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1.  Shrinking Lung Syndrome as a Manifestation of Pleuritis: A New Model Based on Pulmonary Physiological Studies 
The Journal of rheumatology  2013;40(3):273-281.
The pathophysiology of shrinking lung syndrome (SLS) is poorly understood. We sought to define the structural basis for this condition through the study of pulmonary mechanics in affected patients.
Since 2007, most patients evaluated for SLS at our institutions have undergone standardized respiratory testing including esophageal manometry. We analyzed these studies to define the physiological abnormalities driving respiratory restriction. Chest computed tomography data were post-processed to quantitate lung volume and parenchymal density.
Six cases met criteria for SLS. All presented with dyspnea as well as pleurisy and/or transient pleural effusions. Chest imaging was free of parenchymal disease and corrected diffusing capacities were normal. Total lung capacities were 39-50% of predicted. Maximal inspiratory pressures were impaired at high lung volumes, but not low lung volumes, in 5 patients. Lung compliance was strikingly reduced in all patients, accompanied by increased parenchymal density.
Patients with SLS exhibited symptomatic and/or radiographic pleuritis associated with two characteristic physiological abnormalities: 1) impaired respiratory force at high but not low lung volumes, and 2) markedly decreased pulmonary compliance in the absence of identifiable interstitial lung disease. These findings suggest a model in which pleural inflammation chronically impairs deep inspiration, for example via neural reflexes, leading to parenchymal reorganization that impairs lung compliance, a known complication of persistently low lung volumes. Together these processes could account for the association of SLS with pleuritis as well as the gradual symptomatic and functional progression that is a hallmark of this syndrome.
PMCID: PMC4112073  PMID: 23378468
Shrinking Lung Syndrome; Pleuritis; Pleurisy; Systemic Lupus Erythematosus; Lung
2.  Clinical application of pharmacokinetic analysis as a biomarker of solitary pulmonary nodules: Dynamic contrast enhanced MR imaging 
The purpose of this study is to evaluate perfusion indices and pharmacokinetic parameters in solitary pulmonary nodules (SPNs). Thirty patients of 34 enrolled with SPNs (15–30 mm) were evaluated in this study. T1 and T2-weighted structural images and 2D turbo FLASH perfusion images were acquired with shallow free breathing. B-spline non-rigid image registration and optimization by χ2 test against pharmacokinetic model curve were performed on dynamic contrast enhanced (DCE) MRI. This allowed pixel-by-pixel calculation of kep, the rate constant for tracer transport to and from plasma and the extravascular extracellular space (EES). Mean transit time (MTT), time-to-peak (TTP), initial slope (IS), and maximum enhancement (Emax) were calculated from time-intensity curves fitted to a gamma variate function. After blinded data analysis, correlation with tissue histology from surgical resection or biopsy samples was performed. Histologic evaluation revealed 25 malignant and 5 benign SPNs. All benign SPNs had kep <1.0 min−1. Nineteen of 25 (76%) malignant SPNs showed kep > 1.0 min−1. Sensitivity to diagnose malignant SPNs at a cutoff of kep = 1.0 min−1 was 76%, specificity was 100%, positive predictive value (PPV) was 100%, negative predictive value (NPV) was 45%, and accuracy was 80%. Of all indices studied, kep was the most significant in differentiating malignant from benign SPNs.
PMCID: PMC3335927  PMID: 22231729
perfusion MRI; pharmacokinetic parameters; lung tumor; biomarker
3.  Impact of Non-rigid Motion Correction Technique on Pixel-wise Pharmacokinetic Analysis of Free-breathing Pulmonary Dynamic Contrast-Enhanced MR Imaging 
To investigates the impact of non-rigid motion correction on pixel-wise pharmacokinetic analysis of free-breathing DCE-MRI in patients with solitary pulmonary nodules (SPNs). Misalignment of focal lesions due to respiratory motion in free-breathing dynamic contrast-enhanced MRI (DCE-MRI) precludes obtaining reliable time-intensity curves, which are crucial for pharmacokinetic analysis for tissue characterization.
Materials and Methods
Single-slice 2D DCE-MRI was obtained in 15 patients. Misalignments of SPNs were corrected using non-rigid B-spline image registration. Pixel-wise pharmacokinetic parameters Ktrans, ve and kep were estimated from both original and motion-corrected DCE-MRI by fitting the two-compartment pharmacokinetic model to the time-intensity curve obtained in each pixel. The “goodness-of-fit” was tested with χ2-test in pixel-by-pixel basis to evaluate the reliability of the parameters. The percentages of reliable pixels within the SPNs were compared between the original and motion-corrected DCE-MRI. In addition, the parameters obtained from benign and malignant SPNs were compared.
The percentage of reliable pixels in the motion-corrected DCE-MRI was significantly larger than the original DCE-MRI (p=4×10−7). Both Ktrans and kep derived from the motion-corrected DCE-MRI showed significant differences between benign and malignant SPNs (p=0.024, 0.015).
The study demonstrated the impact of non-rigid motion correction technique on pixel-wise pharmacokinetic analysis of free-breathing DCE-MRI in SPNs.
PMCID: PMC3069717  PMID: 21448965
dynamic contrast-enhanced MRI; pharmacokinetic analysis; non-rigid image registration; motion correction; solitary pulmonary nodule
4.  Transforming Growth Factor-β Receptor-3 Is Associated with Pulmonary Emphysema 
Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome, including emphysema and airway disease. Phenotypes defined on the basis of chest computed tomography (CT) may decrease disease heterogeneity and aid in the identification of candidate genes for COPD subtypes. To identify these genes, we performed genome-wide linkage analysis in extended pedigrees from the Boston Early-Onset COPD Study, stratified by emphysema status (defined by chest CT scans) of the probands, followed by genetic association analysis of positional candidate genes. A region on chromosome 1p showed strong evidence of linkage to lung function traits in families of emphysema-predominant probands in the stratified analysis (LOD score = 2.99 in families of emphysema-predominant probands versus 1.98 in all families). Association analysis in 949 individuals from 127 early-onset COPD pedigrees revealed association for COPD-related traits with an intronic single-nucleotide polymorphism (SNP) in transforming growth factor-β receptor-3 (TGFBR3) (P = 0.005). This SNP was significantly associated with COPD affection status comparing 389 cases from the National Emphysema Treatment Trial to 472 control smokers (P = 0.04), and with FEV1 (P = 0.004) and CT emphysema (P = 0.05) in 3,117 subjects from the International COPD Genetics Network. Gene-level replication of association with lung function was seen in 427 patients with COPD from the Lung Health Study. In conclusion, stratified linkage analysis followed by association testing identified TGFBR3 (betaglycan) as a potential susceptibility gene for COPD. Published human microarray and murine linkage studies have also demonstrated the importance of TGFBR3 in emphysema and lung function, and our group and others have previously found association of COPD-related traits with TGFB1, a ligand for TGFBR3.
PMCID: PMC2742752  PMID: 19131638
betaglycan; chronic obstructive pulmonary disease; computed tomography; linkage; single nucleotide polymorphism
5.  Effects of school-based interventions on mental health stigmatization: a systematic review 
Stigmatizing, or discriminatory, perspectives and behaviour, which target individuals on the basis of their mental health, are observed in even the youngest school children. We conducted a systematic review of the published and unpublished, scientific literature concerning the benefits and harms of school-based interventions, which were directed at students 18 years of age or younger to prevent or eliminate such stigmatization. Forty relevant studies were identified, yet only a qualitative synthesis was deemed appropriate. Five limitations within the evidence base constituted barriers to drawing conclusive inferences about the effectiveness and harms of school-based interventions: poor reporting quality, a dearth of randomized controlled trial evidence, poor methods quality for all research designs, considerable clinical heterogeneity, and inconsistent or null results. Nevertheless, certain suggestive evidence derived both from within and beyond our evidence base has allowed us to recommend the development, implementation and evaluation of a curriculum, which fosters the development of empathy and, in turn, an orientation toward social inclusion and inclusiveness. These effects may be achieved largely by bringing especially but not exclusively the youngest children into direct, structured contact with an infant, and likely only the oldest children and youth into direct contact with individuals experiencing mental health difficulties. The possible value of using educational activities, materials and contents to enhance hypothesized benefits accruing to direct contact also requires investigation. Overall, the curriculum might serve as primary prevention for some students and as secondary prevention for others.
PMCID: PMC2515285  PMID: 18644150

Results 1-5 (5)