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Background: Pulmonary hypertension (PH) is a significant cause of morbidity and mortality in sarcoidosis. We established a multi-national registry of sarcoidosis associated PH (SAPH) patients., Methods: Sarcoidosis patients with PH confirmed by right heart catheterization (RHC) were studied. Patients with pulmonary artery wedge pressure (PAWP) of 15 mmHg or less and a mean pulmonary artery pressure (mPAP) ≥ 25 Hg were subsequently analyzed. Data collected included hemodynamics, forced vital capacity (FVC), diffusion capacity of carbon monoxide (DL CO ), chest x-ray, and 6-min walk distance (6MWD)., Results: A total of 176 patients were analyzed. This included 84 (48%) cases identified within a year of entry into the registry and 94 (53%) with moderate to severe PH. There was a significant correlation between DL CO percent predicted (% pred) andmPAP (Rho = -0.228, p = 0.0068) and pulmonary vascular resistance (PVR) (Rho = -0.362, p < 0.0001). PVR was significantly higher in stage 4 disease than in stage 0 or 1 disease (p < 0.05 for both comparisons). About two-thirds of the SAPH patients came from the United States (US). There was a significant difference in the rate of treatment between US (67.5%) versus non-US (86%) (Chi Square 11.26, p = 0.0008) sites., Conclusions: The clinical features of SAPH were similar across multiple centers in the US, Europe, and the Middle East. The severity of SAPH was related to reduced DLCO. There were treatment differences between the US and non-US centers., (Copyright © 2018. Published by Elsevier Ltd.)

This study aimed to determine if short-term exposure to particulate matter (PM 2.5 ) and ozone (O₃) is associated with increased symptoms or lung function decline in fibrotic sarcoidosis. Sixteen patients with fibrotic sarcoidosis complicated by frequent exacerbations completed pulmonary function testing and questionnaires every three months for one year. We compared 7-, 10-, and 14-day average levels of PM 2.5 and O₃ estimated at patient residences to spirometry (forced expiratory volume in 1 s (FEV1), to forced vital capacity (FVC), episodes of FEV1 decline > 10%) and questionnaire outcomes (Leicester cough questionnaire (LCQ), Saint George Respiratory Questionnaire (SGRQ), and King's Sarcoidosis Questionnaire (KSQ)) using generalized linear mixed effect models. PM 2.5 level averaged over 14 days was associated with lower KSQ general health status (score change -6.60 per interquartile range (IQR) PM 2.5 increase). PM 2.5 level averaged over 10 and 14 days was associated with lower KSQ lung specific health status (score change -6.93 and -6.91, respectively). PM 2.5 levels were not associated with FEV₁, FVC, episodes of FEV₁ decline > 10%, or respiratory symptoms measured by SGRQ or LCQ. Ozone exposure was not associated with any health outcomes. In this small cohort of patients with fibrotic sarcoidosis, PM 2.5 exposure was associated with increased severity of respiratory and quality of life symptoms.

Background: Education about an advance directive is frequently not addressed in the outpatient, ambulatory care setting. The objective of this study was to identify patients that do not have an advance directive in a Chronic Multi-Organ Rare Disease Clinic model, and define the role of a social worker in providing advance care planning (ACP)., Methods: The Chronic Multi-Organ Rare Disease Clinic in-corporates a multi-disciplinary team to provide outpatient care to over 600 patients. A review of advance directives filed in the electronic health record (EHR) prior to hiring a clinic social worker was examined in this high risk population., Results: A total of 15 patients (2%) of this patient population were identified as having a completed, active advance directive filed with their EHR prior to hiring a clinic social worker. The clinic social worker began ACP discussions and inquiries about the status of patient advance directives with a total of 162 patients during September 2016-April 2017. Of these 162 patients, 14 patients (8.6%) submitted their completed advance directives for filing with their EHR after advanced care discussions were initiated by the clinic social worker. Two patients who completed an advance directive, died during this 7-month time period. Only three patients declined to complete advance directives during this same time period., Conclusions: Patient-centered care must incorporate ACP. A clinic social worker is an effective member of a multi-disciplinary team and can incorporate education about advance directives in order to improve health care quality.

Objectives: In systemic sclerosis (SSc) the most common gastrointestinal tract (GIT) complaint is gastroesophageal reflux disease (GERD), which may contribute to oesophagitis, stricture, Barrett's oesophagus, and oesophageal adenocarcinoma. We used a genealogical resource the Utah Population Database (UPDB) to analyse SSc pedigrees for hereditability of oesophageal disease., Methods: SSc, GERD, oesophagitis, stricture, Barrett's, and oesophageal adenocarcinoma were defined by ICD Ninth and Tenth Revision codes. Familial aggregation, relative risk (RR) of the GIT disease in SSc proband and their relatives was estimated by Cox regression model. The model (adjusted for sex and birth year) was used to evaluate the effects of having or being related to, a case or control for SSc, on GIT diseases., Results: We identified 2,227 unique SSc patients and 11,136 randomly selected controls matched by birth year, gender, and whether born in Utah, in an approximately 1:5 ratio. A SSc proband had a significant high risk of GERD (RR: 3.28), dysphagia (RR 5.58), oesophageal stricture (RR: 5.16), oesophagitis (RR: 4.86), and Barrett's (RR: 4.52) all with significant p-values <2e-16. First-degree relatives of a SSc proband were at elevated risk of GERD (RR: 1.14, p=6.85e-05), dysphagia (RR: 1.22 p=0.002), and oesophagitis (RR: 1.37, p=2.10e-06). First cousins (RR: 1.09, p=0.03) and spouses (RR; 1.37, p=0.02) were at increased risk of esophagitis and dysphagia., Conclusions: These data suggest that independent of GERD, oesophagitis in SSc patients and their relatives may have both a hereditable and environmental etiology. There does not seem to be a heritable component to Barrett's oesophagus.

Multinucleate cellular syncytial formation is a hallmark of skeletal muscle differentiation. Myomaker, encoded by Mymk (Tmem8c), is a well-conserved plasma membrane protein required for myoblast fusion to form multinucleated myotubes in mouse, chick, and zebrafish. Here, we report that autosomal recessive mutations in MYMK (OMIM 615345) cause Carey-Fineman-Ziter syndrome in humans (CFZS; OMIM 254940) by reducing but not eliminating MYMK function. We characterize MYMK-CFZS as a congenital myopathy with marked facial weakness and additional clinical and pathologic features that distinguish it from other congenital neuromuscular syndromes. We show that a heterologous cell fusion assay in vitro and allelic complementation experiments in mymk knockdown and mymk insT/insT zebrafish in vivo can differentiate between MYMK wild type, hypomorphic and null alleles. Collectively, these data establish that MYMK activity is necessary for normal muscle development and maintenance in humans, and expand the spectrum of congenital myopathies to include cell-cell fusion deficits.

Value in healthcare must focus on accessibility, quality, and affordability. This article describes how a healthcare team provides value by meeting the needs of a rare disease patient and underscores the importance of a chronic multiorgan rare disease home. A nurse practitioner can ensure that barriers to evaluation are removed and communication is prioritized in order to provide accessible and affordable care to a patient with rare disease without jeopardizing quality of care.

Background: 12 months of oral cyclophosphamide has been shown to alter the progression of scleroderma-related interstitial lung disease when compared with placebo. However, toxicity was a concern and without continued treatment the efficacy disappeared by 24 months. We hypothesised that a 2 year course of mycophenolate mofetil would be safer, better tolerated, and produce longer lasting improvements than cyclophosphamide., Methods: This randomised, double-blind, parallel group trial enrolled patients from 14 US medical centres with scleroderma-related interstitial lung disease meeting defined dyspnoea, pulmonary function, and high-resolution CT (HRCT) criteria. The data coordinating centre at the University of California, Los Angeles (UCLA, CA, USA), randomly assigned patients using a double-blind, double-dummy, centre-blocked design to receive either mycophenolate mofetil (target dose 1500 mg twice daily) for 24 months or oral cyclophosphamide (target dose 2·0 mg/kg per day) for 12 months followed by placebo for 12 months. Drugs were given in matching 250 mg gel capsules. The primary endpoint, change in forced vital capacity as a percentage of the predicted normal value (FVC %) over the course of 24 months, was assessed in a modified intention-to-treat analysis using an inferential joint model combining a mixed-effects model for longitudinal outcomes and a survival model to handle non-ignorable missing data. The study was registered with ClinicalTrials.gov, number NCT00883129., Findings: Between Sept 28, 2009, and Jan 14, 2013, 142 patients were randomly assigned to either mycophenolate mofetil (n=69) or cyclophosphamide (n=73). 126 patients (mycophenolate mofetil [n=63] and cyclophosphamide [n=63]) with acceptable baseline HRCT studies and at least one outcome measure were included in the primary analysis. The adjusted % predicted FVC improved from baseline to 24 months by 2·19 in the mycophenolate mofetil group (95% CI 0·53-3·84) and 2·88 in the cyclophosphamide group (1·19-4·58). The course of the % FVC did not differ significantly between the two treatment groups based on the prespecified primary analysis using a joint model (p=0·24), indicating that the trial was negative for the primary endpoint. However, in a post-hoc analysis of the primary endpoint, the within-treatment change from baseline to 24 months derived from the joint model showed that the % FVC improved significantly in both the mycophenolate mofetil and cyclophosphamide groups. 16 (11%) patients died (five [7%] mycophenolate mofetil and 11 [15%] cyclophosphamide), with most due to progressive interstitial lung disease. Leucopenia (30 patients vs four patients) and thrombocytopenia (four vs zero) occurred more often in patients given cyclophosphamide than mycophenolate mofetil. Fewer patients on mycophenolate mofetil than on cyclophosphamide prematurely withdrew from study drug (20 vs 32) or met prespecified criteria for treatment failure (zero vs two). The time to stopping treatment was shorter in the cyclophosphamide group (p=0·019)., Interpretation: Treatment of scleroderma-related interstitial lung disease with mycophenolate mofetil for 2 years or cyclophosphamide for 1 year both resulted in significant improvements in prespecified measures of lung function over the 2 year course of the study. Although mycophenolate mofetil was better tolerated and associated with less toxicity, the hypothesis that it would have greater efficacy at 24 months than cyclophosphamide was not confirmed. These findings support the potential clinical effectiveness of both cyclophosphamide and mycophenolate mofetil for progressive scleroderma-related interstitial lung disease, and the present preference for mycophenolate mofetil because of its better tolerability and toxicity profile., Funding: National Heart, Lung and Blood Institute, National Institutes of Health; with drug supply provided by Hoffmann-La Roche and Genentech., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p < 8 X 10-10) pQTLs in 38 (43%) of blood proteins tested. Most pQTL SNPs were novel with low overlap to eQTL SNPs. The pQTL SNPs explained >10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10-392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group.

FG-3019 is a fully human monoclonal antibody that interferes with the action of connective tissue growth factor, a central mediator in the pathogenesis of fibrosis.This open-label phase 2 trial evaluated the safety and efficacy of two doses of FG-3019 administered by intravenous infusion every 3 weeks for 45 weeks in patients with idiopathic pulmonary fibrosis (IPF). Subjects had a diagnosis of IPF within the prior 5 years defined by either usual interstitial pneumonia (UIP) pattern on a recent high-resolution computed tomography (HRCT) scan, or a possible UIP pattern on HRCT scan and a recent surgical lung biopsy showing UIP pattern. Pulmonary function tests were performed every 12 weeks, and changes in the extent of pulmonary fibrosis were measured by quantitative HRCT scans performed at baseline and every 24 weeks.FG-3019 was safe and well-tolerated in IPF patients participating in the study. Changes in fibrosis were correlated with changes in pulmonary function.Further investigation of FG-3019 in IPF with a placebo-controlled clinical trial is warranted and is underway., (Copyright ©ERS 2016.)

This study aimed to determine if naturally occurring episodes of ozone air pollution in the Salt Lake Valley in Utah, USA, during the summer are associated with increased pulmonary inflammation and oxidative stress, increased respiratory symptoms, and decreased lung function in individuals with chronic obstructive pulmonary disease (COPD) compared to controls. We measured biomarkers (nitrite/nitrate (NOx), 8-isoprostane) in exhaled breath condensate (EBC), spirometry, and respiratory symptoms in 11 former smokers with moderate-to-severe COPD and nine former smokers without airflow obstruction during periods of low and high ozone air pollution. High ozone levels were associated with increased NOx in EBC in both COPD (8.7 (±8.5) vs. 28.6 (±17.6) μmol/L on clean air vs. pollution days, respectively, p < 0.01) and control participants (7.6 (±16.5) vs. 28.5 (±15.6) μmol/L on clean air vs. pollution days, respectively, p = 0.02). There was no difference in pollution effect between COPD and control groups, and no difference in EBC 8-isoprostane, pulmonary function, or respiratory symptoms between clean air and pollution days in either group. Former smokers both with and without airflow obstruction developed airway oxidative stress and inflammation in association with ozone air pollution episodes.

Purpose/aim: Acute Respiratory Distress Syndrome (ARDS) is an important clinical and public health problem. Why some at-risk individuals develop ARDS and others do not is unclear but may be related to differences in inflammatory and cell signaling systems. The Receptor for Advanced Glycation Endproducts (RAGE) and Granulocyte-Monocyte Stimulating Factor (GM-CSF) pathways have recently been implicated in pulmonary pathophysiology; whether genetic variation within these pathways contributes to ARDS risk or outcome is unknown., Materials and Methods: We studied 842 patients from three centers in Utah and 14 non-Utah ARDS Network centers. We studied patients at risk for ARDS and patients with ARDS to determine whether Single Nucleotide Polymorphisms (SNPs) in the RAGE and GM-CSF pathways were associated with development of ARDS. We studied 29 SNPs in 5 genes within the two pathways and controlled for age, sepsis as ARDS risk factor, and severity of illness, while targeting a false discovery rate of ≤ 5%. In a secondary analysis we evaluated associations with mortality., Results: Of 842 patients, 690 had ARDS, and 152 were at-risk. Sepsis was the risk factor for ARDS in 250 (30%) patients. When controlling for age, APACHE III score, sepsis as risk factor, and multiple comparisons, no SNPs were significantly associated with ARDS. In a secondary analysis, only rs743564 in CSF2 approached significance with regard to mortality (OR 2.17, unadjusted p = 0.005, adjusted p = 0.15)., Conclusions: Candidate SNPs within 5 genes in the RAGE and GM-CSF pathways were not significantly associated with development of ARDS in this multi-centric cohort.

Background: A polymorphism (rs35705950) in the promoter region of the mucin MUC5B is associated with both familial and sporadic forms of idiopathic pulmonary fibrosis. (IPF) We hypothesize that this common MUC5B variant will impact the expression of cough, a frequent disabling symptom seen in subjects with IPF., Methods: We genotyped 136 subjects with IPF. All living subjects were provided with a Leicester Cough Questionnaire (LCQ) to measure cough severity. We assessed allele effects of the MUC5B polymorphism on the LCQ scores using SAS General Linear Models (GLM) in the patients with IPF., Results: In the 68 of the total 136 IPF patients who returned the LCQ, MUC5B minor allele frequency (T) is consistent with prior published studies (31%). We found a significant independent effect of the T allele on the LCQ score (p = 0.002 for subjects with IPF). This effect is independent of other common causes of cough, including gastroesophogeal reflux disease and upper airway cough syndrome., Conclusions: Cough severity, a common disabling phenotypic component of IPF, is significantly associated with the presence of the minor allele of a MUC5B promoter polymorphism. This study highlights a possible genetic mechanism for phenotypic heterogeneity in pulmonary fibrosis.

Background: As a part of the longitudinal Chronic Obstructive Pulmonary Disease (COPD) study, Subpopulations and Intermediate Outcome Measures in COPD study (SPIROMICS), blood samples are being collected from 3200 subjects with the goal of identifying blood biomarkers for sub-phenotyping patients and predicting disease progression. To determine the most reliable sample type for measuring specific blood analytes in the cohort, a pilot study was performed from a subset of 24 subjects comparing serum, Ethylenediaminetetraacetic acid (EDTA) plasma, and EDTA plasma with proteinase inhibitors (P100)., Methods: 105 analytes, chosen for potential relevance to COPD, arranged in 12 multiplex and one simplex platform (Myriad-RBM) were evaluated in duplicate from the three sample types from 24 subjects. The reliability coefficient and the coefficient of variation (CV) were calculated. The performance of each analyte and mean analyte levels were evaluated across sample types., Results: 20% of analytes were not consistently detectable in any sample type. Higher reliability and/or smaller CV were determined for 12 analytes in EDTA plasma compared to serum, and for 11 analytes in serum compared to EDTA plasma. While reliability measures were similar for EDTA plasma and P100 plasma for a majority of analytes, CV was modestly increased in P100 plasma for eight analytes. Each analyte within a multiplex produced independent measurement characteristics, complicating selection of sample type for individual multiplexes., Conclusions: There were notable detectability and measurability differences between serum and plasma. Multiplexing may not be ideal if large reliability differences exist across analytes measured within the multiplex, especially if values differ based on sample type. For some analytes, the large CV should be considered during experimental design, and the use of duplicate and/or triplicate samples may be necessary. These results should prove useful for studies evaluating selection of samples for evaluation of potential blood biomarkers.

Background: Pulmonary fibrosis (PF) is a progressive fatal disease of unknown etiology. Identification of risk genes and pathways will enhance our understanding of this disease. Analysis of Utah genealogical resources has shown previously strong evidence for a genetic contribution to other disease, such as cancer. This approach has led to gene discovery in diseases, such as breast cancer and colon cancer and is used here for PF to quantify the heritability., Hypothesis: We hypothesize that there is a heritable contribution to death from PF and use existing genealogic and death certificate data to examine patterns of relatedness amongst individuals who have died of PF., Methods: We analyzed familial clustering of individuals who died from PF using the Utah Population Database, a unique population-based genealogical resource that has been linked to death certificates dating from 1904. We identified 1,000 individuals with at least three generations of genealogy data and a cause of death documented as PF (cases). We estimated the relative risk (RR) of death from PF among the first-, second-, and third-degree relatives of cases. We also tested the hypothesis of excess relatedness among the cases by comparing the average pairwise relatedness of all cases to the average pair-wise relatedness of 1,000 sets of matched controls., Results: We observed significantly increased risk for death from PF among the first- (RR = 4.69), second- (RR = 1.92), and third-degree relatives (RR = 1.14) of cases. The average relatedness of the 1,000 cases was significantly higher than the expected average relatedness of matched control sets (p < 0.001). When close (first- and second-degree) relationships were ignored, significantly increased relatedness remained (p = 0.002)., Conclusions: Our results demonstrate significant clustering among both close and distant relatives, providing strong support for genetic contributions to death from PF. High-risk pedigrees derived from this unique resource may help identify new risk genes and gene pathways.

Background: The availability of large complex data sets generated by high throughput technologies has enabled the recent proliferation of disease biomarker studies. However, a recurring problem in deriving biological information from large data sets is how to best incorporate expert knowledge into the biomarker selection process., Objective: To develop a generalizable framework that can incorporate expert knowledge into data-driven processes in a semiautomated way while providing a metric for optimization in a biomarker selection scheme., Methods: The framework was implemented as a pipeline consisting of five components for the identification of signatures from integrated clustering (ISIC). Expert knowledge was integrated into the biomarker identification process using the combination of two distinct approaches; a distance-based clustering approach and an expert knowledge-driven functional selection., Results: The utility of the developed framework ISIC was demonstrated on proteomics data from a study of chronic obstructive pulmonary disease (COPD). Biomarker candidates were identified in a mouse model using ISIC and validated in a study of a human cohort., Conclusions: Expert knowledge can be introduced into a biomarker discovery process in different ways to enhance the robustness of selected marker candidates. Developing strategies for extracting orthogonal and robust features from large data sets increases the chances of success in biomarker identification.

Although there are nonmodifiable genetic risk factors for COPD, most known risk factors for development and progression of COPD can be corrected. Continued efforts to encourage smoking cessation and measures to reduce exposure to SHS, outdoor air pollution, biomass smoke, and occupational and related amateur exposures will have a significant impact on worldwide health., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Nitric oxide is a physiological regulator of endothelial function and hemodynamics. Oxidized products of nitric oxide can form nitrotyrosine, which is a marker of nitrative stress. Cigarette smoking decreases exhaled nitric oxide, and the underlying mechanism may be important in the cardiovascular toxicity of smoking. Even so, it is unclear if this effect results from decreased nitric oxide production or increased oxidative degradation of nitric oxide to reactive nitrating species. These two processes would be expected to have opposite effects on nitrotyrosine levels, a marker of nitrative stress., Objective: In this study, we evaluated associations of cigarette smoking and chronic obstructive pulmonary disease (COPD) with nitrotyrosine modifications of specific plasma proteins to gain insight into the processes regulating nitrotyrosine formation., Methods: A custom antibody microarray platform was developed to analyze the levels of 3-nitrotyrosine modifications on 24 proteins in plasma. In a cross-sectional study, plasma samples from 458 individuals were analyzed., Results: Average nitrotyrosine levels in plasma proteins were consistently lower in smokers and former smokers than in never smokers but increased in smokers with COPD compared with smokers who had normal lung-function tests., Conclusions: Smoking is associated with a broad decrease in 3-nitrotyrosine levels of plasma proteins, consistent with an inhibitory effect of cigarette smoke on endothelial nitric oxide production. In contrast, we observed higher nitrotyrosine levels in smokers with COPD than in smokers without COPD. This finding is consistent with increased nitration associated with inflammatory processes. This study provides insight into a mechanism through which smoking could induce endothelial dysfunction and increase the risk of cardiovascular disease.

Pulmonary arterial hypertension (PAH) is a clinical condition characterised by the presence of precapillary pulmonary hypertension (PH). Included within the subcategorisation of PAH are heritable (HPAH) and PAH associated various conditions (APAH) including systemic sclerosis (SSc). The pathogenesis of HPAH and SSc has been linked to both a genetic predisposition and epigenetic factors. TGF-β superfamily signalling has also been implicated in the development of these conditions. In this review, we discuss the role of genetic predisposition, epigenetic factors along with dysregulation in TGF-β superfamily signalling in the pathogenesis of PAH and SSc., (© 2011 Blackwell Publishing Ltd.)

Pruritus is a common symptom in systemic sclerosis (SSc), an autoimmune disease which causes fibrosis and vasculopathy in skin, lung, and gastrointestinal tract (GIT). Unfortunately, pruritus has limited treatment options in this disease. Pilot trials of low-dose naltrexone hydrochloride (LDN) for pruritus, pain, and quality of life (QOL) in other GIT diseases have been successful. In this case series we report three patients that had significant improvement in pruritus and total GIT symptoms as measured by the 10-point faces scale and the University of California Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 (UCLA SCTC GIT 2.0) questionnaire. This small case series suggests LDN may be an effective, highly tolerable, and inexpensive treatment for pruritus and GIT symptoms in SSc.

Rationale: Several family-based studies have identified genetic linkage for lung function and airflow obstruction to chromosome 2q., Objectives: We hypothesized that merging results of high-resolution single nucleotide polymorphism (SNP) mapping in four separate populations would lead to the identification of chronic obstructive pulmonary disease (COPD) susceptibility genes on chromosome 2q., Methods: Within the chromosome 2q linkage region, 2,843 SNPs were genotyped in 806 COPD cases and 779 control subjects from Norway, and 2,484 SNPs were genotyped in 309 patients with severe COPD from the National Emphysema Treatment Trial and 330 community control subjects. Significant associations from the combined results across the two case-control studies were followed up in 1,839 individuals from 603 families from the International COPD Genetics Network (ICGN) and in 949 individuals from 127 families in the Boston Early-Onset COPD Study., Measurements and Main Results: Merging the results of the two case-control analyses, 14 of the 790 overlapping SNPs had a combined P < 0.01. Two of these 14 SNPs were consistently associated with COPD in the ICGN families. The association with one SNP, located in the gene XRCC5, was replicated in the Boston Early-Onset COPD Study, with a combined P = 2.51 x 10(-5) across the four studies, which remains significant when adjusted for multiple testing (P = 0.02). Genotype imputation confirmed the association with SNPs in XRCC5., Conclusions: By combining data from COPD genetic association studies conducted in four independent patient samples, we have identified XRCC5, an ATP-dependent DNA helicase, as a potential COPD susceptibility gene.

Although only a subset of smokers develop lung cancer, we cannot determine which smokers are at highest risk for cancer development, nor do we know the signaling pathways altered early in the process of tumorigenesis in these individuals. On the basis of the concept that cigarette smoke creates a molecular field of injury throughout the respiratory tract, this study explores oncogenic pathway deregulation in cytologically normal proximal airway epithelial cells of smokers at risk for lung cancer. We observed a significant increase in a genomic signature of phosphatidylinositol 3-kinase (PI3K) pathway activation in the cytologically normal bronchial airway of smokers with lung cancer and smokers with dysplastic lesions, suggesting that PI3K is activated in the proximal airway before tumorigenesis. Further, PI3K activity is decreased in the airway of high-risk smokers who had significant regression of dysplasia after treatment with the chemopreventive agent myo-inositol, and myo-inositol inhibits the PI3K pathway in vitro. These results suggest that deregulation of the PI3K pathway in the bronchial airway epithelium of smokers is an early, measurable, and reversible event in the development of lung cancer and that genomic profiling of these relatively accessible airway cells may enable personalized approaches to chemoprevention and therapy. Our work further suggests that additional lung cancer chemoprevention trials either targeting the PI3K pathway or measuring airway PI3K activation as an intermediate endpoint are warranted.

Chronic obstructive pulmonary disease (COPD) is a prevalent pulmonary disease characterized by a progressive decline in lung function. The identification of biomarkers capable of predicting the rate of lung function decline or capable of giving an early read on drug efficacy in clinical trials would be very useful. The aim of this study was to identify plasma biomarkers capable of accurately distinguishing patients with COPD from healthy controls. Eighty-nine plasma markers in 40 COPD patients and 20 healthy smoker controls were analyzed. The COPD patients were divided into two subgroups, rapid and slow decliners based on their rate of lung function decline measured over 15 years. Univariate analysis revealed that 25 plasma markers were statistically different between rapid decliners and controls, 4 markers were different between slow decliners and controls, and 10 markers were different between rapid and slow decliners (p < 0.05). Multivariate analysis led to the identification of groups of plasma markers capable of distinguishing rapid decliners from controls (signature 1), slow decliners from controls (signature 2) and rapid from slow decliners (signature 3) with over 90% classification accuracy. Importantly, signature 1 was shown to be longitudinally stable using plasma samples taken a year later from a subset of patients. This study describes a novel set of plasma markers differentiating slow from rapid decline of lung function in COPD. If validated in distinct and larger cohorts, the signatures identified will have important implications in both disease diagnosis, as well as the clinical evaluation of new therapies.

The role of the vascular microenvironment in the pathogenesis Systemic Sclerosis (SSc) is appreciated clinically as Raynaud's syndrome with capillary nail bed change. This manifestation of vasculopathy is used diagnostically in both limited and diffuse cutaneous subsets of SSc, and is thought to precede fibrosis. The degree of subsequent fibrosis may also be determined by the vascular microenvironment. This paper describes why the vascular microenvironment might determine the degree of end-organ damage that occurs in SSc, with a focus on vascular cell senescence, endothelial progenitor cells (EPC) including multipotential mesenchymal stem cells (MSC), pericytes, and angiogenic monocytes. An explanation of the role of EPC, pericytes, and angiogenic monocytes is important to an understanding of SSc pathogenesis. An evolving understanding of the vascular microenvironment in SSc may allow directed treatment.

Introduction: Previous research revealed significant associations between haplotypes in the CHRNA5-A3-B4 subunit cluster and scores on the Fagerström Test for Nicotine Dependence among individuals reporting daily smoking by age 17. The present study used subsamples of participants from that study to investigate associations between the CHRNA5-A3-B4 haplotypes and an array of phenotypes not analyzed previously (i.e., withdrawal severity, ability to stop smoking, and specific scales on the Wisconsin Inventory of Smoking Dependence Motives (WISDM-68) that reflect loss of control, strong craving, and heavy smoking., Methods: Two cohorts of current or former smokers (N = 886) provided both self-report data and DNA samples. One sample (Wisconsin) comprised smokers making a quit smoking attempt, which permitted the assessment of withdrawal and relapse during the attempt. The other sample (Utah) comprised participants studied for risk factors for nicotine dependence and chronic obstructive pulmonary disease and included individuals originally recruited in the Lung Health Study., Results: The CHRNA5-A3-B4 haplotypes were significantly associated with the targeted WISDM-68 scales (Tolerance, Craving, Loss of Control) in both samples of participants but only among individuals who began smoking early in life. The haplotypes were significantly associated with relapse likelihood and withdrawal severity, but these associations showed no evidence of an interaction with age at daily smoking., Discussion: The CHRNA5-A3-B4 haplotypes are associated with a broad range of nicotine dependence phenotypes, but these associations are not consistently moderated by age at initial smoking.

Chronic obstructive pulmonary disease (COPD) is characterized by the degradation of elastin, the major insoluble protein of lung tissues. The degradation of elastin gives rise to desmosine (DES) and isodesmosine (IDES), two major urinary products typified by a hydrophilic pyridinium-based cross-linker structure. A high sensitivity method based on nanoflow liquid chromatography tandem mass spectrometry with multiple reaction monitoring was developed for the analysis of urinary DES and IDES. The analytes were derivatized with propionic anhydride and deuterated DES (D(4)-DES) was used as an internal standard. This method enables the quantification of DES and IDES in as little as 50 microL of urine and provides a detection limit of 0.10 ng/mL (0.95 fmol on-column). We report the analysis of DES and IDES in a cohort of 40 urine specimens from four groups of individuals: (a) COPD rapid decliners (11.8 +/- 3.7 ng/mg creatine (crea)), (b) COPD slow decliners (16.0 +/- 3.1 ng/mg crea), (c) healthy smokers (13.2 +/- 1.9 ng/mg crea), and (d) healthy nonsmokers (14.9 +/- 2.9 ng/mg crea). Our analysis reveals a statistically significant decrease in the level of urinary DES and IDES in COPD rapid decliner patients compared to healthy nonsmoker controls and COPD slow decliner patients. This methodology may be useful for monitoring DES and IDES levels in well controlled animal models for COPD or for longitudinal studies in COPD patients.

Introduction: Hypercapnia during avalanche burial may increase core temperature cooling rate by decreasing the temperature threshold for shivering or by increasing respiratory heat loss., Methods: We studied the effect of hypercapnia on rectal core temperature (T(re)) cooling rate, respiratory heat loss, heat production, and the T(re) shivering threshold during snow burial (mean snow temperature -3.2 + 2.7 degrees C) in 11 subjects. In a 60-min hypercapnic burial subjects breathed a 5% carbon dioxide and 21% oxygen inhaled gas mixture and in a separate 60-min normocapnic burial subjects breathed ambient air. After extrication from snow burial subjects were passively rewarmed in a 15 degrees C shelter and T(re) afterdrop was measured., Results: The deltaT(re) over 1 h of burial in the hypercapnic study was 1.28 +/- 0.4 degrees C and in the normocapnic study was 0.97 +/- 0.4 degrees C (P = 0.045). Minute ventilation, respiratory heat loss, total metabolic rate, and metabolic rate of the respiratory muscles were greater during the hypercapnic burial. There was no difference in shivering threshold between the hypercapnic and normocapnic conditions. Afterdrop in the hypercapnic study (0.69 +/- 0.4 degrees C at 21 +/- 8.1 min after extrication) was not different than in the normocapnic study (0.86 +/- 0.3 degrees C at 23.1 +/- 5.3 min after extrication). In both the hypercapnic and normocapnic studies afterdrop cooling rate was significantly greater during extrication than during snow burial., Discussion: Hypercapnia significantly increased T(re) cooling rate by increasing respiratory heat loss but did not suppress shivering. Afterdrop may significantly contribute to hypothermia during rescue of avalanche burial victims.

People who begin daily smoking at an early age are at greater risk of long-term nicotine addiction. We tested the hypothesis that associations between nicotinic acetylcholine receptor (nAChR) genetic variants and nicotine dependence assessed in adulthood will be stronger among smokers who began daily nicotine exposure during adolescence. We compared nicotine addiction-measured by the Fagerstrom Test of Nicotine Dependence-in three cohorts of long-term smokers recruited in Utah, Wisconsin, and by the NHLBI Lung Health Study, using a candidate-gene approach with the neuronal nAChR subunit genes. This SNP panel included common coding variants and haplotypes detected in eight alpha and three beta nAChR subunit genes found in European American populations. In the 2,827 long-term smokers examined, common susceptibility and protective haplotypes at the CHRNA5-A3-B4 locus were associated with nicotine dependence severity (p = 2.0x10(-5); odds ratio = 1.82; 95% confidence interval 1.39-2.39) in subjects who began daily smoking at or before the age of 16, an exposure period that results in a more severe form of adult nicotine dependence. A substantial shift in susceptibility versus protective diplotype frequency (AA versus BC = 17%, AA versus CC = 27%) was observed in the group that began smoking by age 16. This genetic effect was not observed in subjects who began daily nicotine use after the age of 16. These results establish a strong mechanistic link among early nicotine exposure, common CHRNA5-A3-B4 haplotypes, and adult nicotine addiction in three independent populations of European origins. The identification of an age-dependent susceptibility haplotype reinforces the importance of preventing early exposure to tobacco through public health policies., Competing Interests: The authors have declared that no competing interests exist.

The Patient Health Questionnaire-9 (PHQ-9; R. L. Spitzer, K. Kroenke, J. B. W. Williams, & The Patient Health Questionnaire Primary Care Study Group, 1999), modified to ask about the worst period of depression lifetime, was validated against lifetime mood disorder diagnoses established by the Structured Clinical Interview for DSM-IV (SCID; M. B. First, R. L. Spitzer, M. Gibbon, & J. B. W. Williams, 2001) in 526 participants. PHQ-9 dichotomous scores corresponded highly with major depressive episode (MDE) Criterion A, MDE, and major depressive disorder (MDD), odds ratios >or= 9.5, and area under the receiver operating characteristic curve (AUC) >or= 0.84. The continuous scale score was higher in participants who did (M=17.14, SD=7.36) than in those who did not (M=6.05, SD=6.29) meet MDE Criterion A, t(524)=18.09, p<.001; was correlated with number of MDE Criterion A symptoms, r(525)=.67, p<.001; and detected MDE Criterion A (AUC=0.88). The PHQ-9 as a lifetime measure may be used to complement or replace more costly interview assessments., ((c) 2007 APA, all rights reserved)

Context: The most common lung tissue samples seen by pathologists worldwide are obtained with the flexible bronchoscope. Specimens taken for examination of diffuse or multifocal parenchymal lung abnormalities pose special challenges for the general surgical pathologist, and these challenges are often compounded by high clinical expectations for accurate and specific diagnosis., Objective: To present and discuss the most common histopathologic patterns and diagnostic entities seen in transbronchial biopsy specimens in the setting of diffuse or multifocal lung disease. Specifically, acute lung injury, eosinophilic pneumonia, diffuse alveolar hemorrhage, chronic cellular infiltrates, organizing pneumonia, alveolar proteinosis, sarcoidosis, Wegener granulomatosis, intravenous drug abuse-related microangiopathy, Langerhans cell histiocytosis, and lymphangioleiomyomatosis are presented. Clinical and radiologic context is provided for the more specific diagnostic entities., Data Sources: The published literature and experience from a consultation practice., Conclusions: The transbronchial biopsy specimen can provide valuable information for clinical management in the setting of diffuse or multifocal lung disease. Computed tomographic scans are useful for selecting appropriate patients to undergo biopsy and in limiting the differential diagnosis. Knowledge of the clinical context, radiologic distribution of abnormalities, and histopathologic patterns is essential. With this information, the surgical pathologist can substantially influence the diagnostic workup and help guide the clinician to an accurate clinical/radiologic/pathologic diagnosis.

Background: Vasoreactivity tests are fundamental in evaluating pulmonary arterial hypertension (PAH). Mutations of the transforming growth factor-beta type II receptor gene, BMPR2, predispose to the development of pulmonary hypertension and may alter the response to vasodilators. Previous investigations have not examined the relationship of BMPR2 mutations to vasoreactivity., Methods and Results: We identified 133 consecutive unrelated patients with either idiopathic or familial PAH. Sixty-six patients were excluded because we lacked either DNA samples (n=18) or complete data from a vasoreactivity test (n=48). The remaining 67 patients were screened for BMPR2 DNA sequence variations, and specific variations were confirmed by gene sequencing. The vasoreactivity of patients with nonsynonymous BMPR2 variations was compared with that of patients without nonsynonymous BMPR2 variations. We found nonsynonymous BMPR2 variations in 27 of 67 patients with idiopathic (n=16 of 52) or familial (n=11 of 15) PAH. Vasoreactivity was identified in 3.7% of 27 patients with nonsynonymous BMPR2 variations and in 35% of 40 patients without nonsynonymous BMPR2 variations (P=0.003). Five of the 27 nonsynonymous variations occur commonly in healthy individuals. None of the remaining 22 patients with BMPR2 variations demonstrated vasoreactivity, and the analysis remained unchanged when we assumed that nonsynonymous BMPR2 variations were present in all 15 patients with familial PAH., Conclusions: Patients with familial or idiopathic PAH and nonsynonymous BMPR2 variations are unlikely to demonstrate vasoreactivity. Further trials are required to determine whether long-term therapy can be directed by tests for BMPR2 variations.

Phenotypic evidence indicates that the ability to taste the bitter compounds phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP) may protect against cigarette smoking. In this study, PTC gene haplotypes were found to be associated with both the odds of being a smoker and the importance of cigarette taste as a smoking motive. Smokers (n = 384) and nonsmokers (n = 183) were genotyped for polymorphisms that affect taste sensitivity to PTC and PROP. The "taster" PAV haplotype, relative to the "nontaster" AVI haplotype, was predicted to be associated with reduced odds of being a smoker and lower taste motivation as measured by the Wisconsin Inventory of Smoking Dependence Motives-68 taste/sensory processes scale. The results did not support the predicted association between the PAV and AVI haplotypes and smoker odds, but the AAV haplotype, which confers intermediate PTC/PROP taste sensitivity, was associated with reduced smoker prevalence (49% vs. 70%), chi(2)(1, N = 567) = 10.392, p = .001. The predicted relationship between PAV and AVI and taste motivation was found, F(2, 348) = 3.303, p = .038. The results encourage further exploration of the role of taste/sensory processes in tobacco dependence.

Previous retrospective studies report a core body temperature cooling rate of 3 degrees C/h during avalanche burial. Hypercapnia occurs during avalanche burial secondary to rebreathing expired air, and the effect of hypercapnia on hypothermia during avalanche burial is unknown. The objective of this study was to determine the core temperature cooling rate during snow burial under normocapnic and hypercapnic conditions. We measured rectal core body temperature (T(re)) in 12 subjects buried in compacted snow dressed in a lightweight clothing insulation system during two different study burials. In one burial, subjects breathed with a device (AvaLung 2, Black Diamond Equipment) that resulted in hypercapnia over 30-60 min. In a control burial, subjects were buried under identical conditions with a modified breathing device that maintained normocapnia. Mean snow temperature was -2.5 +/- 2.0 degrees C. Burial time was 49 +/- 14 min in the hypercapnic study and 60 min in the normocapnic study (P = 0.02). Rate of decrease in T(re) was greater with hypercapnia (1.2 degrees C/h by multiple regression analysis, 95% confidence limits of 1.1-1.3 degrees C/h) than with normocapnia (0.7 degrees C/h, 95% confidence limit of 0.6-0.8 degrees C/h). In the hypercapnic study, the fraction of inspired carbon dioxide increased from 1.4 +/- 1.0 to 7.0 +/- 1.4%, minute ventilation increased from 15 +/- 7 to 40 +/- 12 l/min, and oxygen saturation decreased from 97 +/- 1 to 90 +/- 6% (P < 0.01). During the normocapnic study, these parameters remained unchanged. In this study, T(re) cooling rate during snow burial was less than previously reported and was increased by hypercapnia. This may have important implications for prehospital treatment of avalanche burial victims.

The term interstitial lung disease (ILD) encompasses a large variety of entities. The clinical diagnosis is often difficult and is a multidisciplinary process. Achieving the correct diagnosis often involves 3 elements: a clinical impression, radiologic evaluation, and a pathologic opinion. All 3 components play a critical role. Frequently, the goal is differentiating idiopathic pulmonary fibrosis (IPF) from more treatable entities. This article provides an overview of the input provided by the 3 specialties cited earlier, as well as the interrelationship among these specialties in the diagnosis of ILD. Additional consideration is given to the decision-making process involved in determining when to obtain a biopsy specimen from a patient with ILD, and a review of current treatment strategies.

Objective: To confirm that the accumulation of exhaled carbon dioxide (CO2) is the principal cause of nonmechanical asphyxiation during avalanche burial by demonstrating that complete exclusion of exhaled CO2 during experimental snow burial results in normal oxygenation and ventilation utilizing the air within the snowpack., Methods: In the experimental group, 8 healthy volunteers (mean age 32 years, range 19-44 years) were fully buried up to 90 minutes in compacted snow with a density ranging from 300 to 680 kg/ m3 at an elevation of 2385 m. The 6 men and 2 women breathed directly from the snow utilizing a device containing no air pocket around the inhalation intake, in addition to an extended exhalation tube running completely out of the snowpack to remove all exhaled CO2. Continuous physiologic monitoring included oxygen saturation, end-tidal CO2, inspired CO2, electrocardiogram, rectal core temperature, and respiratory rate. As controls, 5 of the 8 subjects repeated the study protocol breathing directly into a small, fist-sized air pocket with no CO2 removal device., Results: In the experimental group, the mean burial time was 88 minutes, despite the absence of an air pocket. No significant changes occurred in any physiologic parameters in this group compared to baseline values. In contrast, the controls remained buried for a mean of 10 minutes (P = .003) and became significantly hypercapnic (P < .01) and hypoxic (P < .02)., Conclusions: There is sufficient oxygen contained within a densified snowpack comparable to avalanche debris to sustain normal oxygenation and ventilation for at least 90 minutes during snow burial if exhaled CO2 is removed. The prolonged oxygenation observed during CO2 exclusion is irrespective of the presence of an air pocket.