Publications by authors named "Lori J Silveira"

27 Publications

  • Page 1 of 1

IVIG Compared to IVIG Plus Infliximab in Multisystem Inflammatory Syndrome in Children.

Pediatrics 2021 Sep 22. Epub 2021 Sep 22.

Department of Pediatrics, Section of Infectious Diseases, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO.

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http://dx.doi.org/10.1542/peds.2021-052702DOI Listing
September 2021

IVIG Compared to IVIG Plus Infliximab in Multisystem Inflammatory Syndrome in Children.

Pediatrics 2021 Sep 21. Epub 2021 Sep 21.

Department of Pediatrics, Section of Infectious Diseases, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO;

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http://dx.doi.org/10.1542/peds.2021-052702DOI Listing
September 2021

Anesthesia for Maternal-Fetal Interventions: A Survey of Fetal Therapy Centers in the North American Fetal Therapy Network.

Fetal Diagn Ther 2021 7;48(5):361-371. Epub 2021 Apr 7.

Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colorado, USA.

Introduction: A wide range of fetal interventions are performed across fetal therapy centers (FTCs). We hypothesized that there is significant variability in anesthesia staffing and anesthetic techniques.

Methods: We conducted an online survey of anesthesiology directors at every FTC within the North American Fetal Therapy Network (NAFTNet). The survey included details of fetal interventions performed in 2018, anesthesia staffing models, anesthetic techniques, fetal monitoring, and postoperative management.

Results: There was a 92% response rate. Most FTCs are located within an adult hospital and employ a small team of anesthesiologists. There is heterogeneity when evaluating anesthesiology fellowship training and staffing, indicating there is a multidisciplinary specialty team-based approach even within anesthesiology. Minimally invasive fetal interventions were the most commonly performed. The majority of FTCs also performed ex utero intrapartum treatment (EXIT) and open mid-gestation procedures under general anesthesia (GA). Compared to FTCs only performing minimally invasive procedures, FTCs performing open fetal procedures were more likely to have a pediatric surgeon as director and performed more minimally invasive procedures.

Conclusions: There is considerable variability in anesthesia staffing, caseload, and anesthetic techniques among FTCs in NAFTNet. Most FTCs used maternal sedation for minimally invasive procedures and GA for EXIT and open fetal surgeries.
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http://dx.doi.org/10.1159/000514897DOI Listing
November 2021

Hepatic steatosis relates to gastrointestinal microbiota changes in obese girls with polycystic ovary syndrome.

PLoS One 2021 19;16(1):e0245219. Epub 2021 Jan 19.

Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.

Objective: Hepatic steatosis (HS) is common in adolescents with obesity and polycystic ovary syndrome (PCOS). Gut microbiota are altered in adults with obesity, HS, and PCOS, which may worsen metabolic outcomes, but similar data is lacking in youth.

Methods: Thirty-four adolescents with PCOS and obesity underwent stool and fasting blood collection, oral glucose tolerance testing, and MRI for hepatic fat fraction (HFF). Fecal bacteria were profiled by high-throughput 16S rRNA gene sequencing.

Results: 50% had HS (N = 17, age 16.2±1.5 years, BMI 38±7 kg/m2, HFF 9.8[6.5, 20.7]%) and 50% did not (N = 17, age 15.8±2.2 years, BMI 35±4 kg/m2, HFF 3.8[2.6, 4.4]%). The groups showed no difference in bacterial α-diversity (richness p = 0.202; evenness p = 0.087; and diversity p = 0.069) or global difference in microbiota (β-diversity). Those with HS had lower % relative abundance (%RA) of Bacteroidetes (p = 0.013), Bacteroidaceae (p = 0.009), Porphyromonadaceae (p = 0.011), and Ruminococcaceae (p = 0.008), and higher Firmicutes:Bacteroidetes (F:B) ratio (47.8% vs. 4.3%, p = 0.018) and Streptococcaceae (p = 0.034). Bacterial taxa including phyla F:B ratio, Bacteroidetes, and family Bacteroidaceae, Ruminococcaceae and Porphyromonadaceae correlated with metabolic markers.

Conclusions: Obese adolescents with PCOS and HS have differences in composition of gut microbiota, which correlate with metabolic markers, suggesting a modifying role of gut microbiota in HS and PCOS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245219PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815089PMC
May 2021

Different Measures of Diet Diversity During Infancy and the Association with Childhood Food Allergy in a UK Birth Cohort Study.

J Allergy Clin Immunol Pract 2020 06 28;8(6):2017-2026. Epub 2020 Jan 28.

The David Hide Asthma and Allergy Centre, St. Mary's Hospital, Isle of Wight, United Kingdom; Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.

Background: Diet diversity (DD) during infancy may prevent food allergies (FA), possibly by exposing the gastrointestinal microbiota to diverse foods and nutrients.

Objective: To investigate the association between 4 different measures of DD during infancy and development of FA over the first decade of life.

Methods: A birth cohort born between 2001 and 2002 were followed prospectively, providing information on sociodemographic, environmental, and dietary exposures. Information on age of introduction of a range of foods and food allergens was collected during infancy. Children were assessed for FA at 1, 2, 3, and 10 years. DD was defined using 4 measures in the first year of life: the World Health Organization definition of minimum DD at 6 months, as food diversity (FD) and fruit and vegetable diversity (FVD) at 3, 6, and 9 months, and as food allergen diversity (FAD) at 3, 6, 9, and 12 months.

Results: A total of 969 pregnant women were recruited at 12-week gestation. A total of 900, 858, 891, and 827 offspring were assessed at 1, 2, 3, and 10 years. Univariate analysis showed that World Health Organization DD (P = .0047), FD (P = .0009), FAD (P = .0048), and FVD (P = .0174) at 6 months and FD (P = .0392), FAD (P = .0233), and FVD (.0163) at 9 months significantly reduced the odds of FA over the first decade of life. DD measures at 3 months were not associated with FA, but only 33% of the cohort had solid foods introduced by this age.

Conclusion: Increased infant DD, as measured by 4 different methods, decreased the likelihood of developing FA.
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http://dx.doi.org/10.1016/j.jaip.2020.01.029DOI Listing
June 2020

Obese Adolescents With PCOS Have Altered Biodiversity and Relative Abundance in Gastrointestinal Microbiota.

J Clin Endocrinol Metab 2020 06;105(6)

Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Context: Alterations in gut microbiota relate to the metabolic syndrome, but have not been examined in at-risk obese youth with polycystic ovary syndrome (PCOS).

Objective: Compare the composition and diversity of the gut microbiota and associations with metabolic and hormonal measures between 2 groups of female adolescents with equal obesity with or without PCOS.

Design: Prospective, case-control cross-sectional study.

Setting: Tertiary-care center.

Participants: A total of 58 obese female adolescents (n = 37 with PCOS; 16.1 ± 0.3 years of age; body mass index [BMI] 98.5th percentile) and (n = 21 without PCOS; 14.5 ± 0.4 years of age; BMI 98.7th percentile).

Outcomes: Bacterial diversity, percent relative abundance (%RA), and correlations with hormonal and metabolic measures.

Results: Participants with PCOS had decreased α-diversity compared with the non-PCOS group (Shannon diversity P = 0.045 and evenness P = 0.0052). β-diversity, reflecting overall microbial composition, differed between groups (P < 0.001). PCOS had higher %RA of phyla Actinobacteria (P = 0.027), lower Bacteroidetes (P = 0.004), and similar Firmicutes and Proteobacteria. PCOS had lower %RA of families Bacteroidaceae (P < 0.001) and Porphyromonadaceae (P = 0.024) and higher Streptococcaceae (P = 0.047). Lower bacterial α-diversity was strongly associated with higher testosterone concentrations. Several individual taxa correlated with testosterone and metabolic measures within PCOS and across the entire cohort. Receiver operative curve analysis showed 6 taxa for which the %RA related to PCOS status and lower Bacteroidaceae conferred a 4.4-fold likelihood ratio for PCOS.

Conclusion: Alterations in the gut microbiota exist in obese adolescents with PCOS versus obese adolescents without PCOS and these changes relate to markers of metabolic disease and testosterone. Further work is needed to determine if microbiota changes are reflective of, or influencing, hormonal metabolism.
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http://dx.doi.org/10.1210/clinem/dgz263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147870PMC
June 2020

DNA Methylation Changes in Lung Immune Cells Are Associated with Granulomatous Lung Disease.

Am J Respir Cell Mol Biol 2019 01;60(1):96-105

1 Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.

Epigenetic marks are likely to explain variability of response to antigen in granulomatous lung disease. The objective of this study was to identify DNA methylation and gene expression changes associated with chronic beryllium disease (CBD) and sarcoidosis in lung cells obtained by BAL. BAL cells from CBD (n = 8), beryllium-sensitized (n = 8), sarcoidosis (n = 8), and additional progressive sarcoidosis (n = 9) and remitting (n = 15) sarcoidosis were profiled on the Illumina 450k methylation and Affymetrix/Agilent gene expression microarrays. Statistical analyses were performed to identify DNA methylation and gene expression changes associated with CBD, sarcoidosis, and disease progression in sarcoidosis. DNA methylation array findings were validated by pyrosequencing. We identified 52,860 significant (P < 0.005 and q < 0.05) CpGs associated with CBD; 2,726 CpGs near 1,944 unique genes have greater than 25% methylation change. A total of 69% of differentially methylated genes are significantly (q < 0.05) differentially expressed in CBD, with many canonical inverse relationships of methylation and expression in genes critical to T-helper cell type 1 differentiation, chemokines and their receptors, and other genes involved in immunity. Testing of these CBD-associated CpGs in sarcoidosis reveals that methylation changes only approach significance, but are methylated in the same direction, suggesting similarities between the two diseases with more heterogeneity in sarcoidosis that limits power with the current sample size. Analysis of progressive versus remitting sarcoidosis identified 15,215 CpGs (P < 0.005 and q < 0.05), but only 801 of them have greater than 5% methylation change, demonstrating that DNA methylation marks of disease progression changes are more subtle. Our study highlights the significance of epigenetic marks in lung immune response in granulomatous lung disease.
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http://dx.doi.org/10.1165/rcmb.2018-0177OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348713PMC
January 2019

Marijuana's Influence on Pain Scores, Initial Weight Loss, and Other Bariatric Surgical Outcomes.

Perm J 2018 ;22:18-002

At the time of this study an Attending Physician in the Department of Metabolic-Surgical Weight Management at Kaiser Permanente Colorado, and an Assistant Professor of Surgery in the Bariatric Surgery Division in the Department of Surgery at Oregon Health and Science University in Portland.

Introduction: Pain management can be challenging following bariatric surgery, and patients with obesity tend to increase opioid use after undergoing surgery. This report quantifies marijuana (MJ) use and its relationship to pain and other surgery-related outcomes in a population from a state that has legalized MJ.

Methods: Data were collected for consecutive patients undergoing weight reduction surgeries between May 1, 2014 and July 31, 2015. Demographics, preoperative comorbidities, medications, and perioperative opioid use were analyzed. The primary outcome evaluated was inpatient opioid pain medication use quantified using natural log morphine equivalents. Secondary outcomes included percentage of total body weight loss after three months, postoperative complications, and changes in medical comorbidities.

Results: A total of 434 patients, among whom 36 (8.3%) reported MJ use, comprised the study population. Perioperative opioid requirements were significantly higher in the MJ-user group (natural log morphine equivalents of 3.92 vs 3.52, p = 0.0015) despite lower subjective pain scores (3.70 vs 4.24, p = 0.07). MJ use did not affect percentage of 90-day total body weight loss, development of postoperative complications, or improvement in medical comorbidities.

Conclusion: Perioperative opioid use was significantly higher in the MJ-user group despite lower subjective pain scores. The difference in opioid requirements suggests an interaction between MJ use and opioid tolerance or pain threshold. The percentage of total body weight loss, improvement in medical comorbidity, and incidence of postoperative complications at 90-day follow-up were not affected by MJ use in this cohort analysis.
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http://dx.doi.org/10.7812/TPP/18-002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047845PMC
December 2018

Estimated Cost Savings: Everyone With Diabetes Counts (EDC) Program.

Fam Community Health 2018 Jul/Sep;41(3):185-193

Telligen, West Des Moines, Iowa (Drs Silveira and Brock and Mss Zhang and Irby); Centers for Medicare & Medicaid Services, Baltimore, Maryland (Mss Fleck and Dr Sonnenfeld); and Quality Insights, Charleston, West Virginia (Ms Manna).

Everyone with Diabetes Counts (EDC) is a national disparities reduction program funded by the Centers for Medicare & Medicaid Services to improve outcomes in the underserved minority, diverse, and rural populations. This analysis evaluates West Virginia's pilot program of diabetes self-management education (DSME), one component of EDC. We frequency-matched 422 DSME completers to 1688 others by demographics and enrollment from Medicare fee-for service claims. We estimated savings associated with reduced hospitalizations in multivariable negative binomial models. DSME completers had 29% fewer hospitalizations (adjusted P < .0069). We estimated savings of $35 900 per 100 DSME completers in West Virginia.
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http://dx.doi.org/10.1097/FCH.0000000000000189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5965937PMC
December 2018

Clinical tool for disease phenotyping in granulomatous lung disease.

PLoS One 2017 16;12(11):e0188119. Epub 2017 Nov 16.

Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.

Background: Exposure to beryllium may lead to granuloma formation and fibrosis in those who develop chronic beryllium disease (CBD). Although disease presentation varies from mild to severe, little is known about CBD phenotypes. This study characterized CBD disease phenotypes using longitudinal measures of lung function.

Methods: Using a case-only study of 207 CBD subjects, subject-specific trajectories over time were estimated from longitudinal pulmonary function and exercise-tolerance tests. To estimate linear combinations of the 30-year values that define underlying patterns of lung function, we conducted factor analysis. Cluster analysis was then performed on all the predicted lung function values at 30 years. These estimates were used to identify underlying features and subgroups of CBD.

Results: Two factors, or composite measures, explained nearly 70% of the co-variation among the tests; one factor represented pulmonary function in addition to oxygen consumption and workload during exercise, while the second factor represented exercise tests related to gas exchange. Factors were associated with granulomas on biopsy, exposure, steroid use and lung inflammation. Three clusters of patients (n = 53, n = 59 and, n = 95) were identified based on the collection of test values. Lower levels of each of the factor composite scores and cluster membership were associated with baseline characteristics of patients.

Conclusions: Using factor analysis and cluster analysis, we identified disease phenotypes that were associated with baseline patient characteristics, suggesting that CBD is a heterogeneous disease with varying severity. These clinical tools may be used in future basic and clinical studies to help define the mechanisms and risk factors for disease severity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0188119PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5690625PMC
December 2017

Beryllium-induced lung disease exhibits expression profiles similar to sarcoidosis.

Eur Respir J 2016 06 21;47(6):1797-808. Epub 2016 Apr 21.

Dept of Medicine, National Jewish Health, Denver, CO, USA Division of Pulmonary and Critical Care Sciences, Dept of Medicine, School of Medicine, Denver, CO, USA Environmental Occupational Health Dept, School of Public Health, University of Colorado, Denver, CO, USA.

A subset of beryllium-exposed workers develop beryllium sensitisation (BeS) which precedes chronic beryllium disease (CBD). We conducted an in-depth analysis of differentially expressed candidate genes in CBD.We performed Affymetrix GeneChip 1.0 ST array analysis on peripheral blood mononuclear cells (PBMCs) from 10 CBD, 10 BeS and 10 beryllium-exposed, nondiseased controls stimulated with BeSO4 or medium. The differentially expressed genes were validated by high-throughput real-time PCR in this group and in an additional group of cases and nonexposed controls. The functional roles of the top candidate genes in CBD were assessed using a pharmacological inhibitor. CBD gene expression data were compared with whole blood and lung tissue in sarcoidosis from the Gene Expression Omnibus.We confirmed almost 450 genes that were significantly differentially expressed between CBD and controls. The top enrichment of genes was for JAK (Janus kinase)-STAT (signal transducer and activator of transcription) signalling. A JAK2 inhibitor significantly decreased tumour necrosis factor-α and interferon-γ production. Furthermore, we found 287 differentially expressed genes overlapped in CBD/sarcoidosis. The top shared pathways included cytokine-cytokine receptor interactions, and Toll-like receptor, chemokine and JAK-STAT signalling pathways.We show that PBMCs demonstrate differentially expressed gene profiles relevant to the immunnopathogenesis of CBD. CBD and sarcoidosis share similar differential expression of pathogenic genes and pathways.
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http://dx.doi.org/10.1183/13993003.01469-2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5134922PMC
June 2016

Differential somatostatin receptor (SSTR) 1-5 expression and downstream effectors in histologic subtypes of growth hormone pituitary tumors.

Mol Cell Endocrinol 2015 Dec 21;417:73-83. Epub 2015 Sep 21.

Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Research Service Veterans Affairs Medical Center, Denver, CO 80220, USA.

Purpose: The aim of this study was to examine whether differential expression of somatostatin receptors (SSTR) 1-5 and downstream effectors are different in densely (DG) and sparsely (SG) granulated histological growth hormone (GH) pituitary tumor subtypes.

Methods: The study included 33 acromegalic patients with 23 DG and 10 SG tumors. SSTR1-5 were measured by qPCR and immunoblotting. Signaling candidates downstream of SSTR2 were also assessed.

Results: SSTR2 mRNA and protein levels were significantly higher in DG compared to SG tumors. Downstream of SSTR2, p27(kip1) was decreased (2.6-fold) in SG compared to DG tumors, suggesting a potential mechanism of SSA resistance in SG tumors with intact SSTR2 expression. Re-expression of E-cadherin in GH pituitary cell increased p27(kip1) levels.

Conclusions: Histological subtyping correlated with SSTR2, E cadherin and p27(kip) protein levels and these may serve as useful biomarkers in GH tumors to predict behavior and response to therapy with SSA.
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http://dx.doi.org/10.1016/j.mce.2015.09.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4641524PMC
December 2015

Vorticity is a marker of right ventricular diastolic dysfunction.

Am J Physiol Heart Circ Physiol 2015 Sep 7;309(6):H1087-93. Epub 2015 Aug 7.

Department of Mechanical Engineering, University of Colorado, Boulder, Colorado;

Right ventricular diastolic dysfunction (RVDD) is an important prognostic indicator in pulmonary arterial hypertension (PAH). RV vortex rings have been observed in healthy subjects, but their significance in RVDD is unknown. Vorticity, the local spinning motion of an element of fluid, may be a sensitive measure of RV vortex dynamics. Using four-dimensional (4D) flow cardiac magnetic resonance imaging (CMR), we investigated the relationship between right heart vorticity with echocardiographic indexes of RVDD. Thirteen (13) PAH subjects and 10 controls underwent same-day 4D flow CMR and echocardiography. RV diastolic function was assessed using trans-tricuspid valve (TV) early (E) and late (A) velocities, E/A ratio, and e' and a' tissue Doppler velocities. RV and right atrial (RA) integrated mean vorticity was calculated for E and A-wave filling periods using 4D datasets. Compared with controls, A-wave vorticity was significantly increased in RVDD subjects in both the RV [2343 (1,559-3,295) vs. 492 (267-2,649) 1/s, P = 0.028] and RA [30 (27-44) vs. 9 (5-27) 1/s, P = 0.005]. RA E vorticity was significantly decreased [13 (7-22) vs. 28 (15-31) 1/s, P = 0.038] in RVDD. E-wave vorticity correlated TV e', E-,and TV E/A (P < 0.05), and A-wave vorticity associated with both TV A and E/A (P < 0.02). RVDD is associated with alterations in E- and A-wave vorticity, and vorticity correlates with multiple echocardiographic markers of RVDD. Vorticity may be a robust noninvasive research tool for the investigation of RV fluid and tissue mechanical interactions in PAH.
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http://dx.doi.org/10.1152/ajpheart.00278.2015DOI Listing
September 2015

Galectin-3 levels are associated with right ventricular functional and morphologic changes in pulmonary arterial hypertension.

Heart Vessels 2016 Jun 15;31(6):939-46. Epub 2015 May 15.

Division of Pulmonary Medicine, National Jewish Health, Denver, CO, USA.

The response of the right ventricle (RV) to pulmonary arterial hypertension (PAH) involves changes in contractile function, chamber size, hypertrophy, and extracellular matrix (ECM). Galectin-3 (Gal-3) is a mediator of myocardial ECM metabolism and biomarker for left heart remodeling, yet its ability to reflect RV remodeling is unknown. We hypothesized that serum Gal-3 levels correlate with RV morphology and function in PAH, and that Gal-3 is associated with circulating markers of ECM. Fifteen subjects with PAH and 10 age-matched controls underwent same-day echocardiography, cardiac magnetic resonance (CMR) imaging, and phlebotomy for Gal-3 and ECM biomarkers including N-terminal propeptide of type III collagen type (PIIINP), tissue inhibitor of metalloproteinase-1 (TIMP-1), and hyaluronic acid (HA). RV ejection fraction, end diastolic volume index, end systolic volume index, and mass index were calculated using CMR. Echocardiography was used to estimate RV systolic pressure and measure RV strain. Serum Gal-3, TIMP-1, and HA levels were all significantly increased in PAH subjects when compared to controls. Gal-3 correlated with RV ejection fraction (ρ -0.44, p 0.03), end diastolic volume index (ρ 0.42, p 0.03), end systolic volume index (ρ 0.44, p 0.027), mass index (ρ 0.47, p 0.016), systolic pressure (ρ 0.55, p < 0.001), and strain (ρ 0.43, p 0.03). Gal-3 levels positively correlated with the ECM markers TIMP-1 and HA but not with PIIINP. In conclusion, Gal-3 levels are associated with multiple indices of RV function and morphology. Gal-3 may represent a novel biomarker for RV remodeling and associated ECM turnover in PAH.
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http://dx.doi.org/10.1007/s00380-015-0691-zDOI Listing
June 2016

Cystatin C: a potential biomarker for pulmonary arterial hypertension.

Respirology 2014 May 14;19(4):583-9. Epub 2014 Mar 14.

Division of Cardiology, National Jewish Health, Denver, Colorado, USA.

Background And Objective: Cystatin C (CysC), a novel marker of renal function, predicts left heart failure and cardiovascular mortality. The hypothesis that serum CysC levels correlate with right ventricular (RV) morphology, function and pressure in pulmonary arterial hypertension (PAH) was tested.

Methods: As part of a prospective study, 14 PAH subjects and 10 matched controls underwent same-day echocardiography, cardiac magnetic resonance imaging (CMR), and phlebotomy for CysC, brain natriuretic peptide (BNP), and N-terminal BNP (NT-ProBNP). RV ejection fraction (RVEF), end-diastolic volume, end-systolic volume and mass were calculated using CMR. RV systolic pressure (RVSP), strain and diastolic function (including tricuspid valve (TV) E velocity, A velocity, e' velocity, E/A ratio and E/e' ratio) were assessed using echocardiography.

Results: RVSP was significantly elevated in PAH subjects versus controls (57 ± 17 vs. 28 ± 8 mm Hg, P < 0.0001). CysC was abnormally elevated in the PAH cohort when compared with controls (1.00 ± 0.23 vs 0.78 ± 0.05 mg/L, P = 0.001). CysC positively correlated with RVSP (rho 0.61, P = 0.002), RV end-diastolic volume (rho 0.50, P = 0.01), RV end-systolic volume (rho 0.58, P = 0.003), mass index (rho 0.66, P = 0.0004), strain (rho 0.51, P = 0.01) and strain rate (rho 0.51, P = 0.01) and negatively correlated with RVEF (rho -0.58, P = 0.003) and TV e' (rho -0.75, P < 0.0001). The same correlations with BNP and NT-ProBNP were comparable with CysC.

Conclusions: In a small cohort, CysC accurately correlates with RV pressure, function and morphology. CysC may represent a novel PAH biomarker.
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http://dx.doi.org/10.1111/resp.12259DOI Listing
May 2014

Cytosolic phospholipase A(2)α and eicosanoids regulate expression of genes in macrophages involved in host defense and inflammation.

PLoS One 2013 25;8(7):e69002. Epub 2013 Jul 25.

Department of Pediatrics, National Jewish Health, Denver, CO, USA.

The role of Group IVA cytosolic phospholipase A2 (cPLA2α) activation in regulating macrophage transcriptional responses to Candida albicans infection was investigated. cPLA2α releases arachidonic acid for the production of eicosanoids. In mouse resident peritoneal macrophages, prostacyclin, prostaglandin E2 and leukotriene C4 were produced within minutes of C. albicans addition before cyclooxygenase 2 expression. The production of TNFα was lower in C. albicans-stimulated cPLA2α(+/+) than cPLA2α(-/-) macrophages due to an autocrine effect of prostaglandins that increased cAMP to a greater extent in cPLA2α(+/+) than cPLA2α(-/-) macrophages. For global insight, differential gene expression in C. albicans-stimulated cPLA2α(+/+) and cPLA2α(-/-) macrophages (3 h) was compared by microarray. cPLA2α(+/+) macrophages expressed 86 genes at lower levels and 181 genes at higher levels than cPLA2α(-/-) macrophages (≥2-fold, p<0.05). Several pro-inflammatory genes were expressed at lower levels (Tnfα, Cx3cl1, Cd40, Ccl5, Csf1, Edn1, CxCr7, Irf1, Irf4, Akna, Ifnγ, several IFNγ-inducible GTPases). Genes that dampen inflammation (Socs3, Il10, Crem, Stat3, Thbd, Thbs1, Abca1) and genes involved in host defense (Gja1, Csf3, Trem1, Hdc) were expressed at higher levels in cPLA2α(+/+) macrophages. Representative genes expressed lower in cPLA2α(+/+) macrophages (Tnfα, Csf1) were increased by treatment with a prostacyclin receptor antagonist and protein kinase A inhibitor, whereas genes expressed at higher levels (Crem, Nr4a2, Il10, Csf3) were suppressed. The results suggest that C. albicans stimulates an autocrine loop in macrophages involving cPLA2α, cyclooxygenase 1-derived prostaglandins and increased cAMP that globally effects expression of genes involved in host defense and inflammation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0069002PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3742295PMC
March 2014

Association between the MUC5B promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis.

JAMA 2013 Jun;309(21):2232-9

Department of Epidemiology, School of Public Health, University of Colorado Denver, USA.

Importance: Current prediction models of mortality in idiopathic pulmonary fibrosis (IPF), which are based on clinical and physiological parameters, have modest value in predicting which patients will progress. In addition to the potential for improving prognostic models, identifying genetic and molecular features that are associated with IPF mortality may provide insight into the underlying mechanisms of disease and inform clinical trials.

Objective: To determine whether the MUC5B promoter polymorphism (rs35705950), previously reported to be associated with the development of pulmonary fibrosis, is associated with survival in IPF.

Design, Setting, And Participants: Retrospective study of survival in 2 independent cohorts of patients with IPF: the INSPIRE cohort, consisting of patients enrolled in the interferon-γ1b trial (n = 438; December 15, 2003-May 2, 2009; 81 centers in 7 European countries, the United States, and Canada), and the Chicago cohort, consisting of IPF participants recruited from the Interstitial Lung Disease Clinic at the University of Chicago (n = 148; 2007-2010). The INSPIRE cohort was used to model the association of the MUC5B genotype with survival, accounting for the effect of matrix metalloproteinase 7 (MMP-7) blood concentration and other demographic and clinical covariates. The Chicago cohort was used for replication of findings.

Main Outcomes And Measures: The primary end point was all-cause mortality.

Results: The numbers of patients in the GG, GT, and TT genotype groups were 148 (34%), 259 (59%), and 31 (7%), respectively, in the INSPIRE cohort and 41 (28%), 98 (66%), and 9 (6%), respectively, in the Chicago cohort. The median follow-up period was 1.6 years for INSPIRE and 2.1 years for Chicago. During follow-up, there were 73 deaths (36 GG, 35 GT, and 2 TT) among INSPIRE patients and 64 deaths (26 GG, 36 GT, and 2 TT) among Chicago patients. The unadjusted 2-year cumulative incidence of death was lower among patients carrying 1 or more copies of the IPF risk allele (T) in both the INSPIRE cohort (0.25 [95% CI, 0.17-0.32] for GG, 0.17 [95% CI, 0.11-0.23] for GT, and 0.03 [95% CI, 0.00-0.09] for TT) and the Chicago cohort (0.50 [95% CI, 0.31-0.63] for GG, 0.22 [95% CI, 0.13-0.31] for GT, and 0.11 [95% CI, 0.00-0.28] for TT). In the INSPIRE cohort, the TT and GT genotypes (risk for IPF) were associated with improved survival compared with GG (hazard ratios, 0.23 [95% CI, 0.10-0.52] and 0.48 [95% CI, 0.31-0.72], respectively; P < .001). This finding was replicated in the Chicago cohort (hazard ratios, 0.15 [95% CI, 0.05-0.49] and 0.39 [95% CI, 0.21-0.70], respectively; P < .002). The observed association of MUC5B with survival was independent of age, sex, forced vital capacity, diffusing capacity of carbon monoxide, MMP-7, and treatment status. The addition of the MUC5B genotype to the survival models significantly improved the predictive accuracy of the model in both the INSPIRE cohort (C = 0.71 [95% CI, 0.64-0.75] vs C = 0.68 [95% CI, 0.61-0.73]; P < .001) and the Chicago cohort (C = 0.73 [95% CI, 0.62-0.78] vs C = 0.69 [95% CI, 0.59-0.75]; P = .01).

Conclusions And Relevance: Among patients with IPF, a common risk polymorphism in MUC5B was significantly associated with improved survival. Further research is necessary to refine the risk estimates and to determine the clinical implications of these findings.
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http://dx.doi.org/10.1001/jama.2013.5827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4545271PMC
June 2013

Chronic beryllium disease, HLA-DPB1, and the DP peptide binding groove.

J Immunol 2012 Oct 12;189(8):4014-23. Epub 2012 Sep 12.

National Jewish Health, Denver, CO 80206, USA.

Multiple epidemiologic studies demonstrate associations between chronic beryllium disease (CBD), beryllium sensitization (BeS), and HLA-DPB1 alleles with a glutamic acid residue at position 69 (E69). Results suggest that the less-frequent E69 variants (non-*0201/*0202 alleles) might be associated with greater risk of CBD. In this study, we sought to define specific E69-carrying alleles and their amino acid sequences in the DP peptide binding groove, as well as their relationship to CBD and BeS risk, using the largest case control study to date. We enrolled 502 BeS/CBD subjects and 653 beryllium-exposed controls from three beryllium industries who gave informed consent for participation. Non-Hispanic white cases and controls were frequency-matched by industry. HLA-DPB1 genotypes were determined using sequence-specific primer PCR. The E69 alleles were tested for association with disease individually and grouped by amino acid structure using logistic regression. The results show that CBD cases were more likely than controls to carry a non-*02 E69 allele than an *02 E69, with odds ratios (95% confidence interval) ranging from 3.1 (2.1-4.5) to 3.9 (2.6-5.9) (p < 0.0001). Polymorphic amino acids at positions 84 and 11 were associated with CBD: DD versus GG, 2.8 (1.8-4.6), p < 0.0001; GD versus GG, 2.1 (1.5-2.8), p < 0.0001; LL versus GG, 3.2 (1.8-5.6), p < 0.0001; GL versus GG, 2.8 (2.1-3.8), p < 0.0001. Similar results were found within the BeS group and CBD/BeS combined group. We conclude that the less frequent E69 alleles confer more risk for CBD than does *0201. Recent studies examining how the composition and structure of the binding pockets influence peptide binding in MHC genes, as well of studies showing the topology of the TCR to likely bind DPB1 preferentially, give plausible biological rationale for these findings.
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http://dx.doi.org/10.4049/jimmunol.1200798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4347851PMC
October 2012

Bronchoalveolar lavage neuregulin-1 is elevated in acute lung injury and correlates with inflammation.

Eur Respir J 2013 Feb 17;41(2):396-401. Epub 2012 May 17.

Dept. of Medicine, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA.

Shedding of neuregulin (NRG)-1 from the pulmonary epithelium leads to activation of the epithelial human epidermal growth factor receptor (HER)2 receptor, increased pulmonary epithelial permeability and acute lung injury (ALI). We sought to determine whether NRG-1 was detectable and elevated in bronchoalveolar lavage (BAL) and plasma from patients with ALI compared with controls and to determine whether a correlation exists between NRG-1 and inflammation and outcome in ALI. Matched BAL and plasma samples were obtained from 23 ALI patients requiring intubation and mechanical ventilation. Control patients (n=5) included healthy volunteers. NRG-1 and indices of inflammation were measured in BAL and plasma via ELISA. The mean±sd BAL NRG-1 concentration in ALI patients was 187.0±21.35 pg·mL(-1) compared with 85.50±9.2 pg·mL(-1) in controls (p=0.001). Increased BAL NRG-1 was associated with markers of inflammation, and inversely correlated with ventilator-free days (VFDs; r= -0.51, p=0.015). Plasma NRG-1 was elevated in ALI patients compared with controls (611.7±354.2 versus 25.17±19.33 pg·mL(-1), p<0.001) and inversely correlated with VFDs (r= -0.51, p=0.04). These results confirm shedding of NRG-1 in ALI and suggest that the NRG-1-HER2 pathway is active in patients with ALI.
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http://dx.doi.org/10.1183/09031936.00004912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4140244PMC
February 2013

Risk of chronic beryllium disease by HLA-DPB1 E69 genotype and beryllium exposure in nuclear workers.

Am J Respir Crit Care Med 2011 Jun 11;183(12):1680-8. Epub 2011 Mar 11.

National Jewish Health, Denver, CO 80206, USA.

Rationale: Beryllium sensitization (BeS) and chronic beryllium disease (CBD) are determined by at least one genetic factor, a glutamic acid at position 69 (E69) of the HLA-DPB1 gene, and by exposure to beryllium. The relationship between exposure and the E69 genotype has not been well characterized.

Objectives: The study goal was to define the relationship between beryllium exposure and E69 for CBD and BeS.

Methods: Workers (n = 386) from a U.S. nuclear weapons facility were enrolled into a case-control study (70 BeS, 61 CBD, and 255 control subjects). HLA-DPB1 genotypes were determined by sequence-specific primer-polymerase chain reaction. Beryllium exposures were reconstructed on the basis of worker interviews and historical exposure measurements.

Measurements And Main Results: Any E69 carriage increased odds for CBD (odds ratio [OR], 7.61; 95% confidence interval [CI], 3.66-15.84) and each unit increase in lifetime weighted average exposure increased the odds for CBD (OR, 2.27; 95% CI, 1.26-4.09). Compared with E69-negative genotypes, a single E69-positive *02 allele increased the odds for BeS (OR, 12.01; 95% CI, 4.28-33.71) and CBD (OR, 3.46; 95% CI, 1.42-8.43). A single non-*02 E69 allele further increased the odds for BeS (OR, 29.54; 95% CI, 10.33-84.53) and CBD (OR, 11.97; 95% CI, 5.12-28.00) and two E69 allele copies conferred the highest odds for BeS (OR, 55.68; 95% CI, 14.80-209.40) and CBD (OR, 22.54; 95% CI, 7.00-72.62).

Conclusions: E69 and beryllium exposure both contribute to the odds of CBD. The increased odds for CBD and BeS due to E69 appear to be differentially distributed by genotype, with non-*02 E69 carriers and E69 homozygotes at higher odds than those with *02 genotypes.
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http://dx.doi.org/10.1164/rccm.201002-0254OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136994PMC
June 2011

Exposure and genetics increase risk of beryllium sensitisation and chronic beryllium disease in the nuclear weapons industry.

Occup Environ Med 2011 Nov 2;68(11):842-8. Epub 2011 Apr 2.

Hollis Laboratory, Division of Environmental and Occupational Health Sciences, National Jewish Health, Denver, Colorado 80206, USA.

Objectives: Beryllium sensitisation (BeS) and chronic beryllium disease (CBD) are caused by exposure to beryllium with susceptibility affected by at least one well-studied genetic host factor, a glutamic acid residue at position 69 (E69) of the HLA-DPβ chain (DPβE69). However, the nature of the relationship between exposure and carriage of the DPβE69 genotype has not been well studied. The goal of this study was to determine the relationship between DPβE69 and exposure in BeS and CBD.

Methods: Current and former workers (n=181) from a US nuclear weapons production facility, the Y-12 National Security Complex (Oak Ridge, Tennessee, USA), were enrolled in a case-control study including 35 individuals with BeS and 19 with CBD. HLA-DPB1 genotypes were determined by PCR-SSP. Beryllium exposures were assessed through worker interviews and industrial hygiene assessment of work tasks.

Results: After removing the confounding effect of potential beryllium exposure at another facility, multivariate models showed a sixfold (OR 6.06, 95% CI 1.96 to 18.7) increased odds for BeS and CBD combined among DPβE69 carriers and a fourfold (OR 3.98, 95% CI 1.43 to 11.0) increased odds for those exposed over an assigned lifetime-weighted average exposure of 0.1 μg/m(3). Those with both risk factors had higher increased odds (OR 24.1, 95% CI 4.77 to 122).

Conclusion: DPβE69 carriage and high exposure to beryllium appear to contribute individually to the development of BeS and CBD. Among workers at a beryllium-using facility, the magnitude of risk associated with either elevated beryllium exposure or carriage of DPβE69 alone appears to be similar.
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http://dx.doi.org/10.1136/oem.2010.064220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4347849PMC
November 2011

Smoking reduces surfactant protein D and phospholipids in patients with and without chronic obstructive pulmonary disease.

BMC Pulm Med 2010 Oct 25;10:53. Epub 2010 Oct 25.

Department of Medicine, National Jewish Health, Denver, CO, USA.

Background: Pulmonary surfactant D (SP-D) has important regulatory functions for innate immunity and has been implicated as a biomarker for chronic obstructive pulmonary disease (COPD). We hypothesized that COPD patients would have reduced bronchoalveolar lavage (BAL) fluid SP-D levels compared to healthy smoking and non-smoking controls.

Methods: BAL SP-D and phospholipids were quantified and corrected for dilution in 110 subjects (65 healthy never smokers, 23 smokers with normal spirometry, and 22 smokers with COPD).

Results: BAL SP-D was highest in never smokers (mean 51.9 μg/mL ± 7.1 μg/mL standard error) compared to both smokers with normal spirometry (16.0 μg/mL ± 11.8 μg/mL) and subjects with COPD (19.1 μg/mL ± 12.9 μg/mL; P < 0.0001). Among smokers with COPD, BAL SP-D correlated significantly with FEV1% predicted (R = 0.43; P < 0.05); however, the strongest predictor of BAL SP-D was smoking status. BAL SP-D levels were lowest in current smokers (12.8 μg/mL ± 11.0 μg/mL), intermediate in former smokers (25.2 μg/mL ± 14.2 μg/mL; P < 0.008), and highest in never smokers. BAL phospholipids were also lowest in current smokers (6.5 nmol ± 1.5 nmol), intermediate in former smokers (13.1 nmol ± 2.1 nmol), and highest in never smokers (14.8 nmol ± 1.1 nmol; P < 0.0001).

Conclusions: These data suggest that smokers, and especially current smokers, exhibit significantly reduced BAL SP-D and phospholipids compared to nonsmokers. Our findings may help better explain the mechanism that leads to the rapid progression of disease and increased incidence of infection in smokers.
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http://dx.doi.org/10.1186/1471-2466-10-53DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2987951PMC
October 2010

Gene-environment interactions influence airways function in laboratory animal workers.

J Allergy Clin Immunol 2010 Aug 25;126(2):232-40. Epub 2010 Jun 25.

Department of Medicine, Division of Environmental and Occupational Health Sciences, National Jewish Health, Denver, CO 80206, USA.

Background: Most diseases, including asthma, result from the interaction between environmental exposures and genetic variants. Functional variants of CD14 negatively affect lung function in farm workers and children exposed to animal allergens and endotoxin.

Objective: We hypothesized that CD14 polymorphisms interact with inhaled endotoxin, mouse allergen, or both to decrease airways function in laboratory animal workers.

Methods: Three hundred sixty-nine Caucasian workers completed a symptom and work exposure questionnaire, skin prick testing, and spirometry. Individual exposure estimates for endotoxin and murine allergen were calculated by weighting task-based breathing zone concentrations by time reported for each task and length of time in the current job. Real-time PCR was used to assess CD14/-1619, -550, and -159 alleles. Multiple linear regression predicting airways function included an interaction term between genotype and exposure.

Results: Workers at the highest quartile of the natural log-transformed cumulative endotoxin exposure and with the endotoxin-responsive CD14/-1619 G allele had significantly lower FEV(1) and forced expiratory flow, midexpiratory phase (FEF(25-75)) percent predicted compared with workers with an AA genotype, with no significant differences noted at lower endotoxin levels for either genotype. The gene-environment effect was marked for atopic workers. Laboratory animal allergy, murine allergen exposure, CD14/-159 or -550 genotype, and a gene-exposure interaction term for these genotypes and exposures did not predict changes in lung function.

Conclusions: A significant gene-environment interaction affects airways function in laboratory animal workers. More highly endotoxin-exposed workers with CD14/-1619G alleles have significantly lower FEV(1) and FEF(25-75) percent predicted than those with CD14/-1619AA alleles. Atopic workers are particularly affected by cumulative endotoxin exposures.
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http://dx.doi.org/10.1016/j.jaci.2010.04.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917520PMC
August 2010

Effect of the inhaled corticosteroid mometasone on small airway patency in patients with asthma.

Allergy Asthma Proc 2009 May-Jun;30(3):284-92

Department of Medicine, National Jewish Health, Denver, Colorado 80206, USA.

The inflammation in asthma involves both the large and the small airways. This study was designed to examine whether mometasone delivered from a dry powder inhaler would improve those parameters thought to reflect patency and obstruction of the small airways (diameter <2 mm). Subjects with mild to moderate asthma, only receiving short-acting beta-agonists, underwent baseline assessment, and then were randomized to receive for 12 weeks either mometasone 400 micrograms once daily in the evening or matching placebo. Outcomes assessed included clinical measures and measures of airway responsiveness and inflammation included methacholine sensitivity (concentration of methacholine causing a 20% fall in forced expiratory volume in 1 second [FEV(1)] [PC(20)]), exhaled nitric oxide, serum ECP, and sputum eosinophils. Pulmonary function was assessed by spirometry, plethysmography, and forced oscillometry. Measures of small airway patency included single breath nitrogen washout and air trapping on expiratory high-resolution computed tomography. Results were available on 12 adult subjects who received mometasone and 14 subjects who received placebo. Among tests reflecting small airway patency, the forced expiratory flow between 25 and 75% of vital capacity was significantly improved by mometasone compared with placebo (+9% versus -6%; p = 0.006 and the closing volume over forced vital capacity (FVC; -2% versus 0%; p = 0.05). Other results significantly favoring mometasone over placebo included FEV(1), FVC, PC(20), and A.M. and P.M. peak expiratory flows, and albuterol use. Mometasone delivered by a dry powder inhaler improved asthma control and pulmonary function in tests reflecting both large and small airways.
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http://dx.doi.org/10.2500/aap.2009.30.3235DOI Listing
August 2009

Response to sublingual immunotherapy with grass pollen extract: monotherapy versus combination in a multiallergen extract.

J Allergy Clin Immunol 2009 Jul 11;124(1):150-156.e1-5. Epub 2009 Jun 11.

National Jewish Health, Denver, CO 80206, USA.

Background: To date, there have been no randomized, double-blind studies showing the effectiveness of sublingual immunotherapy with multiple allergens.

Objective: The purpose of this study was to examine whether the efficacy of sublingual immunotherapy (SLIT) with standardized timothy extract was reduced by combination with other allergen extracts.

Methods: A single-center, randomized, double-blind, placebo-controlled trial with SLIT was conducted. After an observational grass season, SLIT was administered for 10 months to 54 patients randomized to 1 of 3 treatment arms: placebo, timothy extract (19 microg Phl p 5 daily) as monotherapy, or the same dose of timothy extract plus 9 additional pollen extracts. Symptom and medication scores were collected and titrated nasal challenges, titrated skin prick tests, specific IgE, IgG4 and cytokines release by timothy-stimulated lymphocyte proliferation were performed.

Results: Perhaps because of a very low grass pollen season in 2008, there were no significant differences in medication or symptom scores in either treatment group compared with placebo. Compared with placebo, in the timothy monotherapy group, thresholds for titrated nasal challenge and skin prick tests (P = .03 and P = .001, respectively), and serum-specific IgG4 levels (P = .005) significantly increased, and IFN- gamma levels decreased (P = .02), whereas in the multiallergen group, there was significant improvement only in the titrated skin prick tests (P = .04) which was less than in the monotherapy group. There were no significant differences between the 2 active groups in any outcome measure, and both active groups experienced more adverse events than placebo. There were no systemic reactions.

Conclusion: Improvement in multiple relevant outcomes strongly suggests that SLIT with timothy extract alone was effective; however, the results for symptom and medication scores were not significant. The differences between multiple allergen SLIT and placebo only in skin sensitivity to timothy suggest a reduction in SLIT efficacy in this group. However, further studies are required to confirm these observations.
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http://dx.doi.org/10.1016/j.jaci.2009.04.037DOI Listing
July 2009

A new tool to assess sarcoidosis severity.

Chest 2006 May;129(5):1234-45

Pulmonary, Allergy, and Critcal Care Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.

Study Objectives: Sarcoidosis is a granulomatous disorder primarily affecting the lung, but with frequent extrapulmonary organ involvement. There are no comprehensive scoring systems for sarcoidosis disease severity. Our goal was to develop and validate an objective and comprehensive sarcoidosis disease severity scoring system.

Design: Three sarcoidosis experts reviewed clinical data on 104 patients with biopsy-confirmed sarcoidosis. Each expert independently scored disease severity using a visual analog scale. Interrater agreement was assessed. Univariate analysis was performed, and those variables with p values < or = 0.25 were used in backward regression multivariable analysis. A model was obtained including variables with a p value of < or = 0.15 to predict severity scores. This model was subsequently validated using an independent panel of three additional international experts.

Setting: Granuloma clinic at National Jewish Medical and Research Center.

Patients: A total of 104 patients with biopsy-confirmed sarcoidosis.

Interventions: None.

Measurements And Results: Pairwise assessment of interrater agreement yielded high degrees of correlation with Spearman correlation coefficients of 0.86 to 0.89 and an intraclass correlation coefficient of 0.87. Univariate analysis showed that smoking status, immunosuppressive therapy, percent predicted for diffusing capacity of the lung for carbon monoxide (Dlco), FEV1, FVC, and total lung capacity, FEV1/FVC ratio, disease duration, sites of organ involvement, and African-American race were associated with mean severity score. The multivariable model included cardiac and neurologic involvement, current therapy with noncorticosteroid immunosuppressive agents, Dlco percent predicted, FEV1/FVC ratio, African-American race, FVC percent predicted, and skin involvement. This model was validated using additional reviewer scores yielding Spearman correlation coefficients of 0.66 to 0.76 and an intraclass correlation coefficient of 0.74.

Conclusions: We derived an objective disease severity scoring system that incorporates data on demographics, pulmonary function, and organ involvement to produce a whole-body sarcoidosis assessment. This preliminary tool has potential applicability in the assessment of disease severity in sarcoidosis research.
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http://dx.doi.org/10.1378/chest.129.5.1234DOI Listing
May 2006

Beryllium medical surveillance at a former nuclear weapons facility during cleanup operations.

J Occup Environ Med 2004 Sep;46(9):953-61

Division of Environmental and Occupational Health Sciences, National Jewish Medical and Research Center, Denver, CO 80206, USA.

Despite increasing need to remediate beryllium-contaminated buildings in industry, little is known about the magnitude of risk associated with beryllium abatement or the merits of beryllium medical surveillance for cleanup workers. We examined beryllium lymphocyte proliferation tests and reviewed medical evaluations on workers at a nuclear weapons facility during the process of decontamination and decommissioning. Of 2,221 workers, 19 (0.8%) were beryllium sensitized based on two or more abnormal beryllium lymphocyte proliferation tests. Eight of 19 sensitized individuals underwent full clinical evaluation, of whom two were diagnosed with chronic beryllium disease (CBD). Notably, seven beryllium sensitized and CBD cases were hired after the start of cleanup operations. Beryllium medical surveillance detects sensitization and CBD in cleanup workers. Exposure controls and medical surveillance need to be 'broad-based' to include all cleanup workers involved in beryllium-contaminated building remediation.
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http://dx.doi.org/10.1097/01.jom.0000139872.80118.bdDOI Listing
September 2004
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