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Showing papers by "National Jewish Health published in 2012"


Journal ArticleDOI
TL;DR: The results indicate that multiple features of pulmonary vascular remodeling are present in patients treated with modern PAH therapies, and perivascular inflammation may have an important role in the processes ofascular remodeling, all of which may ultimately lead to increased pulmonary artery pressure.
Abstract: Rationale: The impact of modern treatments of pulmonary arterial hypertension (PAH) on pulmonary vascular pathology remains unknown. Objectives:Toassessthespectrumofpulmonaryvascularremodeling in the modern era of PAH medication. Methods: Assessmentofpulmonaryvascularremodelingandinflammation in 62 PAH and 28 control explanted lungs systematically sampled. Measurements and Main Results: Intima and intima plus media fractional thicknesses of pulmonary arteries were increased in the PAH group versus the control lungs and correlated with pulmonary hemodynamicmeasurements.DespiteahighvariabilityofmorphologicalmeasurementswithinagivenPAHlungandamongallPAHlungs, distinct pathological subphenotypes were detected in cohorts of PAH lungs. These included a subset of lungs lacking intima or, most prominently, media remodeling, which had similar numbers of profiles of plexiform lesions as those in lungs with more pronounced remodeling.Markedperivascularinflammationwaspresentinahigh number of PAH lungs and correlated with intima plus media remodeling. The number of profiles of plexiform lesions was significantly lower in lungs of male patients and those never treated with prostacyclin or its analogs. Conclusions:Our resultsindicate thatmultiplefeaturesofpulmonary vascular remodeling are present in patients treated with modern PAH therapies. Perivascular inflammation may have an important role in the processes of vascular remodeling, all of which may ultimately lead to increased pulmonary artery pressure. Moreover, our study provides a framework to interpret and design translational studies in PAH.

476 citations


Journal ArticleDOI
TL;DR: Treatment with warfarin was associated with an increased risk of mortality in an IPF population who lacked other indications for anticoagulation and was recommended to stop after 145 of the planned 256 subjects were enrolled.
Abstract: Rationale: Animal and human studies support the importance of the coagulation cascade in pulmonary fibrosis.Objectives: In a cohort of subjects with progressive idiopathic pulmonary fibrosis (IPF), we tested the hypothesis that treatment with warfarin at recognized therapeutic doses would reduce rates of mortality, hospitalization, and declines in FVC.Methods: This was a double-blind, randomized, placebo-controlled trial of warfarin targeting an international normalized ratio of 2.0 to 3.0 in patients with IPF. Subjects were randomized in a 1:1 ratio to warfarin or matching placebo for a planned treatment period of 48 weeks. International normalized ratios were monitored using encrypted home point-of-care devices that allowed blinding of study therapy.Measurements and Main Results: The primary outcome measure was the composite outcome of time to death, hospitalization (nonbleeding, nonelective), or a 10% or greater absolute decline in FVC. Due to a low probability of benefit and an increase in mortality o...

405 citations


Journal ArticleDOI
TL;DR: Statin use is associated with ILA among smokers in the COPDGene study and enhances bleomycin-induced lung inflammation and fibrosis in the mouse through a mechanism involving enhanced NLRP3-inflammasome activation, suggesting that statins may influence the susceptibility to, or progression of, ILD.
Abstract: Rationale: The role of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) in the development or progression of interstitial lung disease (ILD) is controversial.Objectives: To evaluate the association between statin use and ILD.Methods: We used regression analyses to evaluate the association between statin use and interstitial lung abnormalities (ILA) in a large cohort of smokers from COPDGene. Next, we evaluated the effect of statin pretreatment on bleomycin-induced fibrosis in mice and explored the mechanism behind these observations in vitro.Measurements and Main Results: In COPDGene, 38% of subjects with ILA were taking statins compared with 27% of subjects without ILA. Statin use was positively associated in ILA (odds ratio, 1.60; 95% confidence interval, 1.03–2.50; P = 0.04) after adjustment for covariates including a history of high cholesterol or coronary artery disease. This association was modified by the hydrophilicity of statin and the age of the subject. Next, we demonstrate ...

127 citations


Journal ArticleDOI
TL;DR: A microvascular model is proposed in which chronic intermittent hypoxemia causes vasculopathy that ultimately is expressed as cognitive impairment in the older adult and it remains unclear whether the effects of SDB on cognition are the same regardless of age or whether there is a synergistic interaction between age and SDB.
Abstract: Both sleep-disordered breathing (SDB) and cognitive impairment are common among older adults, yet few studies have examined their relationship within this population to determine whether the effect of SDB on cognition is of a magnitude similar to or greater than that observed in younger and middle-aged adults. Here, we review the extant literature and report that studies are largely supportive of an association between SDB and cognitive impairment in older adults, particularly in the domains of attention/vigilance, executive function, and verbal delayed recall memory. Presence of the APOE4 allele may confer increased vulnerability to SDB-associated cognitive dysfunction among elderly individuals. Although findings are mixed, there is strong evidence to suggest that SDB-related intermittent hypoxemia is the primary mechanism through which SDB exerts its adverse effects on cognition. We propose a microvascular model in which chronic intermittent hypoxemia causes vasculopathy that ultimately is expressed as cognitive impairment in the older adult. However, it remains unclear whether the effects of SDB on cognition are the same regardless of age or whether there is a synergistic interaction between age and SDB.

72 citations


Journal ArticleDOI
TL;DR: Recent studies in the context of depression, post-traumatic stress disorder, and alcohol dependence are reviewed, finding promising results have been obtained, not only with regard to insomnia improvement but also concurrent improvements in comorbid psychiatric conditions.
Abstract: Insomnia is frequently comorbid with psychiatric conditions, mostly depression and anxiety disorders. Because disturbed sleep is a symptom of most major mental disorders, it has been traditionally assumed that effective treatment of the psychiatric condition will resolve the coincident insomnia also. However, insomnia often persists after successful treatment of the comorbid mental disorder, suggesting that insomnia often warrants separate treatment attention. Cognitive-behavioral therapy (CBT) is a well established and efficacious treatment for insomnia. Most evidence supporting the efficacy of CBT comes from studies conducted with patients suffering from primary insomnia, yet over the past 20 years there has been growing support for the use of cognitive-behavioral insomnia intervention for patients with comorbid psychiatric conditions. Overall, promising results have been obtained from these studies, not only with regard to insomnia improvement but also concurrent improvements in comorbid psychiatric conditions. In this article we review recent studies in this area with particular focus on treatment of insomnia in the context of depression, post-traumatic stress disorder, and alcohol dependence.

55 citations


Journal ArticleDOI
01 Jan 2012-Allergy
TL;DR: This research presents a comparison of school environments with and without legislation for the prevention and management of anaphylaxis in children with peanut allergy and shows clear trends in the support of existing and new legislation.
Abstract: To cite this article: Cicutto L, Julien B, Li NY, Nguyen-Luu NU, Butler J, Clarke A, Elliott SJ, Harada L, McGhan S, Stark D, Vander Leek TK, Waserman S. Comparing school environments with and without legislation for the prevention and management of anaphylaxis. Allergy 2012; 67: 131–137. Abstract Background: School personnel in contact with students with life-threatening allergies often lack necessary supports, creating a potentially dangerous situation. Sabrina’s Law, the first legislation in the world designed to protect such children, requires all Ontario public schools to have a plan to protect children at risk. Although it has captured international attention, the differences a legislative approach makes have not been identified. Our study compared the approaches to anaphylaxis prevention and management in schools with and without legislation. Methods: Legislated (Ontario) and nonlegislated (Alberta, British Columbia, Newfoundland and Labrador, and Quebec) environments were compared. School board anaphylaxis policies were assessed for consistency with Canadian anaphylaxis guidelines. Parents of at-risk children and school personnel were surveyed to determine their perspectives on school practices. School personnel’s EpiPen5 technique was assessed. Results: Consistency of school board policies with anaphylaxis guidelines was significantly better in a legislated environment (P = 0.009). Parents in a legislated environment reported more comprehensive anaphylaxis emergency forms (P 80%), suboptimal technique was commonly observed. However, school personnel in the legislated environment had better technique (P < 0.001). Conclusion: Our results suggest that school boards in legislated environments have made greater efforts to support students at risk for anaphylaxis compared to nonlegislated environments. However, significant gaps exist in both environments, especially with respect to EpiPen5 administration, content, and distribution of anaphylaxis emergency forms, and awareness of school procedures by school personnel and parents.

47 citations


Proceedings ArticleDOI
02 May 2012
TL;DR: This article investigates the suitability of local intensity distributions to analyze six emphysema classes in 342 CT scans obtained from 16 sites hosting scanners by 3 vendors and a total of 9 specific models in subjects with Chronic Obstructive Pulmonary Disease.
Abstract: This article investigates the suitability of local intensity distributions to analyze six emphysema classes in 342 CT scans obtained from 16 sites hosting scanners by 3 vendors and a total of 9 specific models in subjects with Chronic Obstructive Pulmonary Disease (COPD). We propose using kernel density estimation to deal with the inherent sparsity of local intensity histograms obtained from scarcely populated regions of interest. We validate our approach by leave-one-subject-out classification experiments and full-lung analyses. We compare our results with recently published LBP texture-based methodology. We demonstrate the efficacy of using intensity information alone in multi-scanner cohorts, which is a simpler, more intuitive approach.

47 citations


Journal ArticleDOI
TL;DR: Factors independently associated with lower MHS and lower PHS include lower nadir CD4+ T-cell counts, and use of maladaptive coping.
Abstract: We investigated HRQoL among HIV-positive outpatients from October, 2006-December, 2007, incorporating medical chart review, and a survey of coping styles. Consented HIV-positive patients receiving medical care at University of Colorado Denver, with HAART as first antiretroviral regimen, completed the MOS-HIV and Brief COPE survey instruments. Linear regression identified a priori factors hypothesized to be associated with the MOS-HIV composite mental and physical health scores (MHS, PHS). Brief COPE survey maladaptive and adaptive coping components were added to the models and retained if significant. Among the 157 patient cohort, parsimonious multivariable linear regression models (P < 0.05) indicated higher nadir CD4+ T-cell counts and adaptive coping were associated with a higher MHS; public/no insurance, mental illness, current number of non-HIV medications, and maladaptive coping were inversely associated with MHS. Nadir CD4+ T-cell count and efavirenz use were associated with a higher PHS; mental illness, current number of non-HIV mediations, and maladaptive coping were inversely associated with PHS. Factors independently associated with lower MHS and lower PHS include lower nadir CD4+ T-cell counts, and use of maladaptive coping. Efforts to reduce use of maladaptive coping strategies and earlier identification and treatment of HIV may improve HRQoL in HIV-positive patients.

37 citations


Journal ArticleDOI
18 Sep 2012
TL;DR: The Childhood Asthma Management Program (CAMP) has been in continuous existence for almost two decades, which makes it the largest randomized, placebo-controlled clinical trial with extended follow-up for children with mild to moderate asthma.
Abstract: The Childhood Asthma Management Program (CAMP) has been in continuous existence for almost two decades, which makes it the largest randomized, placebo-controlled clinical trial with extended follow-up for children with mild to moderate asthma. As such, its cumulative data from baseline, active treatment, and post-treatment have proved to be an invaluable resource for not only assessing the efficacy and safety of long-term inhaled corticosteroid therapy in childhood, but for discovery of many other aspects of childhood asthma, including genetics and biomarkers.

31 citations


Journal ArticleDOI
TL;DR: This study provides new information on the miRNA landscape during the early stages of HSV-1 infection and reveals novel targets for antagonistic molecules that may curtail the establishment of lytic or latent virus infection.
Abstract: The influence of miRNAs on the host-pathogen environment is largely unknown and under intensive investigation. Whether produced by the pathogen or by the host cell, these miRNAs will sculpt the intracellular landscape, as their activity will ultimately affect levels of target proteins. Using a high-throughput sequencing approach, we identified 19 novel small RNAs produced during the early hours of herpes simplex virus type 1 (HSV-1) infection in epithelial cells. Six of the novel RNAs had predicted folds characteristic of miRNAs. One of the six, miR-92944, which resides in the 5' UTR of the ul42 gene in the sense orientation, was confirmed as a bona fide miRNA by RT-PCR and stem-loop PCR analysis. Northern blot analysis was used to observe the precursor forms of miR-92944. Viral mutants that do not produce miR-92944 exhibited significant reductions in viral titers in both single and multi-step growth analysis and a fourfold reduction in plaque size. The miR-92944 mutants produce wild-type levels of ICP4, UL42, VP5, and gC proteins contain no additional changes in the DNA sequence surrounding the site of mutagenesis. The defective phenotype of miR-92944 mutants was complemented in V42.3 cells, which contain the 5'UTR of ul42. We also found that miR-H1 expression was diminished in cells infected with the miR-92944 mutant virus. This study provides new information on the miRNA landscape during the early stages of HSV-1 infection and reveals novel targets for antagonistic molecules that may curtail the establishment of lytic or latent virus infection.

29 citations


Journal ArticleDOI
TL;DR: The principal computed tomographic features of OP after HSCT are ground glass opacities, consolidation and linear opacITIES, with upper lung predominance, which differ from those reported in cryptogenic OP and OP from other causes.
Abstract: PURPOSE To evaluate computed tomographic (CT) scans of patients with organizing pneumonia (OP) complicating hematopoietic stem cell transplantation (HSCT) MATERIALS AND METHODS A review of patients who underwent HSCT at our institution identified 16 patients who had documented OP on biopsy Computed tomographic scans were reviewed by 2 thoracic radiologists RESULTS Ground glass opacities (GGO) were seen in 15 patients, consolidation in 8 patients, linear opacities in 8 patients, traction bronchiectasis in 2 patients, and septal thickening in 2 patients Ground glass opacity was the dominant abnormality in 7 patients, consolidation in 4 patients, and linear opacities in 5 patients Peribronchovascular distribution was found in 4 patients, peripheral in 2 patients, diffuse in 3 patients; upper lung predominance was found in 10 patients, and lower lung predominance in 5 patients CONCLUSION The principal computed tomographic features of OP after HSCT are ground glass opacities, consolidation and linear opacities, with upper lung predominance Allowing for a possible sampling bias, these findings differ from those reported in cryptogenic OP and OP from other causes

Journal ArticleDOI
TL;DR: It is shown that peptide vaccines can expand T cells that naturally respond to tumor antigens, resulting in more effective antitumor immunity, and future immunotherapies may require similar stringent analysis of the responding T cells to select optimal peptides as vaccine candidates.
Abstract: A major goal of immunotherapy for cancer is the activation of T cell responses against tumor-associated antigens (TAAs). One important strategy for improving antitumor immunity is vaccination with peptide variants of TAAs. Understanding the mechanisms underlying the expansion of T cells that respond to the native tumor antigen is an important step in developing effective peptide-variant vaccines. Using an immunogenic mouse colon cancer model, we compare the binding properties and the TCR genes expressed by T cells elicited by peptide variants that elicit variable antitumor immunity directly ex vivo. The steady-state affinity of the natural tumor antigen for the T cells responding to effective peptide vaccines was higher relative to ineffective peptides, consistent with their improved function. Ex vivo analysis showed that T cells responding to the effective peptides expressed a CDR3β motif, which was also shared by T cells responding to the natural antigen and not those responding to the less effective peptide vaccines. Importantly, these data demonstrate that peptide vaccines can expand T cells that naturally respond to tumor antigens, resulting in more effective antitumor immunity. Future immunotherapies may require similar stringent analysis of the responding T cells to select optimal peptides as vaccine candidates.

Journal ArticleDOI
TL;DR: Although a significant effect of chitinase gene alleles was found on lung function level and decline in the LHS, it was unable to replicate the associations with COPD affection status in the other COPD study groups.
Abstract: Two primary chitinases have been identified in humans--acid mammalian chitinase (AMCase) and chitotriosidase (CHIT1). Mammalian chitinases have been observed to affect the host's immune response. The aim of this study was to test for association between genetic variation in the chitinases and phenotypes related to chronic obstructive pulmonary disease (COPD). Polymorphisms in the chitinase genes were selected based on previous associations with respiratory diseases. Polymorphisms that were associated with lung function level or rate of decline in the Lung Health Study (LHS) cohort were analyzed for association with COPD affection status in four other COPD case-control populations. Chitinase activity and protein levels were also related to genotypes. In the caucasian LHS population, the baseline forced expiratory volume in one second (FEV(1)) was significantly different between the AA and GG genotypic groups of the AMCase rs3818822 polymorphism. Subjects with the GG genotype had higher AMCase protein and chitinase activity compared with AA homozygotes. For CHIT1 rs2494303, a significant association was observed between rate of decline in FEV(1) and the different genotypes. In the African American LHS population, CHIT1 rs2494303 and AMCase G339T genotypes were associated with rate of decline in FEV(1). Although a significant effect of chitinase gene alleles was found on lung function level and decline in the LHS, we were unable to replicate the associations with COPD affection status in the other COPD study groups.


Book ChapterDOI
01 Jan 2012
TL;DR: The goal of this chapter is to provide a practical approach to connective tissue disease (CTD)-associated lung disease by focusing on commonly encountered problems in the management of this complex and heterogeneous patient population.
Abstract: The goal of this chapter is to provide a practical approach to connective tissue disease (CTD)-associated lung disease by focusing on commonly encountered problems in the management of this complex and heterogeneous patient population. Several illustrative cases are incorporated into the text and interstitial lung disease is a major focus because it occurs across the spectrum of the CTDs, is potentially the most devastating of pulmonary manifestations, and often poses the most significant challenges to the practicing clinician.

Journal ArticleDOI
TL;DR: The discovery of the UNC119 defect provides a molecular mechanism for a subset of patients with this previously unexplained disease and meets the criteria of the idiopathic CD4 lymphopenia (ICL).
Abstract: The activation of a T cell through T cell receptor (TCR) is fundamental to adaptive immune responses. The lymphocyte specific kinase (LCK) plays a central role in the initiation of signaling from the TCR. TCR activates LCK through the adaptor protein uncoordinated 119 (UNC119). A mutation of human UNC119 impairs LCK activation and is associated with inadequate signaling, diminished T cell responses to TCR stimulation, CD4 lymphopenia, and infections of viral, bacterial, and fungal origin. The above clinical and immunological findings meet the criteria of the idiopathic CD4 lymphopenia (ICL). The discovery of the UNC119 defect provides a molecular mechanism for a subset of patients with this previously unexplained disease. Here we review our recent findings on the UNC119 mutation in ICL.


Journal ArticleDOI
TL;DR: Food allergy is an increasing public health dilemma in Westernized countries, yet no viable treatments are currently available for those who are afflicted, and allergen-specific therapies such as oral immunotherapy, sublingual Immunotherapy, and epicutaneous immunotherapy with different foods have shown promise.
Abstract: Food allergy is an increasing public health dilemma in Westernized countries, yet no viable treatments are currently available for those who are afflicted. The only options available for patients with food allergies are prevention of reactions by strict avoidance of the offending food(s) and symptomatic treatment of any adverse effects from accidental exposures. Approaches are being pursued to develop treatments, and allergen-specific therapies such as oral immunotherapy, sublingual immunotherapy, and epicutaneous immunotherapy with different foods have shown promise. Other modalities are also being investigated, potentially leading to the discovery of novel therapeutic options.



Journal ArticleDOI
01 May 2012

Book ChapterDOI
01 Jan 2012
TL;DR: This chapter details the clinical presentation, pathophysiology, diagnosis, and management of pulmonary alveolar proteinosis and lymphangioleiomyomatosis and highlights other, rarer, interstitial lung diseases (ILDs).
Abstract: This chapter details the clinical presentation, pathophysiology, diagnosis, and management of pulmonary alveolar proteinosis and lymphangioleiomyomatosis (LAM). It also highlights other, rarer, interstitial lung diseases (ILDs) including aspiration-related ILD, lipoid pneumonia, amyloidosis, Erdheim–Chester disease, Hermansky–Pudlak syndrome, neurofibromatosis, pulmonary alveolar microlithiasis, bronchioloalveolar cell carcinoma, and lymphangitic carcinomatosis.

Journal ArticleDOI
TL;DR: The results show for the first time that the morphogenesis of primordial follicles in the hamster coincides with altered and novel expression of proteins involved in cell proliferation, transcriptional regulation, and metabolism.

Book ChapterDOI
01 Jan 2012
TL;DR: Improvements in technologies like high resolution CT, synchrotron radiation CT, hyperpolarized helium-3 magnetic resonance imaging, and optical coherence tomography allow greater structural and functional characterization of the lungs and airways.
Abstract: Obstructive lung diseases represent a growing burden to society. Chest radiography and computed tomography (CT) have historically been the main imaging resources used to evaluate these disorders. While much information can be learned from conventional studies, more advanced imaging modalities like high resolution CT, synchrotron radiation CT, hyperpolarized helium-3 magnetic resonance imaging, and optical coherence tomography allow greater structural and functional characterization of the lungs and airways. Improvements in these technologies will allow patients to be classified according to disease phenotype, and potentially benefit from more specific treatment of their disease.

Book ChapterDOI
01 Jan 2012
TL;DR: This chapter offers an explanation and application of commonly used techniques, considerations for vocal hygiene and abuse/misuse, questions for comprehension, and case studies with video presentations.
Abstract: Speech therapy for the treatment of functional respiratory disorders serves as an efficient and effective means to resolving vocal cord dysfunction, chronic cough, and dysfunctional breathing patterns. Education regarding the laryngeal and respiratory mechanisms is an essential first step in treating such disorders. Various speech therapy techniques are tailored to the individual patient’s needs and trigger situations. As the patient population is homogenous in diagnosis, but diverse in etiologies, triggers and contributing factors, specialized training in treatment techniques aids the clinician in recognizing treatment barriers, ways to desensitize hyper-functional respiratory responses, and ensures their ultimate resolution. This chapter offers an explanation and application of commonly used techniques, considerations for vocal hygiene and abuse/misuse, questions for comprehension, and case studies with video presentations.



Proceedings ArticleDOI
01 May 2012
TL;DR: Local density histogram is a feasible approach to quantify different types of emphysema in volumetric CT scans and can be run without supervision with low computational demands.
Abstract: Rationale:A major limitation of global densitometry analysis for emphysema quantification is the lack of specificity for early stage disease and differentiation of patterns related to emphysema pathological types. Local approaches that attempt to classify different patterns of emphysema may better quantify the burden of disease and its progression. Methods:We have developed a new approach to classify five patterns of emphysema (normal lung tissue, centrilobular (mild, moderate, severe), panlobular and paraseptal). This approach uses the local density histogram as a differentiating feature among tissue classes. The local density histogram is computed over a local region of 31x31 pixels using a kernel density approach. A training set of image patches (31x31 pixels) was first labeled by an expert in 256 subjects from the COPDGene cohort to create a total of 1525 training samples. A kNN classifier was employed to classify new samples that were not included in the training set. The performance of the classifier was analyzed using the leave-one-subject-out technique. After the lung parenchyma is classified, the percentage of each tissue class is reported with respect to the total lung volume. The algorithm was tested on 342 subjects from COPDGene that were visually characterized by a group of expert radiologists and pulmonologists. The median score provided by the expert was compared with the % amount of each tissue class. Relationships between LAA% and the percentages of each emphysema patterns observed were also computed via linear regression analysis. Results: The classification success rate in the leave-one-subject-out experiment for each emphysema type was: 90.42% for normal lung, 85.37% for paraseptal, 77.03% for panlobular, 37.33% for mild centrilobular, 63.41% for moderate centrilobular and 44.94% for severe centrilobular. 42.4% of the mild centrilobular samples were labeled as normal lung tissue. Figure 1 shows the tissue classification results for a coronal slice (top row) and the agreement between the median score of the readers and the % amount for each tissue class (bottom row). Normal lung tissue and mild centrilobular were negatively associated with LAA% (r2=0.69, p<0.0001 and r2=0.1121,p<0.0001, respectively). Meanwhile, moderate centrilobular, severe centrilobular, paraseptal and panlobular emphysema were positively associated to LAA% with increasing slope for each emphysema class (r2=0.64,p<0.0001, r2=0.85,p<0.0001, r2=0.45,p<0.0001, r2=0.56,p<0.0001, respectively). Conclusions:Local density histogram is a feasible approach to quantify different types of emphysema in volumetric CT scans. The method is fully automatic and it can be run without supervision with low computational demands Patterns of Emphysema Classification