heart Failure Self-care Behavior Scale Among Adults from the United States with Symptomatic Heart Failure 
Heart failure (HF) self-care is an important component of disease management and the focus of many interventions.
The aim of this study was to evaluate the validity and reliability of the 9-item European HF Self-Care Behavior Scale (EHFScB-9) in a sample of 200 adults from the United States with symptomatic HF.
Psychometric tests included item and confirmatory factor analyses, convergent and discriminant validity, and internal consistency.
Item-total correlations ranged from 0.25–0.65. Many fit indices for the EHFScB-9 and the 4-item consulting behaviors reached thresholds of acceptability. As expected, the EHFScB-9 was associated with other measures of HF self-care but not with quality-of-life. Coefficient α was 0.80 for the EHFScB-9 and and 0.85 for the consulting behaviors subscale.
The EHFScB-9 was a valid and reliable measure of HF self-care among English-speaking U.S. adults with symptomatic HF.
PMCID: PMC4010092  PMID: 23263273
13.  Respiratory Function in Healthy Late Preterm Infants Delivered at 33-36 Weeks of Gestation 
The Journal of pediatrics  2012;162(3):464-469.
To compare pulmonary function testing including respiratory compliance (Crs) and time to peak tidal expiratory flow: expiratory time (Tptef:Te) at term corrected age in healthy infants born at 33-36 weeks of gestation versus healthy infants delivered at term.
Study design
We performed a prospective cohort study of late preterm infants born at 33-36 weeks without clinical respiratory disease (<12 hours of >0.21 FiO2) and studied at term corrected age. The comparison group was term infants matched for race and sex to the preterm infants and studied within 72 hours of delivery. Crs was measured with the single breath occlusion technique. A minimum of 50 flow-volume loops were collected to estimate Tptef:Te.
Late preterm infants (n=31; mean gestational age 34.1 weeks, birth weight 2150 g) and 31 term infants were studied at term corrected age. The late preterm infants had decreased Crs (1.14 vs 1.32 mL/cm H2O/kg; p<0.02) and decreased Tptef:Te (0.308 vs 0.423; p<0.01) when compared with the term infants. Late preterm infants also had an increased respiratory resistance (0.064 vs 0.043 cm H2O/mL/sec; p<0.01).
Healthy late preterm infants (33-36 weeks of gestation) studied at term corrected age have altered pulmonary function when compared with healthy term infants.
PMCID: PMC3683449  PMID: 23140884
Expiratory flow ratio; late preterm infants; pulmonary function; respiratory compliance
14.  Oral Antimicrobial Use in Outpatient Cystic Fibrosis Pulmonary Exacerbation Management; a Single Center Experience 
Cystic Fibrosis pulmonary disease is characterized by intermittent episodes of acute lung symptoms known as “pulmonary exacerbations”. While exacerbations are classically treated with parenteral antimicrobials, oral antibiotics are often used in “mild” cases.
We determined how often management progressed to IV therapy. We also examined multiple courses of oral antimicrobials within one exacerbation and identified patient factors associated with unsuccessful treatment.
We performed a retrospective chart audit of oral antibiotic use in CF patients from March 2009 through March 2010, for “mild” CF exacerbations.
Administration of a single versus multiple courses of oral antibiotics for treatment of “mild” CF exacerbation avoided progression to IV therapy 79.8% and 50.0% of the time, respectively. Overall, oral antibiotics circumvented the need for IV therapy 73.8% of the time. Using multi-variant analysis, we found multiple patient characteristics to be independent risk factors for oral antibiotic failure including a history of Pseudomonas infection (OR 2.13, CI 1.29 – 3.54), Cystic Fibrosis Related Diabetes (OR 1.85, CI 1.00 – 3.41), Allergic Bronchopulmonary Aspergillosis (OR 3.81, CI 1.38 – 10.56), low socioeconomic status (OR 1.67, CI 1.04 – 2.67), and calculated Baseline FEV1 < 75% of predicted prior to an acute exacerbation (OR 1.93, CI 1.20 – 3.08). Decline in FEV1 > 10%, weight for age, body mass index, distance from the CF center, and gender were not significant.
Our observations suggest that one course of oral antimicrobials is frequently effective in outpatient CF pulmonary exacerbations but exacerbations requiring more than one course of oral antibiotics are likely to require IV therapy.
PMCID: PMC3934104  PMID: 21595857
Cystic Fibrosis; exacerbation; antibiotics; pneumonia
15.  Simple Estimation of Hidden Correlation in Repeated Measures 
Statistics in medicine  2011;30(29):3403-3415.
In medical and social studies, it is often desirable to assess the correlation between characteristics of interest that are not directly observable. In such cases, repeated measures are often available, but the correlation between the repeated measures is not the same as that between the true characteristics that are confounded with the measurement errors. The latter is called the hidden correlation. Previously, the problem has been treated by assuming prior knowledge about the measurement errors, or by using relatively complex statistical models, such as the mixed effects models, with no closed-form expression for the estimated hidden correlation. We propose a simple estimator of the hidden correlation that is very much like the Pearson correlation coefficient, with a closed-form expression, under assumptions much weaker than the mixed effects model. Simulation results show that the proposed simple estimator performs similarly as the restricted maximum likelihood (REML) estimator in mixed models, but is computationally much more efficient than REML. Simulation comparison with the Pearson correlation is also made. A real data example is considered.
PMCID: PMC3891926  PMID: 21997471
Correlation Coefficient; Hypothesis Testing; Repeated Measures
16.  Unprofessional behavior 
PMCID: PMC3908624  PMID: 24494008
17.  Human Neural Stem Cells Induce Functional Myelination in Mice with Severe Dysmyelination 
Science translational medicine  2012;4(155):10.1126/scitranslmed.3004371.
Shiverer-immunodeficient (Shi-id) mice demonstrate defective myelination in the central nervous system (CNS) and significant ataxia by 2 to 3 weeks of life. Expanded, banked human neural stem cells (HuCNS-SCs) were transplanted into three sites in the brains of neonatal or juvenile Shi-id mice, which were asymptomatic or showed advanced hypomyelination, respectively. In both groups of mice, HuCNS-SCs engrafted and underwent preferential differentiation into oligodendrocytes. These oligodendrocytes generated compact myelin with normalized nodal organization, ultrastructure, and axon conduction velocities. Myelination was equivalent in neonatal and juvenile mice by quantitative histopathology and high-field ex vivo magnetic resonance imaging, which, through fractional anisotropy, revealed CNS myelination 5 to 7 weeks after HuCNS-SC transplantation. Transplanted HuCNS-SCs generated functional myelin in the CNS, even in animals with severe symptomatic hypomyelination, suggesting that this strategy may be useful for treating dysmyelinating diseases.
PMCID: PMC3864816  PMID: 23052293
18.  Hemodynamic and Metabolic Correlates of Perinatal White Matter Injury Severity 
PLoS ONE  2013;8(12):e82940.
Background and Purpose
Although the spectrum of perinatal white matter injury (WMI) in preterm infants is shifting from cystic encephalomalacia to milder forms of WMI, the factors that contribute to this changing spectrum are unclear. We hypothesized that the variability in WMI quantified by immunohistochemical markers of inflammation could be correlated with the severity of impaired blood oxygen, glucose and lactate.
We employed a preterm fetal sheep model of in utero moderate hypoxemia and global severe but not complete cerebral ischemia that reproduces the spectrum of human WMI.
Since there is small but measurable residual brain blood flow during occlusion, we sought to determine if the metabolic state of the residual arterial blood was associated with severity of WMI. Near the conclusion of hypoxia-ischemia, we recorded cephalic arterial blood pressure, blood oxygen, glucose and lactate levels. To define the spectrum of WMI, an ordinal WMI rating scale was compared against an unbiased quantitative image analysis protocol that provided continuous histo-pathological outcome measures for astrogliosis and microgliosis derived from the entire white matter.
A spectrum of WMI was observed that ranged from diffuse non-necrotic lesions to more severe injury that comprised discrete foci of microscopic or macroscopic necrosis. Residual arterial pressure, oxygen content and blood glucose displayed a significant inverse association with WMI and lactate concentrations were directly related. Elevated glucose levels were the most significantly associated with less severe WMI.
Our results suggest that under conditions of hypoxemia and severe cephalic hypotension, WMI severity measured using unbiased immunohistochemical measurements correlated with several physiologic parameters, including glucose, which may be a useful marker of fetal response to hypoxia or provide protection against energy failure and more severe WMI.
PMCID: PMC3886849  PMID: 24416093
19.  Real-time prostate motion assessment: image-guidance and the temporal dependence of intra-fraction motion 
BMC Medical Physics  2013;13:4.
The rapid adoption of image-guidance in prostate intensity-modulated radiotherapy (IMRT) results in longer treatment times, which may result in larger intrafraction motion, thereby negating the advantage of image-guidance. This study aims to qualify and quantify the contribution of image-guidance to the temporal dependence of intrafraction motion during prostate IMRT.
One-hundred and forty-three patients who underwent conventional IMRT (n=67) or intensity-modulated arc therapy (IMAT/RapidArc, n=76) for localized prostate cancer were evaluated. Intrafraction motion assessment was based on continuous RL (lateral), SI (longitudinal), and AP (vertical) positional detection of electromagnetic transponders at 10 Hz. Daily motion amplitudes were reported as session mean, median, and root-mean-square (RMS) displacements. Temporal effect was evaluated by categorizing treatment sessions into 4 different classes: IMRTc (transponder only localization), IMRTcc (transponder + CBCT localization), IMATc (transponder only localization), or IMATcc (transponder + CBCT localization).
Mean/median session times were 4.15/3.99 min (IMATc), 12.74/12.19 min (IMATcc), 5.99/5.77 min (IMRTc), and 12.98/12.39 min (IMRTcc), with significant pair-wise difference (p<0.0001) between all category combinations except for IMRTcc vs. IMATcc (p>0.05). Median intrafraction motion difference between CBCT and non-CBCT categories strongly correlated with time for RMS (t-value=17.29; p<0.0001), SI (t-value=−4.25; p<0.0001), and AP (t-value=2.76; p<0.0066), with a weak correlation for RL (t-value=1.67; p=0.0971). Treatment time reduction with non-CBCT treatment categories showed reductions in the observed intrafraction motion: systematic error (Σ)<0.6 mm and random error (σ)<1.2 mm compared with ≤0.8 mm and <1.6 mm, respectively, for CBCT-involved treatment categories.
For treatment durations >4-6 minutes, and without any intrafraction motion mitigation protocol in place, patient repositioning is recommended, with at least the acquisition of the lateral component of an orthogonal image pair in the absence of volumetric imaging.
PMCID: PMC3849088  PMID: 24059584
Prostate cancer; Real-time motion tracking; Intrafraction variation; Treatment margin; Treatment time
20.  Healing Pathways: A Program for Women with Physical Disabilities and Depression 
Objective. The objective of this study was to test the efficacy of the Healing Pathways (HP) program in reducing clinically significantly depressive symptoms in women with physical disabilities (WPD). Healing Pathways is a peer-implemented group mental health treatment program targeting WPD who have clinically significant cooccurring depressive symptoms. Participants. Eighty women were randomized in this trial. Design. This study used a community-based participatory intervention research design. Using community-based recruiting methods, participants were recruited from Centers for Independent Living, local disability service organizations, via Craig's list as well as other community locations such as grocery stores and bus stops. Women participated in the HP program for 14 weeks. Results. The primary outcome variable for this study was reduction in depressive symptoms as measured by the Center for Epidemiologic Depression Scale (CES-D). We found that there was a significant interaction effect of treatment by time on depression scores, F(3,210) = 9.51, P < 0.0001, partial η2 = 0.101. Investigation of the predicted mean profile over time in the intervention group demonstrated that depression scores decreased greatly from baseline to the first posttest and remained stable in the two followups, whereas there was a little change in the mean profile over time in the control group. Conclusion. The HP program has demonstrated initial efficacy in reducing depressive symptoms in women with physical disabilities.
PMCID: PMC3659440  PMID: 23738072
Annals of Neurology  2012;71(1):93-109.
The major form of MRI-defined white matter injury (WMI) comprises diffuse lesions where the burden of small necrotic foci (microscopic necrosis) is poorly defined. We hypothesized that myelination failure associated with diffuse WMI involves an aberrant injury response linked to arrested pre-oligodendrocyte (preOL) maturation in reactive astrocyte-rich lesions.
A retrospective autopsy series (1983–2000) was selected for cases with diffuse WMI and analyzed relative to prospectively-collected contemporary cases (2003–2010). Controls were age and region-matched to address regional variation in preOL maturation. Successive oligodendrocyte stages were analyzed with lineage-specific markers. Microscopic necrosis was quantified with microglial markers. Axon injury markers defined the burden of axonopathy. Extracellular matrix remodelling was defined by detection of hyaluronic acid (HA), an inhibitor of preOL maturation, and the HA receptor, CD44.
In the contemporary case series, diffuse WMI was accompanied by a significant reduction in the burden of microscopic necrosis and axonopathy. Diffuse astrogliosis extended into the lesion surround with elevated HA and astrocyte-expressed CD44. The total population of OL lineage stages was significantly increased in lesions. This increase coincided with significant expansion of the preOL pool.
Although these data confirm that microscopic necrosis occurs in contemporary cases, the markedly decreased burden supports that it does not contribute substantially to myelination failure. The primary mechanism of myelination failure involves a disrupted cellular response whereby preOLs fail to differentiate in diffuse astrogliotic lesions. Pre-oligodendrocyte maturation arrest converts chronic WMI to a more immature state related to the burden of astrogliosis.
PMCID: PMC3270934  PMID: 22275256
22.  Apex to Base Left Ventricular Twist Mechanics Computed From High Frame Rate Two-Dimensional and Three-Dimensional Echocardiography: A Comparison Study 
The aim of this study was to compare two-dimensional (2D) and three-dimensional (3D) methods for computing left ventricular (LV) rotation.
A two-axis linear/rotary system was designed using rotary motors controlled through a digital interface, and 10 freshly harvested pig hearts were studied. Each heart was mounted on the rotary actuator with the base being rotated at different known degrees of rotation (10°, 15°, 20°, and 25°) and was passively driven by a pump with calibrated stoke volume (50 mL) at a constant rate (60 beats/min) simultaneously. Cardiac motion was scanned to acquire 2D short-axis views using a GE Vivid 7 system for assessing rotation, and 3D apical full-volume loops were acquired using a Toshiba Applio Artida ultrasound system. Full-volume 3D image loops were analyzed online with Toshiba Wall Motion Tracking software, and short-axis 2D images were analyzed offline for LV rotation in GE EchoPAC PC at corresponding LV levels.
At each state, both 2D and 3D echocardiography detected the changes in LV rotation but overestimated the rotation degrees. The biases for overestimation from 3D imaging were smaller compared with 2D imaging at each LV level. Both methods, when compared with each other, showed a linear correlation (r = 0.84, P < .0001). Bland-Altman comparison showed 99% of data points within range, with a constant bias between both methods (adjusted values of 3D = 1.892 + 0.964 × 3D).
Although 3D echocardiography showed smaller bias, the results between 2D and 3D echocardiography were comparable.
PMCID: PMC3321829  PMID: 21995883
LV twist; Validation study; 3D echocardiography
23.  Histopathological Correlates of MRI-Defined Chronic Perinatal White Matter Injury 
Annals of neurology  2011;70(3):493-507.
Although MRI is the optimal imaging modality to define cerebral white-matter injury (WMI) in preterm survivors, the histopathological features of MRI-defined chronic lesions are poorly defined. We hypothesized that chronic WMI is related to a combination of delayed oligodendrocyte (OL) lineage cell death and arrested maturation of pre-oligodendrocytes (preOLs). We determined whether ex vivo MRI can distinguish distinct microglial and astroglial responses related to WMI progression and arrested preOL differentiation.
We employed a preterm fetal sheep model of global cerebral ischemia where acute WMI results in selective preOL degeneration. We developed novel algorithms to register histopathologically defined lesions with contrast- and diffusion-weighted high-field ex vivo MRI data.
Despite mild delayed preOL degeneration, preOL density recovered to control levels by 7 days after ischemia and was ~2 fold greater at 14 days. However, pre-myelinating OLs were significantly diminished at 7 and 14 days. WMI evolved to mostly gliotic lesions where arrested preOL differentiation was directly proportional to the magnitude of astrogliosis. A reduction in cerebral WM volume was accompanied by four classes of MRI-defined lesions. Each lesion type displayed unique astroglial and microglial responses that corresponded to distinct forms of necrotic or non-necrotic injury. High-field MRI defined two novel hypo-intense signal abnormalities on T2-weighted images that coincided with microscopic necrosis or identified astrogliosis with high sensitivity and specificity.
These studies support the potential of high-field MRI for early identification of microscopic necrosis and gliosis with preOL maturation arrest, a common form of WMI in preterm survivors.
PMCID: PMC3170499  PMID: 21796666
24.  Missed opportunity 
PMCID: PMC3567543  PMID: 23509490
25.  Distinct Cytokine Patterns Identified from Multiplex Profiles of Murine DSS and TNBS-Induced Colitis 
Inflammatory bowel diseases  2009;15(3):341-352.
The cytokine network in inflammatory bowel disease (IBD) is a complex, dynamic system that plays an important role in regulating mucosal innate and adaptive immune responses. While several studies have been done to evaluate immunomodulatory profiles in murine IBD, they have been limited to a relatively small number of cytokines that do not take into account its dependency of the interplay of multiple factors, and therefore the diagnostic potential of their cytokine profiles have been inconclusive. Herein we demonstrate a novel approach of comprehensive serum multiplex cytokine profiling to describe the modulation of 16 Th1, Th2, Th17 cytokines and chemokines in both acute and chronic murine models of DSS and TNBS-induced colitis. Distinctive disease-specific cytokine profiles were identified with significant correlations to disease activity and duration of disease. TNBS colitis exhibits heightened Th1-Th17 response (increased IL-12 and IL-17) as the disease becomes chronic. In contrast, DSS colitis switches from a Th1-Th17-mediated acute inflammation (increased TNFα, IL6, IL-17 and KC) to a predominant Th2-mediated inflammatory response (increase in IL-4 and IL-10 and concomitant decrease in TNFα, IL6, IL-17 and KC) in the chronic state. Profiles of multiple cytokines seen systemically were also validated locally in colonic mucosa. Moreover, advanced multivariate analyses identified discriminatory cytokine profiles that can be sufficiently used to distinguish unaffected controls from diseases, and one disease type from another. IL-6 and IL-12 stratified gender-associated disease activity in chronic colitis. Our studies provide insight into disease immunopathogenesis and illustrate the significant potential of utilizing multiplex cytokine profiles and bioinformatics as diagnostic tools in IBD.
PMCID: PMC2643312  PMID: 18942757
Cytokines; Multiplex ELISA; DSS Colitis; TNBS Colitis; Inflammatory Bowel Disease

Results 1-25 (32)